breast committee 2020/ros book... · 2020. 9. 9. · s1007 phase iii ... most recent progress...

SEPTEMBER 23 - 26, 2020 SWOG BREAST 1

BREAST COMMITTEE


CONTENTS

S1007 Phase III .............................................................................................................................................................. 7

S1207 Phase III ............................................................................................................................................................ 17

S1415CD Phase III ...................................................................................................................................................... 25

S1416 Phase II ............................................................................................................................................................. 28

S1418 Phase III - FDA Registration Study .................................................................................................................. 34

S1501 Phase III ............................................................................................................................................................ 42

S1609 Phase II ............................................................................................................................................................. 44

S1614 Phase III ............................................................................................................................................................ 46

S1703 Phase III ............................................................................................................................................................ 48

S1706 Phase II ............................................................................................................................................................. 50

S1714 Observational Cohort........................................................................................................................................ 55

S1904 Pilot .................................................................................................................................................................. 56


Patient Registrations by Study and Arm

BREAST COMMITTEE

Jan 2020

Jun 2020 Jul 2019

Dec 2019 Jan 2019

Jun 2019 All

Patients

S1207 Breast, Adjuvant, Endocrine ± Everolimus

Randomization

Blinded drug + Endocrine 0 0 134 1939

S1416 Breast, TNBC/BRCA, Cisplatin ± ABT-888

Randomization

Blinded Drug + Cisplatin 0 0 60 344

S1418 Breast, Adjuvant, TNBC, MK-3475 (Pembrolizumab)

Tissue Submission

Tissue for PD-L1 testing 182 180 195 951

Randomization

Observation 79 82 84 411

MK-3475 (Pembrolizumab) 78 74 84 401

157 156 168 812

S1706 Breast, Inflammatory, Radiation +/- Olaparib

Randomization

Olaparib + RT 8 8 5 21

RT 9 10 5 24

17 18 10 45


Non-SWOG Studies with SWOG-Credited RegistrationsBREAST COMMITTEE

Studies with Accrual from January 2019 - June 2020

SWOG Accrual

SWOG

Champion

Jan 2020

Jun 2020

Jul 2019

Dec 2019

Jan 2019

Jun 2019

SWOG

Total

Total

Accrued

A011106 Breast, Neoadj, ALTERNATE study A Forero 0 0 14 94 1,473

Date Activated: 02/15/14 Date Closed: 07/15/19

Most Recent Progress Report

A011202 Breast, Nodal XRT ± ALND 2 0 8 104 1,555

Date Activated: 02/07/14


A011401 Breast, Adjuvant, Stage II/III HER2-, weight loss D Hershman 22 40 44 305 2,783



A011502 Breast, Adjuvant, Nodal+ and HER2-, Aspirin vs. Placebo B Symington 20 34 45 165 2,556



A221405 Breast, ET interruption, Pregnancy Outcomes 117

Date Activated: 10/15/15 Date closed: 12/31/19


B51 Breast, Regional Nodal XRT B Symington 3 4 2 42 1,523



B55 Breast, Adjuvant Olaparib for BRCA,TNBC 0 0 2 34 220



EA1131 Breast, TNBC, Post-operation Chemotherapy vs Observation E Rodler 4 5 4 25 360



EA1181 Breast, HER2-pCR, Preoperative THP and Postoperative HP 2 0 0 2 23



MA.39 Breast, Node Positive, Regional RT vs No Regional RT R Jagsi 1 1 0 2 305



0 2 5 4


SWOG Accrual

SWOG

Champion

Jan 2020

Jun 2020

Jul 2019

Dec 2019

Jan 2019

Jun 2019

SWOG

Total

Total

Accrued

NRGBR003 Breast, Adjuvant, TNBC, AC -> WP ± Carbo I Makhoul 2 8 5 84 713



NRGBR004 Breast, Metastatic HER2+, Paclitaxel + Trastuzumab +

Pertuzumab ± AtezolizumabE Cobin 1 1 0 2 51


No Recent Progress Report

NRGBR005 Breast, Stage II & IIIA, Post Neoadjuvant Chemotherapy

Breast Conserving TreatmentA Thompson 0 0 1 7 105


No Recent Progress Report


S1007/III

S1007 Phase III

Coordinating Group: SWOG

A Phase III Randomized Clinical Trial of Standard Adjuvant Endocrine

Therapy +/- Chemotherapy in Patients with 1-3 Positive Nodes, Hormone

Receptor-Positive and HER2-Negative Breast Cancer with Recurrence Score

(RS) of 25 or Less. RxPONDER: A Clinical Trial Rx for Positive Node,

Endocrine Responsive Breast Cancer

Participants:

SWOG, CTSU (Supported by Alliance, CCTG, ECOG-

ACRIN, GEICAM, NRG, UNICANCER)

Study Chairs:

K Kalinsky, J Gralow, P Rastogi (NRG), N Lin

(Alliance), L Goldstein (ECOG-ACRIN), S Chia

(CCTG), E Alba Conejo (GEICAM), S DeLaloge

(UNICANCER)

Statisticians:

W Barlow, D Lew, J Miao

Data Coordinators:

L Kaye, J Scurlock

Date Activated:

01/15/2011

Date Closed:

11/01/2017

SCHEMA

R

E

G

I

S

T

R

A

T

I

O

N

Arm 1:

Chemotherapy and

endocrine therapy

RS < 25Submit tumor

specimen to

Genomic Health

for recurrence

score (RS)

testing

R

A

N

D

O

M

I

Z

E

RS > 25

Off study

Arm 2:

Endocrine therapy

alone


S1007/III

Objectives

To determine the effect of chemotherapy in patients

with node-positive breast cancer who do not have high

Recurrence Scores (RS) by Oncotype DX®. In

patients with 1-3 positive nodes, and hormone receptor

(HR)-positive, HER2-negative breast cancer with RS

≤ 25 treated with endocrine therapy we will test

whether the difference in disease-free survival for

patients treated with chemotherapy compared to no

chemotherapy depends directly on the magnitude of

RS. If benefit depends on the RS score, the trial will

determine the optimal cutpoint for recommending

chemotherapy or not.

To compare overall survival (OS), distant disease-free

survival (DDFS) and local disease-free interval (LDFI)

by receipt of chemotherapy or not and its interaction

with RS.

To compare the toxicity across the treatment arms.

To perform other assays or tests (in particular the

PAM50 risk of relapse score), as they are developed

and validated, that measure potential benefit of

chemotherapy and compare them to Oncotype DX®.

To determine the impact of management with

Oncotype DX® on patient-reported anxiety (co-

primary Health-Related Quality of Life [HRQL]

outcome) prior to screening, after disclosure of test

results, and during the randomized trial.

To determine the impact of Oncotype DX® on the

initial management cost of node-positive, HR-positive,

HER2-negative breast cancer.

To compare patient-reported utilities (e.g. QOL) for

those randomized to chemotherapy versus no

chemotherapy.

Using modeling and DFS information from the trial, to

estimate the cost-effectiveness of management with

Oncotype DX® versus usual care.

To determine the role of other assays (e.g. PAM50) as

predictors of DFS, DDFS and LDFI for patients

randomized to chemotherapy versus no chemotherapy.

To determine the impact of treatment with

chemotherapy versus no chemotherapy on patient-

reported fatigue and cognitive concerns (secondary

HRQL outcomes).

To determine the impact of management with

Oncotype DX® on patient-reported decision conflict,

perceptions regarding Oncotype DX® testing, and

survivor concerns prior to screening, after disclosure

of test results, and during the randomized trial

(secondary HRQL outcomes).

Patient Population

Patients must be women with a histologically

confirmed diagnosis of node-positive (1-3 nodes)

invasive breast carcinoma with positive estrogen

and/or progesterone receptor status, and negative

HER-2 status. HER-2 test result negativity must be

assessed as per ASCO/CAP 2013 guidelines using

IHC, ISH or both. If HER-2 IHC is 2+, evaluation for

gene amplification (ISH) must be performed and the

ISH must be negative; ISH is not required if IHC is 0

or 1+. Patients with equivocal HER-2 are not eligible.

Patients with multifocal, multicentric, and

synchronous bilateral breast cancers are allowed.

Patients must not have inflammatory breast cancer and

must not have metastatic disease.

Patients must have had either breast-conserving

surgery with planned radiation therapy or total

mastectomy (with or without planned postmastectomy

radiation). Patients must have clear margins from both

invasive cancer and DCIS; LCIS at the margins is

allowed. Patients must have undergone axillary

staging by sentinel node biopsy or axillary lymph node

dissection. Patients with positive sentinel node are not

required to undergo full axillary lymph node

dissection; this is at the discretion of the treating

physician. Patients with micrometastases as the only

nodal involvement (pN1mi) are not eligible. Patients

must not have begun chemotherapy or endocrine

therapy for their breast cancer prior to registration.

Patients must be able to receive taxane and/or

anthracycline based chemotherapy. Patients must not

have received an aromatase inhibitor (AI) or a

selective estrogen receptor modulator (SERM) such as

tamoxifen or raloxifene within five years prior to

registration. Partial breast irradiation (including

brachytherapy) is not allowed. Radiation in the

opposite breast is acceptable. Patients with a prior

diagnosis of contralateral DCIS are eligible if they

underwent a mastectomy or lumpectomy with whole

breast radiation. Patients with a prior diagnosis of

ipsilateral DCIS or invasive breast cancer who

received radiation to that breast are not eligible.

Registration of patients who have not yet undergone

Oncotype DX® screening must occur no later than 56

days after definitive surgery. For all patients,

randomization (Step 2 Registration) must occur within


S1007/III

84 days after definitive surgery. If the Oncotype DX®

Breast Cancer Assay has not been performed, patients

must be willing to submit tissue samples directly to

Genomic Health for testing to determine Recurrence

Score value. If the Oncotype DX® Recurrence Score

is already known and is 25 or less, the patient must be

randomized (registered to Step 2) immediately

following initial registration. If the Oncotype DX®

Recurrence Score is already known and is greater than

25, the patient is ineligible.

Patients must have a Zubrod performance status of 0-

2 and must not require chronic treatment with systemic

steroids (inhaled steroids are allowed) or other

immunosuppressive agents.

Stratification/Descriptive Factors

Patient randomization will be stratified by the

following factors: (1) Recurrence Score: 0-13 vs 14-

25; (2) menopausal status: pre vs post; and (3) type of

nodal dissection: axillary lymph node dissection (with

or without sentinel node mapping) vs sentinel node

biopsy without axillary lymph node dissection.

Accrual Goals

The accrual goal for the randomized trial is 4,000

eligible patients, which will require approximately

9,400 women to be screened for inclusion. An

additional 1,000 eligible patients from UNICANCER

in France will be randomized. Annual interim analyses

are planned beginning when 24% of the events have

been observed, approximately 6.6 years after initiation

of the study.

Summary Statement

This study was activated on January 15, 2011, and was

permanently closed on November 1, 2017, after

meeting the accrual goal of 4,000 eligible patients plus

an additional 1,000 eligible patients from

UNICANCER sites. There were 9,383 registrations

to the screening step and 5,083 patients with Oncotype

DX® Recurrence Score ≤ 25 randomized, including

1,022 from UNICANCER. Seventy-four patients are

currently ineligible, the most common reason being

margins not clear. Two patients who refused

participation after randomization and withdrew

consent for all follow up are not analyzable for any

endpoint. Major deviations are coded for 566

additional patients (11%) who refused their

randomized treatment assignment, did not receive any

protocol treatment, or received a non-approved

chemotherapy regimen. These 566 patients are not

evaluable for adverse events, along with one

additional patient who discontinued protocol treatment

without being assessed for adverse events. Among the

3,350 patients off protocol treatment, 78 were

removed for other reasons, primarily due to second

primary.

There have been five treatment-related deaths reported

among 4,366 patients evaluated for adverse events:

one due to small bowel, colon, and liver necrosis

(listed as "GI disorders - Other, specify"), one due to

sepsis, one due to typhlitis, and two due to stroke (one

also listed as "Death NOS"). An additional 123

patients reported Grade 4 adverse events as maximum

degree, primarily hematologic. One Grade 4 and two

Grade 3 adverse events are listed as "Neoplasms, all"

for one patient who experienced secondary AML and

two patients who experienced secondary uterine

cancers.

The study continues to be monitored by the SWOG

Data and Safety Monitoring Committee until time of

final analysis.


S1007/III

Registration by Institution

Screening Registration

Institutions Total Reg

MD Anderson CC 269 National Cancer Ctr 175 Michigan CRC NCORP 134 INCan 132 Michigan, U of 100 City of Hope Med Ctr 91 Cleveland Clinic OH 83 Kaiser Perm NCORP 80 Wichita NCORP 78 Southeast COR NCORP 57 Kansas MU-NCORP 50 Utah, U of 50 KaiserPermanenteSCAL/Kaiser Perm NCORP 49 Columbus NCORP 48 Loyola University 48 New Mexico MU-NCORP 47 Beaumont NCORP 44 Yale University 44 Wayne State Univ 40 Columbia MU-NCORP 39 So Calif, U of 34 St Charles Hlth Sys/PCRC NCORP 34 St Luke's Mt State/PCRC NCORP 34 Houston Methodist 31 Northwest NCORP 31 Poudre Valley Hosp/Colorado, U of 31 Heartland NCORP 29 Hawaii MU-NCORP 28 MUSC MU-NCORP 28 Kansas City NCORP 27 Ozarks NCORP 27 Lahey Hosp & Med Ctr 26 U of Tennessee MC/Tennessee, U of 25 Virginia Mason MC 24 Kentucky, U of 23 S Georgia Med Ctr/San Antonio, U of TX 22 Henry Ford Hospital 20 PCRC NCORP 20

Institutions Total Reg CRC West MI NCORP 19 McLaren Cancer Inst/Wayne State Univ 19 Sacred Heart Hosp/Arkansas, U of 19 San Diego, U of CA 18 Dayton NCORP 17 Good Samaritan Hosp/CORA NCORP 17 INC, Bogota 16 Montana NCORP 16 TTUHSC-Lubbock/San Antonio, U of TX 16 Long Beach Mem MC/Irvine, U of CA 15 Colorado, U of 14 St Joseph Med Ctr/PCRC NCORP 14 Atlanta Reg CCOP 13 Cookeville Reg MC/Southeast COR NCORP 13 Rochester, Univ of 13 Singing River Hosp/Mississippi, Univ of 13 UCH Mem Hosp Central/Colorado, U of 12 Univ of Louisville 12 Harrison Bremerton/Harrison Medical Ctr 11 San Antonio, U of TX 11 Davis, U of CA 10 Oklahoma, Univ of 10 UF Cancer Center/Arkansas, U of 10 Bridgeport Hospital/Yale University 9 Cedars-Sinai Med Ctr 9 Providence Hosp 9 Carolinas Med Ctr/San Antonio, U of TX 8 Northwestern Univ 8 Upstate NCORP 8 Utah Valley Reg MC/Intermountain MC 8 All Other SWOG Institutions 214 UNICANCER 1520 ECOG-ACRIN 1448 GEICAM 1252 ALLIANCE 1074 CCTG 734 NRG 602

Total (143 Institutions) 9383


S1007/III


Randomization


MD Anderson CC 147 National Cancer Ctr 143 INCan 96 Wichita NCORP 57 City of Hope Med Ctr 45 Michigan CRC NCORP 44 Kaiser Perm NCORP 43 KaiserPermanenteSCAL/Kaiser Perm NCORP 42 Kansas MU-NCORP 32 Southeast COR NCORP 31 Beaumont NCORP 30 New Mexico MU-NCORP 27 Cleveland Clinic OH 26 Loyola University 23 Michigan, U of 23 Kentucky, U of 21 Yale University 21 MUSC MU-NCORP 19 Columbus NCORP 18 Lahey Hosp & Med Ctr 18 Utah, U of 18 Sacred Heart Hosp/Arkansas, U of 17 Columbia MU-NCORP 16 Wayne State Univ 16 So Calif, U of 15 Virginia Mason MC 14 Northwest NCORP 13 Hawaii MU-NCORP 12 Heartland NCORP 12

Institutions Total Reg PCRC NCORP 12 Atlanta Reg CCOP 11 Colorado, U of 11 Henry Ford Hospital 11 INC, Bogota 11 Kansas City NCORP 11 Long Beach Mem MC/Irvine, U of CA 11 Poudre Valley Hosp/Colorado, U of 11 San Antonio, U of TX 10 Harrison Bremerton/Harrison Medical Ctr 9 Montana NCORP 9 Ozarks NCORP 9 St Luke's Mt State/PCRC NCORP 9 Cedars-Sinai Med Ctr 8 CORA NCORP 8 Good Samaritan Hosp/CORA NCORP 8 Oklahoma, Univ of 8 Providence Hosp 8 Univ of Louisville 8 All Other SWOG Institutions 215 UNICANCER 1022 GEICAM 792 ECOG-ACRIN 713 ALLIANCE 526 CCTG 328 NRG 265


Registration, Eligibility, and Evaluability

Randomization

Data as of August 3, 2020

TOTAL

Chemo and

Endocrine

Therapy Endocrine

Therapy Alone

NUMBER REGISTERED 5083 2547 2536 INELIGIBLE 74 41 33 ELIGIBLE 5009 2506 2503

Analyzable, Pend. Elig. 28 16 12 Not Analyzable 2 2 0

ADVERSE EVENT ASSESSMENT

Evaluable 4366 2043 2323 Not Evaluable 567 415 152 Too Early 74 46 28


S1007/III

Patient Characteristics

Randomization


Chemo and

Endocrine

Therapy Endocrine

Therapy Alone

(n=2504) (n=2503)

AGE

Median 57.9 57.1

Minimum 28.0 18.3

Maximum 87.6 86.0

HISPANIC

Yes 297 12% 325 13% No 1727 69% 1693 68% Unknown 480 19% 485 19%

RACE

White 1664 66% 1626 65% Black 129 5% 121 5% Asian 154 6% 170 7% Pacific Islander 4 0% 8 0% Native American 11 0% 13 1% Multi-Racial 4 0% 6 0% Unknown 538 21% 559 22%

RECURRENCE SCORE

0-13 1075 43% 1069 43% 14-25 1429 57% 1434 57%

MENOPAUSAL STATUS

Pre-menopausal 832 33% 830 33% Post-menopausal 1672 67% 1673 67%

NODAL DISSECTION

Axillary lymph node dissection (with or

without sentinel node mapping) 1564 62% 1568 63%

Sentinel node biopsy without axillary

lymph node dissection 940 38% 935 37%


S1007/III

Treatment Summary


Total

NUMBER ON PROTOCOL TREATMENT 1657

NUMBER OFF PROTOCOL TREATMENT 3350

REASON OFF TREATMENT

Treatment completed as planned 2603

Adverse Event or side effects 19

Refusal unrelated to adverse event 264

Progression/relapse 178

Death 48

Other - not protocol specified 78

Reason under review 160

MAJOR PROTOCOL DEVIATIONS 566

Number of Patients with a Given Type and Grade of Adverse Event

Adverse Events Unlikely or Not Related to Treatment Excluded

Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed


Total

(n=4366)

Grade

ADVERSE EVENTS <=2 3 4 5

Abdominal pain 4359 7 0 0

Acute kidney injury 4365 1 0 0

Alkaline phosphatase increased 4365 1 0 0

Allergic reaction 4359 7 0 0

ALT increased 4360 6 0 0

Anemia 4346 18 2 0

Anorexia 4364 2 0 0

Anxiety 4363 3 0 0

Arthralgia 4286 80 0 0

AST increased 4365 1 0 0

Atrial fibrillation 4362 4 0 0

Back pain 4364 2 0 0

Blood/lymph disorder-Other 4362 4 0 0

Bone marrow hypocellular 4365 1 0 0

Bone pain 4345 21 0 0

Breast infection 4364 2 0 0

Bronchial infection 4365 1 0 0

Cataract 4365 1 0 0

Catheter related infection 4363 2 1 0

CD4 lymphocytes decreased 4364 2 0 0

Chest pain - cardiac 4365 1 0 0


S1007/III

Total

(n=4366)

Grade


Chest wall pain 4365 1 0 0

Colitis 4361 5 0 0

Constipation 4362 4 0 0

Death NOS 4365 0 0 1

Dehydration 4355 11 0 0

Depression 4357 9 0 0

Dermatitis radiation 4358 8 0 0

Device related infection 4362 3 1 0

Diarrhea 4332 34 0 0

Dizziness 4363 3 0 0

Dry mouth 4365 1 0 0

Dry skin 4365 1 0 0

Dyspareunia 4364 2 0 0

Dyspepsia 4365 1 0 0

Dyspnea 4364 2 0 0

Ear pain 4364 2 0 0

Edema limbs 4365 1 0 0

Ejection fraction decreased 4365 0 1 0

Erythema multiforme 4365 1 0 0

Erythroderma 4364 2 0 0

Esophagitis 4363 3 0 0

Fatigue 4311 55 0 0

Febrile neutropenia 4284 68 14 0

Fever 4363 2 1 0

Flank pain 4365 1 0 0

Flu like symptoms 4365 1 0 0

Gastric hemorrhage 4365 1 0 0

Gastric ulcer 4365 1 0 0

Gastrointestinal pain 4365 1 0 0

Gen disorders/admin site cond 4364 2 0 0

Generalized muscle weakness 4362 4 0 0

GGT increased 4364 2 0 0

GI disorders-Other, specify 4365 0 0 1

Hand-Foot syndrome 4359 7 0 0

Headache 4358 8 0 0

Heart failure 4365 1 0 0

Hematuria 4365 1 0 0

Hemorrhoids 4365 1 0 0

Hot flashes 4340 26 0 0

Hyperglycemia 4349 17 0 0

Hyperhidrosis 4365 1 0 0

Hypertension 4353 13 0 0

Hypokalemia 4361 5 0 0

Hyponatremia 4364 2 0 0


S1007/III

Total

(n=4366)

Grade


Hypotension 4362 4 0 0

Infections/infestations-Other 4363 3 0 0

Injection site reaction 4365 1 0 0

INR increased 4365 1 0 0

Insomnia 4353 13 0 0

Irregular menstruation 4362 4 0 0

Kidney infection 4365 1 0 0

Leukocytosis 4362 3 1 0

Lipase increased 4365 1 0 0

Localized edema 4364 2 0 0

Lung infection 4360 4 2 0

LV systolic dysfunction 4365 1 0 0

Lymphedema 4364 2 0 0

Lymphocyte count decreased 4346 19 1 0

Menorrhagia 4365 1 0 0

MS/connective tissue disorder 4365 1 0 0

Mucositis oral 4343 23 0 0

Muscle weakness lower limb 4365 1 0 0

Myalgia 4333 33 0 0

Myelitis 4365 1 0 0

Myocardial infarction 4364 2 0 0

Nausea 4345 21 0 0

Neck pain 4364 2 0 0

Neoplasms, all 4363 2 1 0

Nervous sys disorders-Other 4365 1 0 0

Neutrophil count decreased 4215 60 91 0

Osteoporosis 4365 1 0 0

Pain 4364 2 0 0

Pain in extremity 4363 3 0 0

Paresthesia 4364 2 0 0

Peripheral ischemia 4365 1 0 0

Peripheral motor neuropathy 4362 3 1 0

Peripheral sensory neuropathy 4343 22 1 0

Platelet count decreased 4364 2 0 0

Pleuritic pain 4365 1 0 0

Pneumonitis 4358 8 0 0

Premature menopause 4365 1 0 0

Pruritus 4360 6 0 0

Rash acneiform 4365 1 0 0

Rash maculo-papular 4356 10 0 0

Renal/urinary disorders-Other 4365 1 0 0

Repro system/breast ds-Oth 4365 1 0 0

ROM decreased 4365 1 0 0

RT recall reaction, derm 4364 2 0 0


S1007/III

Total

(n=4366)

Grade


Secondary Leukemia 4364 0 2 0

Sepsis 4361 0 4 1

Sinus tachycardia 4365 1 0 0

Skin infection 4357 9 0 0

Skin ulceration 4365 0 1 0

Skin/subq tissue ds-Other 4356 10 0 0

Stroke 4361 2 1 2

Suicidal ideation 4365 1 0 0

Supraventricular tachycardia 4364 2 0 0

Surg/medical procedures-Oth 4360 6 0 0

Syncope 4363 3 0 0

Thromboembolic event 4353 11 2 0

Tinnitus 4365 1 0 0

Typhlitis 4365 0 0 1

Upper GI hemorrhage 4365 0 1 0

Upper respiratory infection 4365 1 0 0

Urinary tract infection 4362 4 0 0

Urticaria 4362 4 0 0

Uterine hemorrhage 4365 1 0 0

Vaginal dryness 4362 4 0 0

Vaginal hemorrhage 4364 2 0 0

Vascular access complication 4365 1 0 0

Vomiting 4347 19 0 0

Watering eyes 4362 4 0 0

Weight gain 4361 5 0 0

Weight loss 4364 2 0 0

White blood cell decreased 4301 43 22 0

Wound dehiscence 4365 1 0 0

MAX. GRADE ANY ADVERSE

EVENT 3739 499 123 5


S1207/III

S1207 Phase III

Coordinating Groups: SWOG and NRG

Phase III Randomized, Placebo-Controlled Clinical Trial Evaluating the Use

of Adjuvant Endocrine Therapy +/- One Year of Everolimus in Patients with

High-Risk, Hormone Receptor-Positive and Her2/neu Negative Breast Cancer

e3 Breast Cancer Study - evaluating everolimus with endocrine therapy

Participants:

SWOG, NRG, CTSU (Supported by Alliance)

Study Chairs:

M Chavez MacGregor, L Pusztai, P Ganz (NRG), P

Rastogi (NRG), M Goetz (Alliance)

Statisticians:

W Barlow, J Miao, D Lew

Data Coordinator:

G Herbert

Date Activated:

09/03/2013

Date Closed:

05/01/2019

SCHEMA

Objectives

To compare whether the addition of one year of

everolimus (10 mg daily) to standard adjuvant

endocrine therapy improves invasive disease-free

survival (IDFS) in patients with high-risk, hormone-

receptor (HR) positive and HER2-negative breast

cancer.

To compare whether the addition of one year of

everolimus to standard adjuvant endocrine therapy

improves overall survival (OS) and distant recurrence-

free survival (DRFS) in this patient population.

To evaluate the safety, toxicities, and tolerability of

one year of everolimus in combination with standard

adjuvant endocrine therapy and compare it with

R

A

N

D

O

M

I

Z

E

Everolimus + Endocrine Therapy

Placebo + Endocrine Therapy

Adjuvant/Neoaduvant

Chemotherapy/Surgery/Radiation

Therapy


S1207/III

standard adjuvant endocrine therapy plus placebo in

this patient population.

To determine whether the benefit of one year of

everolimus use in addition to standard adjuvant

endocrine therapy varies by recurrence score (RS),

nodal status, or other commonly used prognostic

factors.

Patient Population

Patients must have histologically confirmed invasive

breast carcinoma with positive ER and/or PgR status

and negative HER-2, for whom standard adjuvant

endocrine therapy is planned. Patients must not have

metastatic breast cancer. Patients with multifocal,

multicentric, synchronous bilateral, and primary

inflammatory breast cancers are allowed. Patients

must be high risk as defined in the protocol, based on

Recurrence Score or MammaPrint and grade, number

of positive nodes, and prior therapy. Patients with

micrometastases as the only nodal involvement

(pN1mi) will be categorized as node negative.

Patients must have completed either breast-conserving

surgery or total mastectomy with negative margins and

appropriate axillary staging. Patients must have

completed appropriate radiation therapy as described

in the protocol. Patients must have completed standard

neoadjuvant or adjuvant taxane and/or anthracycline

based chemotherapy prior to randomization. Patients

may have started endocrine therapy at any time after

the diagnosis of the current breast cancer. Patients

must not be receiving or planning to receive

trastuzumab. Concurrent bisphosphonate therapy is

allowed. Patients must not have prior exposure to

mTOR inhibitors.

Patients must be at least 18 years of age, have a Zubrod

performance status of 0-2, and have adequate

hematologic, hepatic, renal, and cardiac function.

Patients must not have received immunization with an

attenuated live vaccine within seven days prior to

registration. Patients must be able to take oral

medications. Patients at NCORP institutions must be

offered the opportunity to participate in the Behavioral

and Health Outcomes (BAHO) substudy.


Patient randomization will be stratified by risk level as

described in the protocol based on Recurrence Score

or MammaPrint and grade, number of positive nodes,

and prior therapy.

Accrual Goals

The accrual goal is 1,900 patients. Interim analyses are

planned for after approximately 40%, 60%, and 80%

of the events in the control arm have been observed.

Summary Statement

This study was activated on September 3, 2013, and

was permanently closed on May 1, 2019, after

enrolling 1,939 patients. One hundred forty-four

patients are currently ineligible. The most common

reasons for ineligibility include registration too soon

after completion of radiation therapy or too long after

completion of chemotherapy, HER-2/ISH positive or

equivocal, not high risk as defined in the protocol, and

lab values out of range. Major deviations are coded for

33 patients who received no protocol treatment, one

patient who began protocol treatment after the

maximum allowed treatment delay, and one patient

who took twice the full daily dose of the study drug for

the first three weeks of treatment. The 33 patients who

received no protocol treatment are not evaluable for

adverse events, along with six additional patients who

discontinued protocol treatment without being

assessed for adverse events. Sixty patients were

removed from protocol treatment for other non-

protocol specified reasons. The most common reasons

are treatment delay that exceeds protocol guidelines

(including treatment delays due to surgery), physician

decision, and non-compliance.

There have been 36 patients with Grade 4 toxicities

reported among 1,754 patients evaluated for adverse

events, including 15 with Grade 4

hypertriglyceridemia. The Grade 4 "Skin/subq tissue

ds-Other" was cellulitis. Three hundred twenty-seven

patients experienced Grade 3 adverse events as

maximum degree, including 62 cases of oral mucositis.

The study continues to be monitored by the SWOG

Data and Safety Monitoring Committee until time of

final analysis.


S1207/III



MD Anderson CC 80 Kansas MU-NCORP 54 Yale University 52 Kaiser Perm NCORP 49 Southeast COR NCORP 38 Heartland NCORP 30 Wichita NCORP 30 New Mexico MU-NCORP 29 Michigan CRC NCORP 25 Northwestern Univ 23 CORA NCORP 22 Fred Hutchinson CRC 22 City of Hope Med Ctr 21 Gulf South MU-NCORP 21 Michigan, U of 21 So Calif, U of 19 PCRC NCORP 18 Columbus NCORP 17 Good Samaritan MC/Oregon Hlth Sci Univ 17 Colorado, U of 16 Wayne State Univ 16 Ozarks NCORP 15 Arizona CC, Univ of 14 MUSC MU-NCORP 14 Hawaii MU-NCORP 13 Salem Hospital 13

Institutions Total Reg Carle CC NCORP 12 Cleveland Clinic OH 12 Montana NCORP 12 Thompson Ca Surv Ctr/San Antonio, U of TX 12 Cincinnati MC, U of 10 CRC West MI NCORP 10 Loma Linda Univ 10 Providence Hosp 10 Rochester, Univ of 10 Sutter Cancer RC 10 Banner MD Anderson/MD Anderson CC 9 Cedars-Sinai Med Ctr 9 Kansas City NCORP 9 Northwest NCORP 9 Oklahoma, Univ of 9 San Antonio, U of TX 9 Beaumont NCORP 8 Dayton NCORP 8 Irvine, U of CA 8 Tennessee, U of 8 All Other SWOG Institutions 113 NRG 414 ALLIANCE 276 ECOG-ACRIN 253



Data as of July 21, 2020

Total

NUMBER REGISTERED 1939

INELIGIBLE 144

ELIGIBLE 1795

Analyzable, Pend. Elig. 19


Evaluable 1754

Not Evaluable 39

Too Early 2


S1207/III



Total

(n=1795)

AGE

Median 53.9

Minimum 22.2

Maximum 85.5

SEX

Males 11 1% Females 1784 99%

HISPANIC

Yes 172 10% No 1575 88% Unknown 48 3%

RACE

White 1532 85% Black 109 6% Asian 63 4% Pacific Islander 7 0% Native American 6 0% Multi-Racial 5 0% Unknown 73 4%

RISK GROUP

Node-negative and RS > 25 or High Risk

MammaPrint® treated with adjuvant chemotherapy 158 9%

1-3 positive lymph nodes and RS > 25 or High Risk

MammaPrint® or Grade III disease treated with

adjuvant chemotherapy

213 12%

≥ 4 positive lymph nodes (any RS value) treated with

adjuvant chemotherapy 718 40%

≥ 1 positive lymph node (any RS value) after

neoadjuvant chemotherapy 706 39%


S1207/III

Treatment Summary


Total




Treatment completed as planned 1053

Adverse Event or side effects 418

Refusal unrelated to adverse event 164

Progression/relapse 65

Death 2

Other - not protocol specified 60

Reason under review 5






Total

(n=1754)

Grade


Abdominal pain 1746 8 0 0

Allergic reaction 1752 2 0 0

ALT increased 1750 4 0 0

Anemia 1744 10 0 0

Anxiety 1753 1 0 0

Appendicitis 1751 3 0 0

Appendicitis perforated 1752 0 2 0

Arthralgia 1748 6 0 0

Ascites 1753 1 0 0

AST increased 1747 7 0 0

Back pain 1753 1 0 0

Bone pain 1753 1 0 0

Breast infection 1747 7 0 0

Cardiac arrest 1753 0 1 0

Cholecystitis 1753 1 0 0

Cholesterol high 1745 6 3 0

Colitis 1752 2 0 0

Cough 1752 2 0 0

Dehydration 1751 3 0 0

Depression 1752 1 1 0

Diarrhea 1738 16 0 0

Dizziness 1752 2 0 0


S1207/III

Total

(n=1754)

Grade


Dyspnea 1745 8 1 0

Edema face 1753 1 0 0

Edema limbs 1753 1 0 0

Eye disorders - Other, specify 1753 1 0 0

Eye infection 1753 1 0 0

Fatigue 1725 29 0 0

Fever 1753 1 0 0

Gallbladder infection 1753 0 1 0

Gallbladder perforation 1753 0 1 0

Gen disorders/admin site cond 1753 1 0 0

Generalized muscle weakness 1753 1 0 0

GI disorders-Other, specify 1752 2 0 0

Headache 1749 5 0 0

Heart failure 1750 4 0 0

Hip fracture 1753 1 0 0

Hot flashes 1752 2 0 0

Hyperglycemia 1719 33 2 0

Hyperhidrosis 1752 2 0 0

Hyperkalemia 1753 1 0 0

Hypertension 1734 20 0 0

Hypertriglyceridemia 1716 23 15 0

Hypokalemia 1749 5 0 0

Hyponatremia 1752 2 0 0

Hypophosphatemia 1753 1 0 0

Hypoxia 1752 2 0 0

Immune sys disorders-Other 1753 1 0 0

Infections/infestations-Other 1746 8 0 0

Infusion related reaction 1753 1 0 0

Insomnia 1751 3 0 0

Investigations-Other, specify 1753 1 0 0

Irregular menstruation 1752 2 0 0

Joint infection 1753 1 0 0

Kidney infection 1752 2 0 0

Lipase increased 1753 0 1 0

Lung infection 1746 8 0 0

LV systolic dysfunction 1752 2 0 0

Lymphedema 1753 1 0 0

Lymphocyte count decreased 1714 38 2 0

Menorrhagia 1753 1 0 0

MS/connective tissue disorder 1753 1 0 0

Mucositis oral 1692 62 0 0

Muscle weakness lower limb 1753 1 0 0

Muscle weakness upper limb 1753 1 0 0

Myalgia 1752 2 0 0


S1207/III

Total

(n=1754)

Grade


Nasal congestion 1753 1 0 0

Nausea 1752 2 0 0

Neck pain 1752 2 0 0

Nervous sys disorders-Other 1753 1 0 0

Neuralgia 1753 1 0 0

Neutrophil count decreased 1729 24 1 0

Obesity 1753 1 0 0

Otitis media 1753 1 0 0

Pain 1753 1 0 0

Pain in extremity 1753 1 0 0

Papulopustular rash 1753 1 0 0

Paroxysmal atrial tachycardia 1753 1 0 0

Periorbital edema 1752 2 0 0

Peripheral sensory neuropathy 1751 3 0 0

Platelet count decreased 1749 5 0 0

Pleural effusion 1752 1 1 0

Pneumonitis 1746 8 0 0

Portal vein thrombosis 1753 1 0 0

Postoperative hemorrhage 1753 1 0 0

Productive cough 1753 1 0 0

Pruritus 1751 3 0 0

Psych disorders-Other, spec 1753 1 0 0

Pulmonary edema 1753 1 0 0

Rash acneiform 1753 1 0 0

Rash maculo-papular 1750 4 0 0

Rash pustular 1752 2 0 0

Respiratory failure 1753 0 1 0

RT recall reaction, derm 1752 1 1 0

Sepsis 1747 0 7 0

Seroma 1753 1 0 0

Skin infection 1743 11 0 0

Skin ulceration 1752 2 0 0

Skin/subq tissue ds-Other 1751 2 1 0

Soft tissue infection 1752 2 0 0

Sore throat 1753 1 0 0

Suicidal ideation 1753 0 1 0

Suicide attempt 1753 0 1 0

Thromboembolic event 1746 6 2 0

Tooth infection 1753 1 0 0

Upper respiratory infection 1753 1 0 0

Urinary tract infection 1751 3 0 0

Vascular access complication 1753 1 0 0

Vomiting 1752 2 0 0

Weight gain 1752 2 0 0


S1207/III

Total

(n=1754)

Grade


Weight loss 1752 2 0 0

White blood cell decreased 1732 21 1 0

Wound complication 1749 4 1 0

Wound dehiscence 1749 5 0 0

Wound infection 1748 6 0 0


EVENT 1391 327 36 0


S1415CD/III

S1415CD Phase III


Pragmatic Trial to Evaluate a Guideline-Based Colony Stimulating Factor

Standing Order Intervention and to Determine the Effectiveness of Colony

Stimulating Factor Use as Prophylaxis for Patients Receiving Chemotherapy

with Intermediate Risk for Febrile Neutropenia – Trial Assessing CSF

Prescribing Effectiveness and Risk (TrACER)

Participants:

SWOG, CTSU

Study Chairs:

S Ramsey, D Hershman

Statisticians:

A Bansal (UW), W Barlow, K Arnold

Project Manager:

K Watabayashi (HICOR)

Data Coordinator:

K Carvalho

Date Activated:

09/01/2016

Date Closed:

04/15/2020

SCHEMA

Does NCORP component

have existing guideline-

informed PP-CSF order

entry system?

R

A

N

D

O

M

I

Z

E

Yes

No

USUAL CARE:

Investigator discretion

for PP-CSF use

COHORT:

Use existing

guideline-based care

for PP-CSF use

CLOSED to accrual

12/1/2019

INTERVENTION:

Implement guideline-based

standing order entry

system for PP-CSF use

INTERVENTION:

PP-CSF recommended

for all intermediate FN risk

regimens

Guideline-based PP-CSF

use for high and low FN risk

regimens

INTERVENTION:

No PP-CSF recommended

for intermediate FN risk

regimens

Guideline-based PP-CSF

use for high and low FN risk

regimens

Randomization is at the NCORP component level. All patients at participating components will be subject to the

PP-CSF use care as determined by component assignment (Usual Care, Intervention, or Cohort). Only consented

patients registered to the study will participate in the data collection.

R

A

N

D

O

M

I

Z

E


S1415CD/III

Objectives

To compare the use of primary prophylactic colony

stimulating factor (PP-CSF) according to

recommended clinical practice guidelines among

patients registered at Intervention components versus

Usual Care components.

To compare the rate of febrile neutropenia (FN)

among patients registered at Intervention components

versus Usual Care components.

To compare the rate of FN among intermediate risk

patients registered at Intervention components by

component treatment assignment (administer PP-CSF

to intermediate risk patients versus not).

To compare the rate of FN among low-risk patients

registered at Intervention components versus Usual

Care components.

To compare the FN-related health-related quality of

life (HRQL) among low-risk patients registered at

Intervention components versus Usual Care

components.

To compare patient adherence to PP-CSF prescribing

among patients registered at Intervention components

versus Usual Care components.

To compare patient knowledge of the indications for,

efficacy of, and side effects associated with PP-CSF

between the initiation and conclusion of the first cycle

of myelosuppressive systemic therapy among patients


Care components.

To compare the proportion of patients completing the

initial systemic therapy regimen at planned duration

and at planned dose intensity among patients


Care components.

To compare antibiotic use both as prophylaxis and as

treatment for FN among patients registered at

Intervention components versus Usual Care

components.

To compare the rate of FN-related emergency

department visits and hospitalizations among

intermediate risk patients registered to Intervention

components by component treatment assignment

(administer PP-CSF to intermediate risk patients

versus not).

To compare the FN-related health-related quality of

life (HRQL) among intermediate risk patients

registered to Intervention components by component

treatment assignment (administer PP-CSF to

intermediate risk patients versus not).

To compare overall survival among intermediate risk

patients registered to Intervention components by

component treatment assignment (administer PP-CSF

to intermediate risk patients versus not).

Patient Population

Patients must have a current diagnosis of breast cancer,

non-small cell lung cancer, or colorectal cancer.

Cancer may be metastatic or non-metastatic.

Patients must be planning to receive one of the study-

allowed regimens as their initial treatment for their

current cancer diagnosis. Patients must be registered

prior to or on the same day as their first cycle of

chemotherapy. Patient must not have had any systemic

therapy (chemotherapy or combination regimens) in

the 180 days just prior to registration. Prior biologic

therapy, immunotherapy, tyrosine kinase inhibitors,

and hormonal therapy are allowed. Patients must not

be receiving or planning to receive concurrent

radiation therapy during systemic treatment. Patients

must not have any known contraindication to CSFs,

including prior hypersensitivity to E. coli-derived

proteins, filgrastim, pegfilgrastim, or tbo-filgrastim.

Patients must be able to understand and provide

information for the patient-completed study forms in

either English or Spanish. Patients may have had a

prior malignancy. Patients must not be participating or

plan to participate in other clinical trials that involve

investigational systemic cancer treatments or

investigational uses of CSF during their first six

months after registration.


NCORP components eligible for randomization will

be randomly assigned to Usual Care or Intervention

with stratification by component size (number of

patients at that component) and type of NCORP

component (minority/underserved vs not).

Accrual Goals

A total of 3,960 patients will be accrued to achieve

3,600 eligible patients. The Intervention components

will accrue 2,376 patients, the Usual Care components

will accrue 792 patients and the Cohort components

will accrue 792 patients.


S1415CD/III

One interim analysis will be conducted when 360

patients in the intermediate risk group at Intervention

components have complete outcome information. A

second interim analysis will be conducted when 650

patients in the intermediate risk group at Intervention

components have complete outcome information.

Complete outcome is defined as an assessment of FN

after six months of follow-up after treatment

commences.

Summary Statement

For the current status of this study, please refer to the

Cancer Care Delivery chapter.


S1416/II

S1416 Phase II


Phase II Randomized Placebo-Controlled Trial of Cisplatin with or without

ABT-888 (Veliparib) in Metastatic Triple-Negative Breast Cancer and/or

BRCA Mutation-Associated Breast Cancer, with or without Brain Metastases

Participants:

SWOG, CTSU (Supported by Alliance, ECOG-

ACRIN, NRG)

Study Chairs:

E Rodler, P Sharma, C Anders (Alliance), L Goldstein

(ECOG-ACRIN), S Puhalla (NRG)

Statisticians:


Data Coordinator:

L Kaye

Date Activated:

07/07/2016

Date Closed:

06/15/2019

SCHEMA

Objectives

To compare the efficacy of cisplatin with or without

ABT-888 (veliparib) on progression-free survival

(PFS) in each of the following groups:

1. Patients with germline BRCA (gBRCA)

mutation-associated breast cancer

2. Patients with germline BRCA wild-type

breast cancer who have evidence of

BRCAness phenotype

3. Patients with germline BRCA wild-type

breast cancer who do not have evidence of

BRCAness phenotype.

Brain Metastases Cohort: To compare the efficacy of

cisplatin with or without ABT-888 on PFS in patients

with triple negative and/or gBRCA mutation-

associated breast cancer and brain metastases.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Cisplatin + ABT-888

Cisplatin + Placebo


S1416/II

For patients with gBRCA mutation associated breast

cancer (group 1 above) or TNBC with (group 2) or

without (group 3) BRCAness phenotype, to compare

the efficacy of cisplatin with or without ABT-888 on

overall survival (OS), response rate (RR), and clinical

benefit rate.

To compare the differential benefit of ABT-888 across

the three groups using both PFS and OS as outcomes.

For patients in the brain metastases cohort, to compare


OS.

For patients in the brain metastases cohort, to compare


intracranial and extracranial response rates

(intracranial by RANO and extracranial by RECIST

1.1).

To compare toxicities of ABT-888 to placebo in each

of the four groups separately.

Patient Population

Patients must have metastatic and/or recurrent (distant

or locoregionally recurrent) breast cancer and be

HER2 non-overexpressing per 2013 ASCO-CAP HER

testing guidelines, and must also meet at least one of

the following criteria: histologically confirmed

primary and/or metastatic site that is ER- and PR-

negative (≤ 1%) and HER2-negative, or previously

confirmed deleterious or suspected deleterious

BRCA1 or BRCA2 germline mutation. Patients must

have measurable or non-measurable disease with a

chest/abdominal CT scan prior to registration. Patients

with known brain metastases must either meet

additional criteria as outlined in the protocol and enroll

as part of the Progressive Brain Metastases Cohort, or

have clinically controlled neurologic symptoms,

defined as surgical excision and/or radiation therapy

followed by 14 days of stable neurologic function

prior to registration. Patients with progressive brain

metastases following prior treatment are not eligible

for the Standard Cohort, but may be considered for the

Progressive Brain Metastases Cohort which requires a

baseline brain MRI.

Patients must have had no more than one prior

cytotoxic regimen for metastatic disease, unless they

are enrolling in the Progressive Brain Metastases

Cohort which allows up to three prior lines of

cytotoxic chemotherapy for metastatic disease.

Patients must not have received any prior

chemotherapy, radiation therapy, or hormonal therapy

within 14 days prior to registration; any

immunotherapy, biologic, or any investigational drug

within 28 days prior to registration; or any

bevacizumab within 42 days prior to registration.

Patients must not have received prior cisplatin or

PARP inhibitors. Prior carboplatin in the

adjuvant/neoadjuvant setting is allowed, if completed

more than 12 months prior to study entry. Patients may

receive bisphosphonates or denosumab concurrently

with study treatment; if started prior to registration, it

must be started at least seven days prior to registration.

Patients must have recovered to ≤ Grade 2 following a

significant adverse event or toxicity attributed to

previous anti-cancer treatment except neurotoxicity

which must be ≤ Grade 1.

Patients must be at least 18 years of age and have a

Zubrod performance status of 0-2. Patients must have

adequate hematologic, hepatic, and renal function.

Patients must not have a clinically relevant hearing

impairment ≥ Grade 2 or baseline neuropathy that

exceeds Grade 1 and must be able to swallow whole

capsules. Patients must have a complete history and

physical examination within 28 days prior to

registration, have adequate tissue available, and agree

to have specimens submitted for germline DNA

sequencing and other correlative studies.


Patient randomization will be stratified by number of

prior cytotoxic regimens for metastatic disease: 0 prior

regimens vs ≥1 prior regimens. Additionally, patients

within the brain metastases cohort will be stratified by

Modified Breast Graded Prognostic Assessment Index

(modified breast-GPA): ≤ 1 vs >1.

Accrual Goals

The accrual goal is 324 patients in the Standard Cohort

and 98 patients in the Progressive Brain Metastases

Cohort, with a maximum 333 patients to be enrolled.

Summary Statement

This study was activated on July 7, 2016, and was

permanently closed on June 15, 2019, after enrolling

344 patients. Thirteen patients are ineligible, including

11 who received prior therapies not allowed, one with

insufficient baseline scans, and one due to hormone

receptor positive disease without BRCA mutation.

Major deviations are coded for one patient who

received blinded drug assigned to a different patient in

error, one patient who mistakenly received 140% of

prescribed study drug during the first two cycles, one

patient who discontinued after one day of therapy due

to symptomatic deterioration, and 18 patients who did

not receive any protocol treatment; these 18 patients

are also not assessable for adverse events.


S1416/II

Among the 330 patients off protocol treatment, 78

were removed due to adverse events and 14 were

removed for other reasons: physician decision (10

patients), loss of insurance, second cancer, beginning

fertility treatments, receiving IV antibiotics for

unrelated infection (1 patient each).

Among the 313 patients evaluated for adverse events,

there have been two treatment-related deaths, one

from acute kidney injury with Grade 4 heart failure

due to previous Adriamycin contributing, and one due

to sepsis. Thirty-seven other patients experienced

Grade 4 adverse events as maximum degree, primarily

hematologic.

The study results were presented at ASCO in June

2020 and final study report will appear in the Spring

2021 report.


Institutions Total Reg Kaiser Perm NCORP 15 Michigan CRC NCORP 15 New Mexico MU-NCORP 15 Columbus NCORP 14 Fred Hutchinson CRC 13 Davis, U of CA 10 Michigan, U of 9 MUSC MU-NCORP 9 Cleveland Clinic OH 8 Colorado, U of 7 Ozarks NCORP 7 Heartland NCORP 6 PCRC NCORP 5 Southeast COR NCORP 5 Wisconsin NCORP 5 Dayton NCORP 4 CORA NCORP 3 CRC West MI NCORP 3

Institutions Total Reg Good Samaritan MC/Oregon Hlth Sci Univ 3 Montana NCORP 3 Utah, U of 3 Wichita NCORP 3 Beaumont NCORP 2 Carle CC NCORP 2 Gene Upshaw Mem TFCC/Davis, U of CA 2 Greenville NCORP 2 Loyola University 2 Providence Hosp 2 Baptist MU-NCORP 1 Henry Ford Hospital 1 Sutter Cancer RC 1 NRG 66 ALLIANCE 62 ECOG-ACRIN 36



Classified by Cohort


TOTAL Standard

Cohort

Progressive

Brain Mets

Cohort



Evaluable 313 304 9 Not Evaluable 18 18 0


S1416/II




Standard Cohort Progressive Brain

Mets Cohort

(n=322) (n=9)

AGE

Median 56.2 55.4

Minimum 26.4 39.1

Maximum 80.8 69.3

SEX

Males 1 0% 0 0% Females 321 100% 9 100%

HISPANIC

Yes 22 7% 0 0% No 289 90% 9 100% Unknown 11 3% 0 0%

RACE

White 246 76% 7 78% Black 51 16% 2 22% Asian 11 3% 0 0% Pacific Islander 1 0% 0 0% Native American 2 1% 0 0% Unknown 11 3% 0 0%

NUMBER OF PRIOR CYTOTOXIC

REGIMENS FOR METASTATIC

DISEASE

0 222 69% 4 44% 1 100 31% 5 56%

MODIFIED BREAST GPA

≤ 1 0 0% 3 33% > 1 0 0% 6 67% N/A (Standard cohort) 322 100% 0 0%


S1416/II

Treatment Summary



TOTAL

Standard

Cohort

Progressive

Brain Mets

Cohort

NUMBER ON PROTOCOL TREATMENT 1 1 0

NUMBER OFF PROTOCOL TREATMENT 330 321 9


Treatment completed as planned 0 0 0

Adverse Event or side effects 78 77 1

Refusal unrelated to adverse event 27 26 1

Progression/relapse 210 203 7

Death 1 1 0

Other - not protocol specified 14 14 0

Reason under review 0 0 0

MAJOR PROTOCOL DEVIATIONS 21 21 0






Standard Cohort Progressive Brain Mets Cohort

(n=304) (n=9)

Grade Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Abdominal pain 279 13 10 2 0 0 9 0 0 0 0 0

Acute kidney injury 291 3 5 4 0 1 9 0 0 0 0 0

Alkaline phosphatase increased 275 23 5 1 0 0 9 0 0 0 0 0

Anemia 125 59 74 46 0 0 6 1 1 1 0 0

Anorexia 225 39 37 3 0 0 8 0 1 0 0 0

AST increased 281 20 2 1 0 0 9 0 0 0 0 0

Back pain 293 5 3 3 0 0 9 0 0 0 0 0

Blood/lymph disorder-Other 300 0 2 2 0 0 9 0 0 0 0 0

Cholecystitis 303 0 0 0 1 0 9 0 0 0 0 0

Chronic kidney disease 301 0 2 1 0 0 9 0 0 0 0 0

Colitis 303 0 0 1 0 0 9 0 0 0 0 0

Constipation 225 67 11 1 0 0 8 1 0 0 0 0

Creatinine increased 257 23 16 7 1 0 8 0 0 1 0 0

Dehydration 270 10 12 12 0 0 8 0 1 0 0 0

Diarrhea 251 42 9 2 0 0 7 1 0 1 0 0

Dizziness 262 33 6 3 0 0 8 1 0 0 0 0

Dyspnea 280 18 5 1 0 0 9 0 0 0 0 0

Fatigue 124 82 81 17 0 0 4 4 1 0 0 0

Febrile neutropenia 301 0 0 3 0 0 9 0 0 0 0 0


S1416/II

Standard Cohort Progressive Brain Mets Cohort

(n=304) (n=9)

Grade Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Flank pain 300 2 1 1 0 0 9 0 0 0 0 0

Flu like symptoms 301 1 1 1 0 0 9 0 0 0 0 0

Gallbladder infection 303 0 0 1 0 0 9 0 0 0 0 0

Generalized muscle weakness 293 8 1 2 0 0 9 0 0 0 0 0

Headache 256 33 10 5 0 0 9 0 0 0 0 0

Hearing impaired 288 8 5 3 0 0 8 1 0 0 0 0

Heart failure 303 0 0 0 1 0 9 0 0 0 0 0

Hematuria 303 0 0 1 0 0 9 0 0 0 0 0

Hepatic failure 303 0 0 1 0 0 9 0 0 0 0 0

Hyperglycemia 288 12 1 3 0 0 8 1 0 0 0 0

Hypertension 279 10 11 4 0 0 9 0 0 0 0 0

Hypocalcemia 279 18 6 0 1 0 8 1 0 0 0 0

Hypokalemia 256 26 9 12 1 0 8 1 0 0 0 0

Hypomagnesemia 241 52 9 2 0 0 6 2 1 0 0 0

Hyponatremia 278 20 0 5 1 0 9 0 0 0 0 0

Infections/infestations-Other 301 0 1 2 0 0 9 0 0 0 0 0

Infusion related reaction 303 0 0 1 0 0 8 0 1 0 0 0

Insomnia 291 9 3 1 0 0 9 0 0 0 0 0

Lung infection 300 0 2 2 0 0 9 0 0 0 0 0

Lymphocyte count decreased 227 21 36 18 2 0 8 1 0 0 0 0

Myalgia 288 12 3 1 0 0 9 0 0 0 0 0

Nausea 95 78 101 30 0 0 5 3 0 1 0 0

Neutrophil count decreased 150 13 41 77 23 0 6 0 2 0 1 0

Pain 298 3 2 1 0 0 9 0 0 0 0 0

Pain in extremity 298 5 0 1 0 0 9 0 0 0 0 0

Peripheral sensory neuropathy 225 41 34 4 0 0 8 1 0 0 0 0

Platelet count decreased 189 53 29 25 8 0 7 1 1 0 0 0

Pleural effusion 303 0 0 1 0 0 9 0 0 0 0 0

Purpura 302 1 0 1 0 0 9 0 0 0 0 0

Seizure 299 0 3 1 1 0 8 0 1 0 0 0

Sepsis 303 0 0 0 0 1 9 0 0 0 0 0

Supraventricular tachycardia 303 0 0 0 1 0 9 0 0 0 0 0

Syncope 299 0 0 5 0 0 9 0 0 0 0 0

Thromboembolic event 294 2 2 6 0 0 9 0 0 0 0 0

Urinary tract obstruction 303 0 0 1 0 0 9 0 0 0 0 0

Vomiting 183 67 40 14 0 0 7 2 0 0 0 0

Weight loss 269 26 8 1 0 0 9 0 0 0 0 0

White blood cell decreased 152 37 62 49 4 0 6 2 0 1 0 0


EVENT 11 20 82 153 36 2 1 2 2 3 1 0


S1418/III

S1418 Phase III - FDA Registration Study

Coordinating Groups: SWOG and NRG

A Randomized, Phase III Trial to Evaluate the Efficacy and Safety of MK-

3475 (Pembrolizumab) as Adjuvant Therapy for Triple Receptor-Negative

Breast Cancer with ≥ 1 cm Residual Invasive Cancer or Positive Lymph

Nodes (ypN1mi, ypN1-3) after Neoadjuvant Chemotherapy

Participants:

SWOG, NRG, CTSU

Study Chairs:

L Pusztai, J Mammen, P Ganz (NRG)

Statisticians:

W Barlow, J Miao, D Lew

Data Coordinators:

I Syquia, J Scurlock

Date Activated:

11/15/2016

SCHEMA

Objectives

To compare invasive disease-free survival (IDFS) of

patients with triple-negative (TNBC) or low ER

positive and/or HER2 borderline breast cancer who

have >1 cm residual invasive breast cancer and/or

positive lymph nodes (ypN1mi, ypN1, ypN2, ypN3)

after neoadjuvant chemotherapy randomized to

receive 1 year of MK-3475 (pembrolizumab) adjuvant

therapy compared to no MK-3475 (pembrolizumab),

in both the entire study population and also in the PD-

L1 positive subset.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Observation

MK-3475 (Pembrolizumab)

R

E

G

I

S

T

R

A

T

I

O

N

*PD-L1 status determined by central laboratory

Tissue Submission*


S1418/III

To compare the effects of MK-3475 (pembrolizumab)

on overall survival (OS) and distant recurrence-free

survival (DRFS) between the two randomized arms for

the PD-L1 positive patients and then all patients.

To assess the toxicity and tolerability of MK-3475

(pembrolizumab) in this patient population with or

without radiation therapy.

To examine the association between biomarkers of

inflammation and quality of life and patient-reported

outcomes between the two groups during and at the

end of therapy.

To examine the long-term and late effects of treatment

on patient-reported outcomes.

Patient Population

Patients must have histologically confirmed ER, PR

and HER2 negative breast cancer (triple-negative,

TNBC) or ER and PR weakly positive and/or HER2

equivocal status with residual invasive disease after

completion of neoadjuvant chemotherapy. Patients

with HER2 equivocal that do not receive HER2

targeted therapy are eligible. Patients with weakly ER

or PR positive disease, defined as ER and/or PR less

than or equal to 5% by immunohistochemistry, are

eligible if patients are not eligible for adjuvant

endocrine therapy. Residual disease must be ≥ 1 cm in

greatest dimension, and/or have positive lymph nodes

(ypN1mi, ypN1, ypN2, ypN3) determined as

described in the protocol. Patients must not have

metastatic disease or locally recurrent disease. Patients

must have adequate tumor tissue for PD-L1 testing.

Patients must have received neoadjuvant

chemotherapy as recommended by NCCN guidelines

for TNBC. Patients may receive post-operative

(adjuvant) chemotherapy for up to 24 weeks, which

must have been completed within 35 days prior to

registration. Patients must have completed their final

breast surgery with clear resection margins for

invasive cancer and DCIS within 270 days or 90 days

(if no adjuvant chemotherapy) prior to registration.

Patients may receive concomitant radiation therapy

(XRT) or XRT prior to registration; the intention to

use XRT and the extent of intended XRT must be

specified at registration if it has not been initiated.

Patients must not have had prior immunotherapy with

anti PD-L1 or anti-CTLA4 or similar drugs.

Patients must be at least 18 years of age, have a Zubrod

performance status of 0-2, and must not have received

live vaccines within 30 days prior to registration.

Patients must not be known HIV positive or have

known active hepatitis B or C. Patients must not have

active autoimmune disease that has required systemic

treatment in the past two years, non-infectious

pneumonitis, or an active infection requiring systemic

therapy. Patients who speak/read English must agree

to participate in the Behavioral and Health Outcomes

(BAHO) substudy.

Patients must be registered to Step 2 for randomization

within 14 calendar days of receiving e-mail

notification that the patient's tissue specimen was

adequate for PD-L1 testing. Patients must have

adequate hematologic, hepatic, renal and thyroid

function prior to randomization.


Randomization will be stratified by the following

factors: (1) nodal stage: ypN0 vs ypN+ (including

ypN1mi); (2) residual tumor size: ≤ 2 cm vs > 2 cm;

(3) PD-L1 status: positive vs negative; and (4) Prior

use of post-operative (adjuvant) chemotherapy: yes vs.

no

Accrual Goals

The accrual goal is 1,000 patients to achieve 910

eligible patients. Two interim analyses will be

performed when approximately 50% and 75% of the

IDFS events in the PD-L1 positive population have

been observed.

Summary Statement

As of June 30, 2020, 951 patients had been registered

to the PD-L1 status screening step. Seventy-four

patients are currently ineligible, primarily due to

registration not within allowed time frame after

surgery and adjuvant chemotherapy.

As of June 30, 2020, 812 patients had been

randomized, including 51 patients who were ineligible

at the screening step. Six additional patients are

ineligible due to lab values out of range, as well as one

due to registration not within allowed time frame.

Major deviations were coded for nine patients on the

MK-3475 arm who did not receive any protocol

treatment and 16 patients on the observation arm who

withdrew consent immediately after randomization.

Seventeen patients on the observation arm were

removed from protocol for other reasons, primarily

due to planning or starting to receive non-protocol

treatment by physician's or patient's decision. One

patient on the MK-3475 arm was removed from

protocol due to physician's decision and was also

coded as reason off treatment "Other - not protocol

specified."


S1418/III

There have been five patients with treatment-related

Grade 4 toxicities reported among 345 patients

receiving MK-3475 evaluated for adverse events: one

with bilateral sudden vision loss coded as "Eye

disorders - Other, specify," one with left eye sudden

onset blindness also coded as "Eye disorders - Other,

specify," one with increased ALT, one with decreased

lymphocyte count, and one with heart failure. There

have been 56 other patients with treatment-related

Grade 3 adverse events as maximum grade, including

12 patients with hematologic toxicity and eight

patients with diarrhea.

Toxicities are reviewed by treatment group by the

Data Safety and Monitoring Committee, the SWOG

Breast Committee leadership, and the Study Chair.


Screening

Registrations ending June 30, 2020


Kaiser Perm NCORP 46 Southeast COR NCORP 42 Kansas MU-NCORP 22 CRC West MI NCORP 18 Georgia NCORP 18 New Mexico MU-NCORP 18 Heartland NCORP 16 MD Anderson CC 16 Michigan CRC NCORP 15 CORA NCORP 14 MUSC MU-NCORP 12 Wichita NCORP 12 Colorado, U of 11 Columbus NCORP 11 PCRC NCORP 10 Arkansas, U of 9 City of Hope Med Ctr 9 Cleveland Clinic OH 9 Fred Hutchinson CRC 9 Michigan, U of 9 Nevada CRF NCORP 9 Davis, U of CA 8 Baptist MU-NCORP 7 Good Samaritan MC/Oregon Hlth Sci Univ 7

Institutions Total Reg Oregon Hlth Sci Univ 6 Providence Hosp 6 Yale University 6 Columbia MU-NCORP 5 Greenville NCORP 5 Harrington CC 5 Northwestern Univ 5 Ozarks NCORP 5 Arizona CC, Univ of 4 Essentia Hlth NCORP 4 Gulf South MU-NCORP 4 Hawaii MU-NCORP 4 Irvine, U of CA 4 MidMichigan Med Ctr/Michigan, U of 4 Rochester, Univ of 4 Sacred Heart Hosp/Arkansas, U of 4 Thompson Ca Surv Ctr/San Antonio, U of TX 4 All Other SWOG Institutions 48 NRG 239 ALLIANCE 110 ECOG-ACRIN 109 CCTG 9



S1418/III


Screening

Registrations ending June 30, 2020; Data as of July 23, 2020

Tissue for PD-

L1 testing

NUMBER REGISTERED 951

INELIGIBLE 74

ELIGIBLE 877

Analyzable, Pend. Elig. 74


S1418/III


Randomization



Southeast COR NCORP 40 Kaiser Perm NCORP 38 Kansas MU-NCORP 18 CRC West MI NCORP 16 Heartland NCORP 16 Michigan CRC NCORP 15 CORA NCORP 14 Georgia NCORP 14 New Mexico MU-NCORP 14 Wichita NCORP 11 MD Anderson CC 10 PCRC NCORP 10 Michigan, U of 9 MUSC MU-NCORP 9 Nevada CRF NCORP 9 City of Hope Med Ctr 8 Colorado, U of 8 Columbus NCORP 8 Fred Hutchinson CRC 8 Arkansas, U of 7

Institutions Total Reg Cleveland Clinic OH 7 Good Samaritan MC/Oregon Hlth Sci Univ 7 Baptist MU-NCORP 6 Columbia MU-NCORP 5 Harrington CC 5 Oregon Hlth Sci Univ 5 Ozarks NCORP 5 Arizona CC, Univ of 4 Gulf South MU-NCORP 4 Hawaii MU-NCORP 4 Sacred Heart Hosp/Arkansas, U of 4 Thompson Ca Surv Ctr/San Antonio, U of TX 4 Yale University 4 All Other SWOG Institutions 67 NRG 206 ECOG-ACRIN 95 ALLIANCE 91 CCTG 7



Randomization


TOTAL Observation

MK-3475

(Pembrolizumab)


Analyzable, Pend. Elig. 40 24 16

ADVERSE EVENT ASSESSMENT Evaluable 648 303 345 Not Evaluable 15 9 6 Too Early 91 72 19


S1418/III


Randomization


Observation

MK-3475

(Pembrolizumab)

(n=384) (n=370)

AGE

Median 51.0 52.2

Minimum 25.1 26.9

Maximum 85.7 84.1

SEX

Males 1 0% 0 0% Females 383 100% 370 100%

HISPANIC

Yes 38 10% 33 9% No 338 88% 322 87% Unknown 8 2% 15 4%

RACE

White 290 76% 281 76% Black 58 15% 49 13% Asian 10 3% 15 4% Pacific Islander 1 0% 2 1% Native American 2 1% 3 1% Multi-Racial 1 0% 1 0% Unknown 22 6% 19 5%

NODAL STAGE

ypN0 161 42% 151 41% ypN+ 223 58% 219 59%

RESIDUAL TUMOR SIZE

≤ 2 cm 215 56% 205 55% > 2 cm 169 44% 165 45%

PRIOR USE OF POST-

OPERATIVE (ADJUVANT)

CHEMOTHERAPY Yes 223 58% 204 55% No 161 42% 166 45%


S1418/III

Treatment Summary

Randomization


Total

MK-3475

(Pembrolizumab)

Observation

NUMBER ON PROTOCOL TREATMENT 230 109 121

NUMBER OFF PROTOCOL TREATMENT 524 261 263


Treatment completed as planned 233 109 124

Adverse Event or side effects 61 61 0

Refusal unrelated to adverse event 77 22 55

Progression/relapse 125 62 63

Death 1 1 0

Other - not protocol specified 18 1 17

Reason under review 9 5 4

MAJOR PROTOCOL DEVIATIONS 25 9 16


Randomization





(n=345)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 Adrenal insufficiency 342 1 1 1 0 0

Alkaline phosphatase increased 319 21 3 2 0 0

ALT increased 302 32 4 6 1 0

Arthralgia 293 36 12 4 0 0

AST increased 300 37 2 6 0 0

Blood bilirubin increased 336 6 2 1 0 0

Colitis 342 0 1 2 0 0

Concentration impairment 343 1 0 1 0 0

Dehydration 344 0 0 1 0 0

Dermatitis radiation 332 5 7 1 0 0

Diarrhea 289 37 11 8 0 0

Dyspnea 317 14 11 3 0 0

Edema limbs 332 10 2 1 0 0

Eye disorders - Other, specify 339 3 1 0 2 0

Facial nerve disorder 344 0 0 1 0 0

Fatigue 205 104 35 1 0 0

Fever 336 6 2 1 0 0

Fibr deep connect tissue 344 0 0 1 0 0

Generalized muscle weakness 338 3 3 1 0 0

Hand-Foot syndrome 342 2 0 1 0 0

Headache 301 37 6 1 0 0

Heart failure 344 0 0 0 1 0

Hepatobil disorders-Other 343 0 1 1 0 0

Hyperglycemia 329 10 4 2 0 0


S1418/III


(n=345)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 Hypertension 339 0 3 3 0 0

Hyperthyroidism 313 20 11 1 0 0

Hypokalemia 334 8 1 2 0 0

Hypotension 344 0 0 1 0 0

Hypothyroidism 267 21 56 1 0 0

Hypoxia 342 0 2 1 0 0

Infections/infestations-Other 338 2 2 3 0 0

Keratitis 344 0 0 1 0 0

Lymphocyte count decreased 310 14 12 8 1 0

Mucositis oral 331 11 2 1 0 0

Myalgia 312 25 6 2 0 0

Neutrophil count decreased 325 10 6 4 0 0

Pain 328 10 6 1 0 0

Pain in extremity 332 7 4 2 0 0

Papilledema 344 0 0 1 0 0

Paresthesia 337 4 3 1 0 0

Peripheral sensory neuropathy 327 12 5 1 0 0

Pneumonitis 322 1 15 7 0 0

Pneumothorax 344 0 0 1 0 0

Rash maculo-papular 293 38 11 3 0 0

Retinal detachment 344 0 0 1 0 0

RT recall reaction, derm 343 1 0 1 0 0

Scleral disorder 344 0 0 1 0 0

Skin infection 343 1 0 1 0 0

Skin/subq tissue ds-Other 330 6 7 2 0 0

Syncope 343 0 0 2 0 0

White blood cell decreased 310 22 9 4 0 0 MAX. GRADE ANY ADVERSE

EVENT 56 79 149 56 5 0


S1501/III

S1501 Phase III


Prospective Evaluation of Carvedilol in Prevention of Cardiac Toxicity in

Patients with Metastatic HER-2+ Breast Cancer, Phase III

Participants:

SWOG, CTSU

Study Chairs:

J Floyd, M Leja

Statisticians:

K Guthrie, A Darke

Data Coordinators:

R Topacio, S Dzingle

Date Activated:

09/15/2017

SCHEMA

Objectives

To assess whether prophylactic beta blocker therapy

with carvedilol compared with no prophylaxis reduces

the risk of subsequent cardiac dysfunction in patients

with metastatic breast cancer receiving trastuzumab-

based HER-2 targeted therapy.



the risk of predefined subsequent cardiac events in

patients with metastatic breast cancer receiving

trastuzumab-based HER-2 targeted therapy.

To evaluate if prophylactic carvedilol compared with

no prophylaxis results in a longer time to first

interruption of trastuzumab-based HER-2 targeted

therapy due to either cardiac dysfunction or events.



R

E

G

I

S

T

R

A

T

I

O

N

Submit

ECHO for

central read

Current beta

blocker, ARB,

or ACE

inhibitor use

No

Yes

R

A

N

D

O

M

I

Z

A

T

I

O

N

Carvedilol

No Prophylaxis

REGISTRATION

Observation


S1501/III

the risk of subsequent cardiac dysfunction or events in

this population.

To establish and prospectively collect a predefined

panel of baseline core cardiovascular measures and

develop a predictive model of cardiac dysfunction.

To evaluate the rate of cardiac dysfunction in an

observational arm consisting of individuals otherwise

eligible for the study except for use of beta blockers,

angiotensin receptor blocker (ARB), or angiotensin

converting enzyme (ACE) inhibitors for other medical

reasons.

To compare the local and central reads of left

ventricular ejection fraction (LVEF) and strain and

assess if strain changes can predict drop in ejection

fraction.

To assess if strain can be used in the community as a

marker of cardiotoxicity.

Patient Population

Patients must have HER-2 positive metastatic breast

cancer. Patients must be at increased risk of

cardiotoxicity, due to previous anthracycline exposure,

or due to at least one risk factor for heart disease as

specified in the protocol.

Patients must be initiating or continuing trastuzumab-

based HER-2 targeted therapy in the first or second

line setting. Patients must not be taking or planning to

take anthracyclines. To participate in the randomized

portion of the study, patients must not have taken

within 21 days, be taking, or be planning to take once

registered an ARB, ACE inhibitor, or beta blocker. To

participate in the observational portion of the study,

patients must be currently taking an ARB, ACE

inhibitor, or beta blocker and plan to continue this

medication once registered.

Patients must be 18 years or older and must have a

Zubrod performance status of 0-2. Patients must have

LVEF ≥ 50% by 2-D echocardiogram obtained from

an S1501 validated ECHO lab. Patients must have

systolic blood pressure ≥ 80 mm Hg and must be able

to swallow tablets. Patients must not be dialysis

dependent or have uncontrolled asthma.


Patient randomization will be stratified by the

following factors: (1) prior anthracycline therapy: yes

vs no; and (2) baseline LVEF by S1501 ECHO Core

Lab central read: 50%-54% vs ≥ 55%.

Accrual Goals

The accrual goal is 667 patients to achieve 633 eligible

patients in the randomized cohort; 150 patients will be

accrued to the observational cohort. An interim futility

analysis will be performed when 400 patients have

been accrued to the randomized cohort.

Summary Statement


Cancer Survivorship chapter.


S1609/II

S1609 Phase II


DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors

Participants:

SWOG, CTSU

Study Chairs:

S Patel, Y Chae

Statisticians:

M Othus, M Plets, E Mayerson

Data Coordinators:

C Magner, S Gurung

Date Activated:

01/13/2017

Objectives

To evaluate the RECIST 1.1 overall response rate

(ORR) in subsets of patients with advanced rare

cancers treated with ipilimumab plus nivolumab

combination immunotherapy.

To evaluate the overall response rate (ORR) in patients

with gestational trophoblastic tumors treated with

ipilimumab plus nivolumab combination

immunotherapy.

To evaluate the RECIST 1.1 overall response rate

(ORR) in patients PD-L1 amplified cancers treated

with nivolumab immunotherapy.

To evaluate toxicities in each cohort.

To estimate overall survival (OS), progression-free

survival (PFS), clinical benefit rate; and to estimate

immune-related ORR (irORR), and immune-related

PFS (irPFS) by unidimensional immune-related

response criteria.

To collect specimens for banking for use in future

correlative biomarker research studies.

Patient Population

Patients must have histologically confirmed rare

cancer and/or cancer of unknown primary specified on

the list of eligible rare cancer histologic cohorts in the

S1609 protocol or with PD-L1 amplification only. As

of September 11, 2017, patients are no longer required

to have been enrolled in EAY131 (NCI-MATCH) to

be eligible for this study.

Patients must have measurable disease and have

progressed following at least one line of standard

systemic therapy and there must not be other

approved/standard therapy available that has been

shown to prolong overall survival. Patients are also

eligible if no standard treatment exists that has been

shown to prolong overall survival. Patients in one of

the histologically defined rare cancer cohorts may

have received either prior anti-CTLA-4 or other prior

anti-PD-1/anti-PD-L1 therapy, but not both, provided

that it is completed at least 4 weeks prior to registration.

Patients in the PD-L1 amplification cohort must not

have received anti-PD-1/anti-PD-L1 therapy; prior

anti-CTLA-4 is allowed provided that it is completed

at least 4 weeks prior to registration. Patients who had

a prior immune-related adverse event with prior

immunotherapy are not eligible. Patients with brain

metastases or primary brain tumors must have

completed treatment, surgery or radiation therapy at

least 28 days prior to registration and have stable

disease at time of registration. Patients with metastatic

brain parenchymal disease must have been treated and

off steroids for seven days prior to registration.

Patients must have been off all other systemic anti-

cancer therapy at least seven days prior to registration


S1609/II

and any therapy-induced toxicity must have recovered

to Grade 1 or less.


2 and have adequate hematologic, hepatic, renal,

thyroid, and adrenal axis function. Patients must not

have active autoimmune disease that has required

systemic treatment in the past two years or any

uncontrolled intercurrent illness. Patients must not

have known active Hepatitis B Virus (HBV) or

Hepatitis C Virus (HCV) infection at time of

registration. Patients with HBV or HCV that have an

undetectable viral load, or in the opinion of the treating

investigator is well controlled, are eligible. Patients

who are known to be HIV-positive at registration are

eligible if they meet the conditions outlined in the

protocol.


Patients will be described by histologic cohorts, with

the exception of PD-L1 amplification patients.

Accrual Goals

The maximum accrual for this study is 818 patients. A

two-stage design will be used for all cohorts, with the

exception of the NOC and "Cancer of Unknown

Primary" (CuP) cohorts. Initially, six eligible patients

will be registered to each histologic cohort. If at least

one response is observed within a cohort, an additional

10 eligible patients will be registered to that cohort. Up

to 16 eligible patients will be registered to the CuP

cohort with no formal first stage response assessment.

Up to 60 eligible patients will be enrolled to the NOC

cohort, and data may be used to open additional

cohorts.

Summary Statement


Early Therapeutics and Rare Cancers chapter.


S1614/III

S1614 Phase III


A Phase III Randomized Trial of Prophylactic Antiviral Therapy in Patients

with Current or Past Hepatitis B Virus (HBV) Infection Receiving Anti-

Cancer Therapy for Solid Tumors

Participants:

SWOG, CTSU (Supported by ECOG-ACRIN)

Study Chairs:

J Hwang, A Lok, E Mitchell (ECOG-ACRIN)

Statisticians:

J Unger, E Mayerson

Data Coordinators:

S Dzingle, R Topacio

Date Activated:

02/21/2019

Date Closed:

05/20/2020*

*Temporary Closure

SCHEMA

Cohort 1:

Chronic HBV

Prophylactic

Antiviral Therapy

Upon Indication

Antiviral Therapy

Usual Care

Antiviral Therapy

Upon Indication

Antiviral Therapy

Cohort 2:

Past HBV

R

A

N

D

O

M

I

Z

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N


S1614/III

Objectives

Co-primary objectives:

To compare the effect of prophylactic tenofovir

alafenamide (TAF) therapy versus upon indication

TAF therapy on time-to-adverse liver outcomes of

liver failure or liver-related death in patients with

chronic HBV infection (HBsAg+ and anti-HBc+)

receiving anti-cancer therapy for solid tumors.

To compare the effect of upon indication TAF therapy

versus usual care on time-to-adverse liver outcomes of

liver failure or liver-related death in patients with past

HBV infection (HBsAg- and anti-HBc+) receiving

anti-cancer therapy for solid tumors.

Secondary objectives:

Using time-to-event analysis, to compare the effect of

TAF therapy versus upon indication TAF therapy on

HBV reactivation, on the combined endpoint of

adverse liver outcomes (liver failure or liver-related

death) and HBV reactivation, and on HBV flare by

arm in patients with chronic HBV infection receiving

anti-cancer therapy for solid tumors.

Using time-to-event analysis, to compare the effect of

upon indication TAF therapy versus usual care on

HBV reactivation, on the combined endpoint of

adverse liver outcomes (liver failure or liver-related

death) and HBV reactivation, and on HBV flare by

arm in patients with past HBV infection receiving anti-

cancer therapy for solid tumors.

Patient Population

Patients must be diagnosed with Stage I-III solid

tumor malignancy not involving the liver. Patients

must have HBV infection as indicated through positive

HBsAG or anti-HBc tests. Patients must not have

lymphoma, leukemia, or myeloma. Patients must not

have primary liver cancer or evidence of any

malignancy that involves the liver.

Patients must be planning to receive a new regimen of

systemic anti-cancer therapy for their solid tumor

malignancy and must have discontinued all previous

therapies. Patients must not have received anti-CD20

cancer therapy regimens nor had a hematopoietic stem

cell transplant. Patients must have discontinued any

antiviral medications active against HBV at least 90

days prior to registration, and discontinue any

contraindicated medications as identified in the

protocol at time of registration.


2, and have adequate liver, renal, and coagulation

function. Patients must not have known cirrhosis,

known hepatitis-C infection, or history of human

immunodeficiency infection proven by an HIV test

within the past 365 days. Patients must have complete

results for HBsAg, anti-HBc, anti-HBs, and HBV

DNA lab tests as specified in the protocol. Patients

must be able to take oral medications.

Patients must be willing to submit specimens for

ongoing testing of HBV reactivation. Patients must be

offered the opportunity to participate in the

translational medicine studies.


Patients with chronic HBV infection will be

randomized within Cohort 1, with randomization

balanced by planned cancer therapy type: any

cytotoxic therapy vs immunotherapy alone vs targeted

therapy alone vs immunotherapy and targeted therapy.

Patients with past HBV infection will be randomized

within Cohort 2 with randomization balanced by the

following factors: (1) planned cancer therapy type: any

cytotoxic therapy vs immunotherapy alone vs targeted

therapy alone vs immunotherapy and targeted therapy;

and (2) anti-HBs status: positive vs negative.

Accrual Goals

The accrual goal for this study is 444 patients, 222

patients per cohort to achieve 200 eligible patients per

cohort. A single formal interim analysis for efficacy

for each cohort will be conducted when one half of

patients have reached one year of follow-up.

Summary Statement


Symptom Control and QOL chapter.


S1703/III

S1703 Phase III


Randomized Non-Inferiority Trial Comparing Overall Survival of Patients

Monitored with Serum Tumor Marker Directed Disease Monitoring

(STMDDM) Versus Usual Care in Patients with Metastatic Hormone

Receptor Positive HER-2 Negative Breast Cancer

Participants:

SWOG, CTSU

Study Chairs:

M Accordino, D Hershman

Statisticians:

J Unger, A Moseley

Data Coordinator:

D Liggett

Date Activated:

07/16/2018

SCHEMA

Objectives

To assess whether patients with HER-2 negative,

hormone receptor positive, metastatic breast cancer

who are monitored with serum tumor marker directed

disease monitoring (STMDDM) have non-inferior

overall survival compared to patients monitored with

usual care.

To compare cumulative direct healthcare costs (in the

United States) through 48 weeks among patients

monitored with STMDDM versus those monitored

with usual care in this patient population.

To assess whether the patient-reported outcomes

(PROs) of anxiety and quality of life are different

among patients who are monitored with STMDDM

compared with patients who are monitored with usual

care in this patient population.

≥ 1 elevated STM

(± 14 days of

treatment start)

Usual Care

R

E

G

I

S

T

R

A

T

I

O

N

STMDDM

R

A

N

D

O

M

I

Z

A

T

I

O

N

Elevated STM

decreases by ≥ 10%


S1703/III

To assess modality and frequency of disease

monitoring testing in the usual care cohort.

To assess the association of PROs and patient

preferences for disease monitoring testing.

To evaluate predictors of physician preferences for

disease monitoring testing.

Patient Population

Patients must have a diagnosis of hormone receptor

positive (ER+ and/or PR+), HER-2 negative,

metastatic (M1) breast cancer and must be receiving or

planning to receive first-line systemic treatment for

metastatic disease. Patients must have been tested for

the breast cancer specific serum tumor markers (STMs)

CEA (required) and either CA 15-3 or CA 27.29 (one

of these is required). At least one of the tested STMs

must be elevated. To be randomized, patients must

have the same markers retested within the timeframe

specified in the protocol, and at least one of the

previously elevated markers must have decreased by

at least 10%. Patients must not have known brain or

leptomeningeal metastases.

Patients must not have received prior systemic therapy

for metastatic breast cancer except for their current

line of therapy. Patients must have systemic

radiographic imaging prior to or within 30 days after

initiation of systemic therapy and prior to registration.

Patients must be willing to obtain disease monitoring

(imaging and/or STM measurements) from a

consistent facility for the duration of the study.

Patients must not be enrolled currently or plan to

participate in a first-line treatment trial for metastatic

breast cancer with a defined monitoring schedule.

Patients must not have known cirrhosis, untreated B12

deficiency, thalassemia, or sickle cell anemia.

Patients who are able to complete questionnaires in

English or Spanish must participate in the PRO

assessments.


Patient randomization will be stratified by disease type:

bone only disease vs any visceral disease.

Accrual Goals

The accrual goal is 1,320 patients to achieve 1,056

randomized eligible patients (528 per arm).

Summary Statement


Cancer Care Delivery chapter.


S1706/II

S1706 Phase II


A Phase II Randomized Trial of Olaparib (NSC-747856) Administered

Concurrently with Radiotherapy versus Radiotherapy Alone for

Inflammatory Breast Cancer

Participants:

SWOG, CTSU (Supported by Alliance, CCTG, ECOG-

ACRIN, NRG)

Study Chairs:

R Jagsi, P Chalasani, J White (NRG), J Bellon

(Alliance), R Zellars (ECOG-ACRIN), E Rakovitch

(CCTG)

Statisticians:


Data Coordinator:

L Kaye

Date Activated:

09/12/2018

SCHEMA

Objectives

To compare the Invasive Disease-Free Survival

(IDFS) of patients with inflammatory breast cancer

receiving concurrent administration of olaparib with

standard doses of radiotherapy to the chestwall and

regional lymph nodes compared to standard doses of

radiotherapy alone to the chestwall and regional lymph

nodes.

To compare the effect of concurrent administration of

olaparib with radiotherapy versus radiotherapy alone

on improvement in locoregional control (measured by

R

A

N

D

O

M

I

Z

A

T

I

O

N

Standard Radiation + Olaparib

Standard Radiation


S1706/II

Locoregional Recurrence-Free Interval), Distant

Relapse-Free Survival, and Overall Survival in

inflammatory breast cancer patients.

Patient Population

Patients must have inflammatory breast cancer

without distant metastases. All biomarker subtype

groups (ER, PR, HER2) are eligible.

Patients must have completed neoadjuvant

chemotherapy and must have undergone modified

radical mastectomy with negative margins within 3-12

weeks prior to registration. Additional adjuvant

chemotherapy is allowed either completed prior to

registration or planned for after completion of protocol

treatment. Patients must not have a history of radiation

therapy to the ipsilateral chest wall and/or regional

nodes. Patients must not be planning to receive any

other investigational agents or any additional anti-

cancer therapy during radiation therapy with or

without study medication. Pathologic complete

response (pCR) status must be determined post-

surgery prior to registration. Patients must not be

planning to receive CYP3A inhibitors or inducers, live

virus or live bacterial vaccines while receiving

Olaparib.

Patients must be ≥ 18 years of age, have a Zubrod

performance status of 0-2 and have adequate

hematologic, renal, cardiac, and hepatic function.

Patients who are breastfeeding must agree to

discontinue breastfeeding before receiving olaparib.

Female patients must be postmenopausal or have a

negative urine or serum pregnancy test within 14 days

prior to registration. Patients must not have active

uncontrolled infection, symptomatic congestive heart

failure, unstable angina pectoris or cardiac arrhythmia.

Patients must be able to swallow and retain oral

medications. Patients must not have a known

hypersensitivity to olaparib. Patients must not have

unresolved or unstable Grade 2 or greater toxicity

from prior administration of another investigational

drug and/or prior anti-cancer treatment. Patients must

not have had previous allogeneic bone marrow

transplant or double umbilical cord blood

transplantation (dUCBT). Patients must not have had

whole blood transfusions in the last 120 days prior to

registration.

Patients must be offered the opportunity to participate

in specimen submission for banking. Patients who can

complete the patient-reported outcomes

questionnaires in English must be offered the

opportunity to participate in the PRO substudy.


Randomization will be stratified by the following

factors: (1) biologic subtype: HER2 positive vs HER2

negative and ER/PR positive vs triple negative

(HER2/ER/PR negative); and (2) residual disease

status after neoadjuvant chemotherapy: pCR vs no

pCR and no planned or administered adjuvant

chemotherapy vs no pCR and planned or administered

adjuvant chemotherapy after surgery.

Accrual Goals

The accrual goal is 300 patients to achieve 280 eligible

patients. An interim analysis for futility will be

conducted at 50% of the expected IDFS events.

Summary Statement

As of June 30, 2020, there had been 45 patients

registered. One patient was ineligible due to lab value

out of range. Major deviations are coded for three

patients who did not receive any protocol treatment;

these three patients are not evaluable for adverse

events. One patient was removed from protocol

treatment for reasons not specified in the protocol due

to physician’s decision.

Among 38 patients evaluated for adverse events, three

patients on the Olaparib + RT arm and one patient on

the RT arm experienced treatment-related Grade 3

adverse events, all due to dermatitis radiation.


S1706/II




Baptist MU-NCORP 2 Davis, U of CA 2 Kansas MU-NCORP 2 Michigan, U of 2 Providence Hosp 2 Utah, U of 2 CORA NCORP 1 Harrington CC 1 Ohio State Univ 1

Institutions Total Reg Ozarks NCORP 1 Rochester, Univ of 1 Sacred Heart Hosp/Arkansas, U of 1 Shaw Cancer Center/Colorado, U of 1 NRG 17 ALLIANCE 6 ECOG-ACRIN 3



Registrations ending June 30, 2020; Data as of August 13, 2020

TOTAL Olaparib + RT RT


Analyzable, Pend. Elig. 2 2 0


Evaluable 38 18 20 Not Evaluable 3 0 3 Too Early 3 3 0

2

2

3

3

5

5

3

5

3

3

5

6

0

10

20

JanMar

2019

AprJun

2019

JulSep

2019

OctDec

2019

JanMar

2020

AprJun

2020

Time of Registration

Olaparib + RT RT

Divisions by ARM

Randomization by 3 Month Intervals


S1706/II



Olaparib + RT RT

(n=21) (n=23)

AGE

Median 53.5 50.9

Minimum 28.5 31.2

Maximum 66.4 73.2

SEX

Females 21 100% 23 100%

HISPANIC

Yes 1 5% 1 4% No 20 95% 21 91% Unknown 0 0% 1 4%

RACE

White 16 76% 20 87% Black 3 14% 2 9% Asian 0 0% 1 4% Pacific Islander 1 5% 0 0% Unknown 1 5% 0 0%

BIOLOGIC SUBTYPE

HER2 positive 8 38% 8 35% HER2 negative and ER/PR positive 6 29% 9 39% Triple negative 7 33% 6 26%

RESIDUAL DISEASE STATUS AFTER

NEOADJUVANT CHEMOTHERAPY

pCR 4 19% 7 30% No pCR and no planned or administered

adjuvant chemotherapy 9 43% 11 48%

No pCR and planned or administered

adjuvant chemotherapy after surgery 8 38% 5 22%


S1706/II

Treatment Summary


Total




Treatment completed as planned 35 Adverse Event or side effects 1 Refusal unrelated to adverse event 1 Progression/relapse 1 Death 0 Other - not protocol specified 1 Reason under review 0





Olaparib + RT RT

(n=18) (n=20)

Grade Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Abdominal pain 17 0 1 0 0 0 20 0 0 0 0 0

Bloating 17 0 1 0 0 0 20 0 0 0 0 0

Breast pain 17 0 1 0 0 0 20 0 0 0 0 0

Chest wall pain 18 0 0 0 0 0 19 1 0 0 0 0

Dermatitis radiation 12 2 1 3 0 0 17 1 1 1 0 0

Diarrhea 17 1 0 0 0 0 20 0 0 0 0 0

Dry skin 18 0 0 0 0 0 19 1 0 0 0 0

Dysphagia 17 1 0 0 0 0 20 0 0 0 0 0

Erythema multiforme 17 0 1 0 0 0 19 1 0 0 0 0

Esophagitis 17 0 1 0 0 0 20 0 0 0 0 0

Fatigue 14 4 0 0 0 0 12 7 1 0 0 0

Headache 17 1 0 0 0 0 20 0 0 0 0 0

Lymphocyte count decreased 17 1 0 0 0 0 20 0 0 0 0 0

Nausea 14 4 0 0 0 0 20 0 0 0 0 0

Pain 18 0 0 0 0 0 18 2 0 0 0 0

Pain in extremity 18 0 0 0 0 0 19 0 1 0 0 0

Pain of skin 18 0 0 0 0 0 19 1 0 0 0 0

Platelet count decreased 17 1 0 0 0 0 20 0 0 0 0 0

Pruritus 16 2 0 0 0 0 20 0 0 0 0 0

RT recall reaction, derm 17 0 1 0 0 0 20 0 0 0 0 0

Skin hyperpigmentation 17 1 0 0 0 0 19 1 0 0 0 0

Skin/subq tissue ds-Other 18 0 0 0 0 0 19 1 0 0 0 0

Vomiting 17 0 1 0 0 0 20 0 0 0 0 0

White blood cell decreased 17 0 1 0 0 0 20 0 0 0 0 0


EVENT 2 7 6 3 0 0 6 10 3 1 0 0


S1714

S1714 Observational Cohort


A Prospective Observational Cohort Study to Develop a Predictive Model of

Taxane-Induced Peripheral Neuropathy in Cancer Patients

Participants:

SWOG, CTSU

Study Chairs:

M Trivedi, D Hershman

Statisticians:

J Unger, A Darke

Data Coordinators:

M Eng, D Liggett, R Topacio

Date Activated:

03/01/2019

Objectives

To develop and validate a clinical risk prediction

model using clinical factors for the development of

peripheral neuropathy in patients receiving taxane-

based chemotherapy regimens.

To examine patient-reported outcomes (PROs) and

objective measures of chemotherapy induced

peripheral neuropathy (CIPN) to better define the

phenotype of peripheral neuropathy in this patient

population.

To assess the incidence of CIPN within one year in this

patient population.

To identify predictors of treatment dose reductions,

delays, and discontinuations associated with CIPN

symptoms in this patient population.

Patient Population

Patients must have Stage I, II, or III primary non-small

cell lung, primary breast, or primary ovarian/fallopian

tube cancer.

Patients must plan to start treatment with one of the

study-approved taxane-based chemotherapy regimens

within 14 days after registration, and must not have

received a taxane, platinum, vinca alkaloid, or

bortezomib-based chemotherapy regimen prior to

registration.

Patients may have pre-existing neuropathy.

Patients must be able and willing to complete

questionnaires in English or Spanish, agree to submit

all required specimens for translational research, and

be offered the opportunity to submit additional

optional specimens for banking.


Patients will be classified by the following factors: (1)

primary cancer: lung vs breast vs ovarian/fallopian

tube, and (2) planned taxane regimen: paclitaxel vs

docetaxel.

Accrual Goals

The accrual goal is 1050 patients to achieve 1000

eligible patients. When 525 patients have been accrued

to the paclitaxel or docetaxel group, that group will be

closed to further accrual. When 250 lung cancer

patients have been accrued, the lung cancer category

will be closed to further accrual.

Summary Statement


Symptom Control and QOL chapter.


S1904/PILOT

S1904 Pilot


Cluster Randomized Controlled Trial of Patient and Provider Decision

Support to Increase Chemoprevention Informed Choice among Women with

Atypical Hyperplasia or Lobular Carcinoma In Situ - Making Informed

Choices On Incorporating Chemoprevention into Care (MiCHOICE)

Participants:

SWOG, CTSU

Study Chairs:

K Crew, R Kukafka

Statisticians:

G Anderson, K Arnold

Data Coordinator:

M Yee

SCHEMA

Objectives

To compare the frequency of chemoprevention

informed choice at 6 months after registration among

women with atypical hyperplasia (AH) or lobular

carcinoma in situ (LCIS) between the intervention

(RealRisks decision aid/BNAV + standard educational

materials) and control (standard educational materials

alone) arms.

To assess patient chemoprevention knowledge,

chemoprevention intention/decision, perceived breast

cancer risk and worry, accuracy of breast cancer risk

perception, decision conflict and decision regret at

baseline, 6 months, and 12 months in the intervention

and control arms.

R

A

N

D

O

M

I

Z

A

T

I

O

N

*An S1904 Recruitment Center Application must be completed and approved for participation.

Approved Recruitment Centers*

Intervention:

Standard educational materials

+

Implementation of web-based

decision support tools

Control:

Standard educational materials


S1904/PILOT

To compare patient chemoprevention usage,

adherence, and reasons for discontinuation of a

selective estrogen receptor modulator (SERM) or

aromatase inhibitor (AI) annually for up to 5 years

between the intervention and control arms.

To assess shared decision-making about

chemoprevention among patients and healthcare

providers after their 6-month clinic visit in the

intervention and control arms.

To assess the implementation of the decision support

tools, RealRisks and BNAV, into clinic workflow, and

to better understand barriers and facilitators to

chemoprevention usage by conducting

telephone/video-conference interviews of healthcare

providers and high-risk women with AH or LCIS

assigned to the active intervention.

Patient Population

Patients must have histologically confirmed AH or

LCIS documented by breast pathology report at any

time in the past. Patients with borderline breast lesions

and pleomorphic LCIS are also eligible. Patients must

not have a history of invasive breast cancer or ductal

carcinoma in situ.

Patients must not have prior or current use of SERMs

or AIs. Patients must not be currently taking hormone

replacement therapy.

Patients must be women 35 to 74 years of age without

a history of bilateral mastectomy or breast implants.

Both pre/perimenopausal and postmenopausal women

are eligible. Patients must not be pregnant or lactating.

Premenopausal patients must not have a history of

thromboembolism.

Patients must be able to read and write in English or

Spanish. Patients must be able to access the internet,

receive email or text messages, and be able to access

the patient portal for their Recruitment Center.


Recruitment Centers will be randomly assigned to

control or intervention with stratification by the

following factors: (1) eligible patient volume: ≤ 100

vs > 100 patients with a diagnosis of AH or LCIS per

year; and (2) type of component: Minority/

Underserved-NCORP vs. non-Minority/Underserved-

NCORP or NCTN.

Accrual Goals

A total of 415 patients will be accrued to achieve 374

eligible patients.

Summary Statement


Prevention and Epidemiology chapter.

POSITIVE Progress

Inside this issue

POSITIVE World Map 2

POSITIVE Facts 3

Message from the North American Trial Chair 4

Europa Donna Serbia in Uzice 4

Central Trial Coordination and Data Management 5

Patient Voices 6

Challenges & Initiatives 8

Funding 9

Publications & Presentations 11

The POSITIVE Study Awareness video has spread around the world!

The International Breast Cancer Study Group, with the collaboration and finan-

cial support of the young patient group of Southern Switzerland “Anna dai Ca-

pelli Corti”, has produced a video to raise awareness among the scientific and

patient communities about the availability of the POSITIVE Study and to sensi-

tize health providers about the aspects unique to young patients with breast

cancer such as fertility and pregnancy.

In this moving video, two young breast cancer survivors talk about their experi-

ence with breast cancer before completing their families. Dr. Olivia Pagani and

Dr. Fedro Peccatori, breast cancer experts and POSITIVE Study scientific co-

chairs, explain the rationale and design of this study and Dr. Gabriella Bianchi,

psycho-oncologist, describes the psychological component emphasizing health

providers’ challenges while treating young patients with breast cancer.

The video is available on the European School of Oncology (ESO) YouTube

channel with English, German, French, Serbian, Japanese and Korean subtitles.

https://youtu.be/rIPkvmQS_3g

Posted on the websites and

social networks of IBCSG, the

Breast International Group

(BIG), Europa Donna, Pink Rib-

bon and several cooperative

research Groups and participat-

ing Centers, the video has

spread around the world.

July 2018 Volume 1, Issue 2

IBCSG Contact Details

Effingerstrasse 40

CH-3008 Bern

Switzerland

Monica Ruggeri

Head of Program for Young Patients

Phone +41 (0)31 511 94 01

Fax +41 (0)31 389 93 92

[email protected]

https://youtu.be/rIPkvmQS_3g

mailto:[email protected]

2

The POSITIVE World Map

As of 30 June 2018, the trial has been activated in 185 Cen-

ters in 20 countries and many BIG groups (Switzerland/

SAKK, Australia, Italy, Belgium, Spain/SOLTI/GEICAM,

Greece/HORG, Slovenia, USA/Alliance, Canada/CCTG,

Japan/JBCRG, Portugal/SOLTI, Netherlands/BOOG, Hun-

gary, Ireland/CTI, Norway/NBCG, South Korea, Serbia,

Israel, Austria/ABCSG and France). Currently the accrual is

262 patients overall in the main trial and 138 patients in

the Psycho-Oncological Companion Study.

185 participating oncology Centers in 20 countries around the world!

USA/Canada

Alliance/CCTG

(93/7)

Australia (1)

Asia and middle-esat Japan/JBCRG (16) South Korea (2) Israel (1)

Europe Spain/SOLTI-GEICAM (15) Italy (14) Switzerland/SAKK (13) Belgium (5) Ireland/CTI (5) Austria/ABCSG (4) France (3) Norway/NBCG (1) Netherlands/BOOG (1) Slovenia (1) Portugal/SOLTI (1) Greece/HORG (1) Serbia (1) Hungary (on IRB)

(Number of participating Centers)

POSITIVE Facts

3

Participation as of 30 June 2018

Continents 4

Countries 20

Centers 185

Trial Progress as of 30 June 2018

Accrual (target: 500 patients)

Patients enrolled in the main trial

Patients enrolled in the Psycho-oncological

Companion Study

262

138

Number of patients who have become pregnant 81

Number of babies born 34

Patients withdrawn but providing recurrence

status

6

Patients withdrawn, no further participation 10

Number of patients lost to follow-up 0

An enrolled woman may need at least 1.5 years from en-

rollment to have a baby. Among the 81 patients enrolled

prior to December 2016 who have at least 1.5 years of fol-

low-up by June 2018, 43 patients have become pregnant

and 27 births occurred.

Top Ten Recruiting Countries

Italy 49

USA 48

Spain 37

Switzerland 24

Japan 23

Belgium 17

Canada 13

Netherlands 9

Norway 8

Slovenia 6

https://www.google.ch/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjVsa38t-bWAhXJa1AKHVQFAM0QjRwIBw&url=https%3A%2F%2Fwww.udacity.com%2Fcourses%2Fdata-analytics&psig=AOvVaw2viZ0eoTRADGrfVUxcA4dr&ust=1507737980896897

Message from the North American Trial Chair By Ann Partridge, Dana Farber Cancer Institute, Boston, USA

Fertility and the

safety of preg-

nancy after a

breast cancer

diagnosis are

commonly

raised concerns

among young

women with

recently diag-

nosed breast

cancer, young

breast cancer

survivors and their loved ones. As women are hav-

ing children later in life, there are more women fac-

ing breast cancer who have not yet completed their

families. Available data supports the safety of preg-

nancy after breast cancer in general - that women

who go on to have a baby after breast cancer treat-

ment appear to do just as well as women who

don’t. However, for women who have hormone

sensitive breast cancer, recommended hormonal

therapy takes several years during which pregnan-

cy is contraindicated and these women may be

anxious to move on and have children, as well as

face increasing age-based fertility issues.

Recognizing this dilemma, we, the researchers of

the POSITIVE Study, are assessing the effective-

ness and safety of pausing adjuvant endocrine ther-

apy to allow women to bear children and then get

back on therapy to complete a full course. The

study takes a very patient-centered approach and

supports women to try to have a pregnancy earlier

than they otherwise might have after breast can-

cer, and yet guides them to still get the same total

duration of endocrine therapy. This study tests

whether this is a strategy that works for these

women and whether they do just as well as women

who do not take a break for pregnancy. POSITIVE

is currently the only prospective study on this burn-

ing topic; the North American ALLIANCE for Clini-

cal Trials in Oncology is on board with about 100

participating Centers in the US and Canada.

On May 23rd, Europa Donna Serbia organized a meeting in Uzice, a city located in Western Serbia, with one topic: “Is pregnancy safe in breast cancer survivors?” First, we had a meeting with oncolo-gists and gynecologists from Uzice Clinical Center, presenting recently published data on pregnancy and risk from breast cancer relapse. This was an excellent occasion to share our experience from the Institute for Oncology and Radiology of Ser-bia, where 27 breast cancer survivors had 34 preg-nancies with 32 live births. During presentation and discussion we also promoted the POSITIVE

study, which is only conducted at our Institute here in Serbia, addressing the study objective and end points. The same day, we had a meeting with members of the local patient society “Jefimija”, which brings together women with breast cancer. We were talking about breast cancer in young women, and all the challenges it brings to them.

Continued on page 5

Europa Donna Serbia in Uzice By Snezana Susnjar, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia

4

“The study takes a very patient-centered approach and supports women to try to have a pregnancy earlier than they otherwise might have after breast cancer.“

5

It’s been my distinct pleasure and honor to work on

this unique trial for the last three years. The spirit of

this trial, and dedication and commitment from 20

countries is commendable, though it comes with

continuous effort and intense follow up with many

Centers all over the world. It’s been interesting to

learn the different requirements, working style and

logistics of each country.

The nature of the research which we are

investigating in this clinical trial makes data

management challenging. Clinical data management

(CDM) is a phase of clinical research, ideally resulting

in solid, reliable, clean data with high quality in order

for the statistical analysis to be accurate. The objective of

the CDM process is to assure collection, integration

and availability of high quality data. No two patients

will have the same experience on the trial. There

could be many scenarios as every patient is different.

How do you create a database to cover all situations

and how do you accommodate different answers for

those scenarios? After much planning, we created a

database which supports all different kinds of real life

answers. We have learned so much and we have

strived for continuous

improvement to have

clean, accurate and

consistent data. To

achieve this accuracy

and consistency in

every task and to

provide the best

support to our

participating Centers,

we have created

several resources/tools

for our Centers and continuously follow up with them

to share updates and important points regarding the

trial.

We are highly committed to implement whatever it

takes for the success of the trial which will change

lives of the many young breast cancer survivors who

desire a baby.

Central Trial Coordination and Data Management By Poonam Jani, POSITIVE Trial Coordinator & Data Manager, Amherst NY, USA

IBCSG Data Management Center, Amherst NY, USA

Continued from page 4

They had an opportunity to share with us their personal stories, and issues they had to face at the time they were diagnosed, especially the issue of pregnancy after early breast cancer treatment.This meeting showed that all of us dealing with breast cancer, including physicians, psychologists, nurses, and patients themselves, are very much interested in this topic. We are still burdened with many prejudices regarding pregnancy and breast cancer, and we are concerned about the outcome of the disease.

Patient Voices

Sarah Bridgeport, USA Sarah Murray of Bridgeport, Connecticut, is the first U.S. woman in the study to have had a baby. She was only 29 and planning her wedding when her breast cancer was found in 2013. “We had just set the date when I got diagnosed, the same week. So obviously, children were on our minds,” she said. Wor-ries about triggering a recurrence if she got pregnant “did weigh on me quite a bit,” she said, but “I didn’t want the fear to have power over a decision that would bring so much joy.” To see the full interview in the AP NEWS https://apnews.com/cc793b11257a46cd8c13b623efec3a0f/Study-finds-pregnancy-seems-safe-for-breast-cancer-survivors

6 Sarah with her husband Tom and their son Owen

https://apnews.com/cc793b11257a46cd8c13b623efec3a0f/Study-finds-pregnancy-seems-safe-for-breast-cancer-survivors

https://apnews.com/cc793b11257a46cd8c13b623efec3a0f/Study-finds-pregnancy-seems-safe-for-breast-cancer-survivors

Sabrina Kehrsatz, Switzerland “Our daughter Sophia Alina born on 4 May 2017, is a little gift of nature and a sunshine.

She enriches our lives and shares her most beau-tiful smile every day.“

7

Some of the babies born within the POSITIVE Trial!

Monique Baden, Switzerland

“We are tremendously happy to have welcomed our healthy baby daughter in September, to this world. She is a little miracle! Her third name is therefore Mira - the miracle.“

8

On Sunday June 10, 2018, for the second time, the IBCSG Pink Ladies joined by their families and friends, took part in one of the main annual women's sports event in the Switzerland-Schweizer Frauen-lauf Bern 2018. Since last year, the IBCSG Pink Ladies group has grown and our participa-tion in the 5 km walk to sup-port young women with breast cancer was even more success-ful.

This year, IBCSG was invited and honored to be the official partner of the event. Through-

out the day we had an exhibi-tion stand and thanks to the Bra-Pong game we were able to educate many participants about our research Program for Young Patient (PYP). We were impressed to see so many people queuing to play and we greatly enjoyed talking with them about our research pro-jects. It was a wonderful day and we are grateful to all IBCSG Pink Ladies for being part of this initiative. THANKS so much everyone for your sup-port and motivation!

The IBCSG Pink Ladies for young patients with breast cancer!

Challenges & Initiatives

9

Funding

For the fourth consecutive year IBCSG was the beneficiary of the PINK RIBBON Golf Tour 2018. We are honoured and cannot thank enough Ni-cole Zindel, founder of Pink Ribbon Switzerland, and her team for their generous support. “With the Pink Ribbon Golf Tour we have been supporting the POSITIVE Study of the Interna-tional Breast Cancer Study Group for four years and are proud to be able to make a small contri-bution to this important study.” Nicole said. “Also this year a young mother, who had her ba-by within the POSITIVE Study, attended the final tournament in Winterberg. She told her emo-tional story and moved many participants to tears. I am a mother of two children myself and can imagine how bad it must be for patients if they have to bury their desire to have a baby af-ter the devastating diagnosis of breast cancer.

That is why it is so important to help these young patients and we will continue to support the valuable work of IBCSG with the Pink Golf Tour 2019”.

From the right: Nicole Zindel (Pink Ribbon), Cornelia Leo (Head of Breast Center, IBZ Baden), Monique with Mareike and Monica Ruggeri (IBCSG PYP).

10

A huge THANK YOU to all our supporters who made the POSITIVE Trial possible for

the many young patients with breast cancer who wish to have a baby.

The POSITIVE supporters:

Breast International Group (BIG) with Baillet Latour Fund, Belgium Frontier Science & Technology Research Foundation, Southern Switzerland (FSE) Pink Ribbon, Switzerland and Norway Estée Lauder, Switzerland Swiss Cancer League, Switzerland San Salvatore Foundation, Switzerland Swiss Cancer Research Group (SAKK), Switzerland Clinical Cancer Research Foundation of Eastern Switzerland (OSKK) Rising Tide Foundation, Switzerland Piajoh Fondazione di Famiglia, Switzerland Gruppo Giovani Pazienti “Anna dai Capelli Corti“, Ticino, Switzerland Dutch Cancer Society, Netherlands Norwegian Breast Cancer Society, Norway Division of Cancer Prevention of the United States National Cancer Institute, USA Gateway for Cancer Research, USA Breast Cancer Research Foundation (BCRF), USA ELGC K.K., Tokyo, Japan Pink Ring, Tokyo, Japan IBCSG is looking for new supporters to establish a consortium of funders who can ensure the completion of this crucial academic study. All for one, one for all is our motto!

In June 2018, two POSITIVE Trial posters were presented at the ASCO Annual Meeting in Chicago:

The Trial-in-Progress poster Evaluating outcomes after interrupting endocrine therapy (ET) for

premenopausal women with endocrine responsive (ER+) early breast cancer (BC) who desire pregnancy .

Authors: A Partridge, O Pagani, HA Azim Jr, F Peccatori, M Ruggeri, M Regan, R Gelber, Z Sun for the

POSITIVE Steering Committee - International Breast Cancer Study Group.

The methodology poster Estimation of Historical Control Rate for a Single Arm De-escalation Study –

Application to the POSITIVE Trial.

Authors: Z Sun, O Pagani, A Partridge, HA Azim Jr, F Peccatori, M Ruggeri, M Colleoni, R Gelber, M Regan

for International Breast Cancer Study Group.

Publications & Presentations

From the right: Meredith Regan and Richard Gelber, IBCSG Statistical Center, and Poonam Jani, IBCSG Data Management Center

Zhuoxin Sun, POSITIVE Study biostatistician, IBCSG Statistical Center

11

A011401 November 2019

Template Version Date: September 24, 2013

Alliance Study A011401 – Randomized Phase III Trial Evaluating the Role of Weight Loss in Adjuvant Treatment of Overweight and Obese Women with Early Breast Cancer

Data as of 9/17/2019

Committee: Breast Study Statisticians: Karla Ballman, Ph.D. Study Chair: Jennifer Ligibel, MD Linda McCall, M.S. 1.0 OBJECTIVES

Primary To compare the effect of a supervised weight loss intervention plus health education materials versus health education materials alone upon invasive disease free survival (iDFS) in overweight (BMI 27-29.9 kg/m2) and obese (BMI ≥30kg/m2) women diagnosed with HER-2 negative, stage II and III breast cancer.

Secondary

1) To determine the relationship between changes in weight and iDFS, and to explore interaction between the level of clinical benefit from weight loss and the intervention.

2) To evaluate the effect of a supervised weight loss intervention upon:

a) Overall survival b) Distant disease free survival c) Weight d) Body composition (as measured by waist and hip circumference) e) Insulin Resistance Syndrome associated conditions – diabetes, hospitalization for

CV disease

3) To determine the impact of a supervised weight loss intervention on IDFS within subgroups of women with 1) hormone receptor positive breast cancer and 2) hormone receptor negative breast cancer.

4) To determine the impact of a supervised weight loss intervention on IDFS within subgroups of 1) premenopausal women and 2) post-menopausal women.

2.0 CURRENT SCHEMA

REG

ISTR

ATI

ON

Completion of baseline measures,

fasting glucose and blood draws for specimen submission

RA

ND

OM

IZA

TIO

N ARM 1

2 Year Health Education Intervention ARM 2 2 Year Health Education Intervention + Supervised Weight Loss Intervention

3.0 ELIGIBILITY CRITERIA

Disease



Subjects must have histologically confirmed invasive breast cancer and registration must occur within 12 months after the first histologic diagnosis of invasive breast cancer.

A core biopsy interpreted as invasive cancer meets this criterion; if no core biopsy is performed, the date of first histologic diagnosis will be the date of first surgical procedure that identifies invasive cancer (biopsy, lumpectomy, or mastectomy).

Neoadjuvant subjects should have no evidence of clinical T4 disease prior to chemotherapy and surgery. See eligible cTNM classifications below.

Bilateral breast carcinoma is allowed provided diagnoses are synchronous – that is, within 3 months of one another – and at least one of the two breast carcinomas meet the eligibility criteria and neither violates the eligibility criteria.

Her-2 negative, defined as:

ISH ratio of < 2.0 (if performed)

IHC staining of 0-2+ (if performed)

Deemed to not be a candidate for Her-2 directed therapy.

Eligible TNM Stages include:

ER and PR negative (defined as <1% staining for ER and PR by IHC):

T2 or T3 N0, T0-3N1-3

ER and/or PR positive (defined as > 1% staining for ER and/or PR on IHC):

T0-3N1-3 or T3N0

The eligibility of neo_adjuvant subjects is assessed on the basis of cTNM. The same eligible TNM combinations apply

No History of invasive breast cancer in 5 years prior to study registration other than the current diagnosis (prior DCIS at any time is acceptable).

Patients must have mhad a bilateral mammogram within 12 months prior to registration, unless the initial surgery was a total mastectomy, in which case only a mammogram of the remaining breast is required. (Subjects with bilateral total mastectomies do not require imaging).

Investigations, including chest X-ray or CT chest, bone scan (with radiographs of suspicious areas) and abdominal ultrasound or liver scan or CT abdomen have been performed between the first histologic diagnosis and the time of registration as detailed below.

Chest X-Ray, 2 view (or Chest CT, or PET/CT) is mandatory

Bone scans (with x-rays of abnormal areas) are required only if ALT, AST or Alkaline Phosphatase is elevated or if there are signs or symptoms of metastatic disease

Abdominal imaging is required only if ALT, AST or Alkaline Phosphatase is elevated or if there are signs of symptoms of metastatic disease

Prior Treatment

All adjuvant or neoadjuvant chemotherapy (at the discretion of the treating physician) and surgery completed at least 21 days prior to registration.



4.0 TREATMENT SCHEDULE

The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report). 5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors This is a Phase III randomized controlled trial of weight loss interventions in overweight and obese women with early stage breast cancer that consists of two arms: a telephone-based intervention group (Arm 2) and a health education control group (Arm 1). Patients will be randomized 1:1 within stratification factors: menopausal status (premenopausal vs. postmenopausal), hormone receptor status of the tumor (ER and/or PR positive vs. ER and PR negative), and race/ethnicity (African American vs. Hispanic vs. Other).

5.2 Primary Endpoint

To compare the effect of a supervised weight loss intervention plus health education materials versus health education materials alone upon invasive disease free survival (iDFS) in overweight (BMI 27-29.9 kg/m2) and obese (BMI ≥30kg/m2) women diagnosed with HER-2 negative, stage II and III breast cancer.

5.3 Target Accrual The target accrual for this study is 3136 patients over 4 years using a 1:1 randomization. The target accrual rate is 65 patients per month.

6.0 CURRENT ACCRUAL

Study Activation Date 08/29/2016 Target Accrual (n) 3136 Registered (n) 2433 Randomized (n) 2318 Expected Accrual Rate 65/month Accrual Rate – Since activation 63/month Accrual Rate – Past 6 months 62/month Accrual Rate – Past 12 months 64/month Projected closure date 10/09/2020



0729 61

59 5255

63 49 49 55 9379

7277

6766

75 5981

63

8463

7980 61

7369

4980 60

63 6753

65 64

59 38

Aug16 Nov16 Feb17 May17 Aug17 Nov17 Feb18 May18 Aug18 Nov18 Feb19 May19 Aug19

Month

0

500

1000

1500

2000

2500

3000To

tal N

umbe

r of P

atien

tsExpected Accrual 3136 PatientsActual Accrual

A011401 Cumulative Accrual: Actual Versus ExpectedNumbers on the Accrual Line are M onthly Accrual

7.0 CURRENT STUDY STATUS

This study opened on 8/29/2016. As of September 17, 2019, 2433 patients have been registered and 2318 patients have been randomized.

8.0 PATIENT CHARACTERISTICS

Table 8a. Demographics 1

(N=1163) 2

(N=1155) Total

(N=2318) Age N 1163 1155 2318 Mean (SD) 53.3 (10.6) 53.4 (10.4) 53.3 (10.5) Median 53.0 53.0 53.0 Q1, Q3 46.0, 61.0 46.0, 61.0 46.0, 61.0 Range (22.0-82.0) (25.0-82.0) (22.0-82.0) Age Categories < 50 465 (40.0%) 467 (40.4%) 932 (40.2%) 50-64 505 (43.4%) 488 (42.3%) 993 (42.8%) 65+ 193 (16.6%) 200 (17.3%) 393 (17.0%)



Race White 948 (81.5%) 944 (81.7%) 1892 (81.6%) Black or African American 141 (12.1%) 143 (12.4%) 284 (12.3%) Native Hawaiian or Other Pacific Islander 6 (0.5%) 0 (0.0%) 6 (0.3%) Asian 26 (2.2%) 25 (2.2%) 51 (2.2%) American Indian or Alaska Native 4 (0.3%) 6 (0.5%) 10 (0.4%) Not reported: patient refused or not available 20 (1.7%) 13 (1.1%) 33 (1.4%) Unknown: Patient unsure 18 (1.5%) 24 (2.1%) 42 (1.8%) Ethnicity Hispanic or Latino 77 (6.6%) 66 (5.7%) 143 (6.2%) Not Hispanic or Latino 1070 (92.0%) 1074 (93.0%) 2144 (92.5%) Not Reported: Patient refused or not available

7 (0.6%) 6 (0.5%) 13 (0.6%)

Unknown: Patient unsure 9 (0.8%) 9 (0.8%) 18 (0.8%) Gender Female 1163 (100.0%) 1155 (100.0%) 2318 (100.0%) BMI N 1142 1127 2269 Mean (SD) 34.5 (5.8) 34.5 (5.9) 34.5 (5.9) Median 33.3 33.2 33.3 Q1, Q3 30.1, 37.4 30.1, 37.4 30.1, 37.4 Range (22.7-66.4) (26.6-69.1) (22.7-69.1) BMI Categories Overweight-ineligible (BMI 25 – 26.9 kg/m2) 12 (1.1%) 5 (0.4%) 17 (0.7%) Overweight (BMI 27 – 29.9 kg/m2) 261 (22.9%) 263 (23.3%) 524 (23.1%) Obese (BMI >30 kg/m2) 869 (76.1%) 859 (76.2%) 1728 (76.2%) Unknown 21 (1.8%) 28 (2.4%) 49 (2.1%) Combined Income 120000 or above 271 (27.9%) 261 (26.4%) 532 (27.2%) 20000 to 49999 199 (20.5%) 218 (22.1%) 417 (21.3%) 50000 to 89999 261 (26.9%) 277 (28.0%) 538 (27.5%) 90000 to 119999 168 (17.3%) 157 (15.9%) 325 (16.6%) Less than 20000 71 (7.3%) 75 (7.6%) 146 (7.5%) Unknown 193 (16.6%) 167 (14.5%) 360 (15.5%) Highest Level of Education Completed College graduate 351 (30.8%) 346 (30.8%) 697 (30.8%) Graduate degree 210 (18.4%) 248 (22.1%) 458 (20.2%) High school graduate or GED 143 (12.6%) 125 (11.1%) 268 (11.8%) Less than 9 years of school 10 (0.9%) 6 (0.5%) 16 (0.7%)



Post graduate education but no higher degree 75 (6.6%) 85 (7.6%) 160 (7.1%) Some college or technical school 333 (29.2%) 299 (26.6%) 632 (27.9%) Some high school (9-11 years) 17 (1.5%) 15 (1.3%) 32 (1.4%) Unknown 24 (2.1%) 31 (2.7%) 55 (2.4%) Region Mid-West 366 (33.7%) 377 (34.9%) 743 (34.3%) North East 242 (22.3%) 253 (23.4%) 495 (22.8%) South 292 (26.9%) 265 (24.5%) 557 (25.7%) West 186 (17.1%) 186 (17.2%) 372 (17.2%) Unknown 77 (6.6%) 74 (6.4%) 151 (6.5%) *BMI comes from the On-Study form; new patients will not have this entered yet Table 8b. Stratification Factors

1 (N=1163)

2 (N=1155)

Total (N=2318)

Menopausal Status Premenopausal 478 (41.1%) 483 (41.8%) 961 (41.5%) Postmenopausal 685 (58.9%) 672 (58.2%) 1357 (58.5%) Hormone Receptor Status ER and/or PgR positive 917 (78.8%) 912 (79.0%) 1829 (78.9%) ER and/or PgR negative 246 (21.2%) 243 (21.0%) 489 (21.1%) Race/Ethnicity African American 140 (12.0%) 141 (12.2%) 281 (12.1%) Hispanic or Latino 73 (6.3%) 67 (5.8%) 140 (6.0%) Other (including white/Asian/etc.) 950 (81.7%) 947 (82.0%) 1897 (81.8%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary 1878 patients (Arm 1: 938, Arm 2: 940) are evaluable for adverse events. One patient on arm 2 experienced a grade 4 adverse event [depression, not related] and two patients on arm 1 experienced a grade 4 adverse event [hypertension, not related; sepsis, not related]. Another patient had a vasovagal reaction [grade 3, definitely related]. Four patients on arm 1 have had a grade 5 adverse events [3 Death NOS, not related; Hemolytic uremic syndrome, not related].

Summary of Grade 3+ Adverse Events Regardless of Attribution

Number of Evaluable Patients: Arm 1=938 Arm 2=940

Patients with a maximum: Arm n (%) Total





Patients with a maximum: Arm n (%)

Grade 3 Event 1 30 (9.0%)

2 40 (11.2%)


2 1 (0.3%)


2 0 (0.0%)

Hematologic Adverse Events


2 3 (0.8%)


2 0 (0.0%)


2 0 (0.0%)

Non-Hematologic Adverse Events


2 38 (10.6%)


2 1 (0.3%)


2 0 (0.0%)

Note: Summaries are based on available patient data

Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event

Regardless of Attribution Number of Evaluable Patients:

Arm 1=938 Arm 2=940 Grade of AdverseEvent

Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)

Hematologic Adverse Events Blood/Bone Marrow

Neutrophils/granulocytes (ANC/AGC)

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 3 ( 1%) 0 ( 0%) 0 ( 0%)







White blood cell decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events **

Breast infection 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 0 ( 0%) 0 ( 0%) Dyspareunia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Eye disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Hemolytic uremic syndrome 1 0 ( 0%) 0 ( 0%) 1 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Joint range of motion decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Musculoskeletal, conn tissue - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 5 ( 1%) 0 ( 0%) 0 ( 0%) Myocardial infarction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Premature menopause 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Renal calculi 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Surgical and medical proced - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary tract obstruction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)







Vasovagal reaction 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Wound complication 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Auditory/Hearing Hearing loss 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Cardiovascular Hypertension 1 3 ( 1%) 1 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) Hypotension 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Constitutional Symptoms Fatigue (asthenia, lethargy, malaise)

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Fever 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Obesity 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 0 ( 0%) 0 ( 0%)

Death Death not associated with CTCAE term

1 0 ( 0%) 0 ( 0%) 3 ( 1%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Dermatology/Skin

Wound complication, non-infectious

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Endocrine

Hot flashes/flushes 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Gastrointestinal Dehydration 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Hepatic







ALT, SGPT 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) AST, SGOT 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Cholecystitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Infection/Febrile Neutropenia Infection w/ normal or Grade 1/2 ANC

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection with unknown ANC 1 2 ( 1%) 1 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Metabolic/Laboratory Glucose, serum-high (hyperglycemia)

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Musculoskeletal

Exostosis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Fracture 1 4 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Seroma 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Soft tissue necrosis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Neurology Cognitive disturbance 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Dizziness 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) Mood alteration 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) Neuropathy: motor 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Neuropathy: sensory 1 0 ( 0%) 0 ( 0%) 0 ( 0%)







2 1 ( 0%) 0 ( 0%) 0 ( 0%) Syncope (fainting) 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%)

Ocular/Visular Cataract 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Pain Pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 6 ( 2%) 0 ( 0%) 0 ( 0%) Vaginal dryness 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Pulmonary Cough 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Dyspnea (shortness of breath) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%)

Sexual/Reproductive Function Irregular menses (change from baseline)

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) 10.0 IMBEDDED CORRELATIVES

Serum and plasma markers is mandatory for all patients who consent and enroll on A011401. Insulin:

To evaluate whether fasting insulin at baseline predicts benefit of the intervention upon iDFS (Primary) and OS (Secondary).

Glucose: To evaluate whether fasting glucose at baseline predicts benefit of the intervention upon iDFS and OS.

Adipokines: To evaluate whether levels of leptin at baseline predict benefit of the intervention upon iDFS and OS.

Markers of systemic inflammation: To evaluate whether levels of hsCRP at baseline predicts benefit of the intervention upon iDFS and OS.



Tissue-based and genomic biomarkers (A011401-ST1) must be offered to all patients enrolled on Alliance A011401 (although patients may opt not to participate). Insulin Receptor (IR), IGF-1R, Signaling Pathway Activation (tumor):

To evaluate whether expression of IR in tumor tissue predicts benefit of the intervention on iDFS and OS.

To explore the interaction between expression of insulin receptor on tumor tissue and activation of PI3K and ras pathways as assessed using IRS-1, P-AKT, P-4E-BP1 and pERK.

To explore the interaction between expression of insulin receptor on tumor tissue and TUNEL, Ki67.

To evaluate the relationship between expression of IRS-1, P-AKT, P-4E-BP1 and P-ERK as well as Ki67 and TUNEL in tumor tissue and the impact of the intervention on iDFS and OS.

To explore whether IR expression influences any relationship of insulin at baseline (or change from baseline at 6 and 24 months) with the effect of the intervention in iDFS.

Crown-Like Structures of the Breast (CLS-B):

To evaluate whether the presence of CLS-B in benign breast tissue adjacent to tumors predicts benefit of the intervention on iDFS and OS.

To evaluate the relationship between the presence of CLS-Bs in benign breast tissue adjacent to tumors and baseline BMI

Genomic/Gene Expression Profile Predictive of Intervention Benefit (tumor):

To identify a genetic signature associated with intervention benefit on iDFS and OS by performing comprehensive genomic/gene expression profiling of tumor material

Whole blood banking for future use: Participants will also be asked for consent to obtain a sample of whole blood at baseline, and 6 and 24 months after enrollment for isolation of DNA for future assessments of methylation, telomere length and activity and germline profiling. These samples will be collected and stored only for patients who opt in for participation of ST1 and for future use (see model consent question #s 1 and 2). The study team will seek future NCI approval for any use of the banked whole blood samples.

Health behaviors and patient reported outcomes substudy A011401-HO1 is mandatory for the first 514 patients who consent and enroll on A011401.

To evaluate the impact of a supervised weight loss intervention upon: Minutes of weekly moderate or vigorous physical activity (as measured by the Actigraph accelerometer). Patient-reported physical functioning (as measured by the PROMIS 29 Profile v2.0).

CCTG SPRING MEETING / GCEC CONGRÈS DU PRINTEMPS 2019 MA.39 -- Page 1 CONFIDENTIAL

TAILOR RT: A RANDOMIZED TRIAL OF REGIONAL RADIOTHERAPY IN BIOMARKER LOW RISK NODE POSITIVE BREAST CANCER

MA.39

Study Chair: Timothy Whelan Alliance Co-Chairs Jennifer Bellon Alice Ho NRG Co-Chair Julia White SWOG Co-Chair Reshma Jagsi ECOG Co-Chair Richard Zellars Trial Committee: Tanya Berrang Iwa Kong Eileen Rakovitch Valerie Théberge Karen Gelmon Stephen Chia Senior Investigator: Wendy Parulekar Biostatistician: Bingshu Chen Correlative Science Coordinator: Anita Bane Surgical Coordinator: Jean-Francois Boileau Quality of Life Coordinator: Julie Lemieux Health Economics Coordinator: Nicole Mittmann Study Coordinator: Alexander Montenegro Report generated: March 4, 2019 Objectives Primary: To compare the breast cancer recurrence-free interval (BCRFI) between patients that received regional radiotherapy (RT) or not, defined as time from randomization to time of invasive recurrent disease in the ipsilateral chest wall, breast, regional nodes, distant sites or death due to BC. Secondary: To compare the following between patients that received regional RT or not: • Locoregional recurrence-free interval (RFI)

• Distant RFI • Invasive disease-free survival (DFS) • Breast cancer mortality • Overall survival (OS)

• Toxicity • Cost effectiveness • Patient reported outcomes (PROs) and quality of life

(QOL) • Arm volume and mobility measurements Patient Population The study population consists of patients with newly diagnosed biomarker low risk node positive breast cancer with no evidence of metastases that have been treated by mastectomy or breast conserving surgery (BCS). Stratification • Surgery type (mastectomy or BCS) • Axillary dissection (yes or no) • Lymphovascular invasion (present or absent) • Adjuvant chemotherapy (yes or no) • Oncotype DX score (0-10 or 11-17) Summary This is an international multi-centre, randomized, non-inferiority phase III trial evaluating regional radiotherapy (RT) in patients with ER +ve biomarker low risk breast cancer (defined as Oncotype DX recurrence score < 18) and limited nodal disease that have had a mastectomy or breast-conserving surgery (BCS) and will receive endocrine therapy for 5 years. At this time 17 sites are active in Canada and 72 in the U.S.

Schema

R A N D O M I Z E

ARM 1: No Regional RT No RT following mastectomy, OR whole breast irradiation (WBI) following BSC

Follow-up at 6 months, then annually after randomization for recurrence and toxicity

ARM 2: Regional RT RT to the chestwall and regional nodes following mastectomy, OR

WBI plus RT to the regional nodes following BSC

Planned Sample Size: 2140 patients

Data for this trial is entered at the centre by Electronic Data Capture.

The following tables include data from all folders regardless of whether or not the folder is "completed" (i.e. Folder Completion date has been entered). The percentage of folders that are "completed" for this trial is 90.8%.


CCTG ACCRUAL CENTRE REGISTRATIONS RANDOMIZATIONS ETHICS CENTRE TO DATE TO DATE RECEIVED ACTIVATED (yy-mm-dd) (yy-mm-dd) CABN 0 0 18-09-17 18-10-29 CAGB 0 0 18-09-06 18-10-11 CAGH 5 2 18-09-28 18-10-03 CAGQ 5 5 18-08-01 18-08-13 CAHJ 4 3 18-08-14 18-10-25 CAHU 0 0 18-10-31 19-01-22 CAKO 2 0 18-08-21 18-10-09 CALC 0 0 18-08-16 18-11-01 CALM 9 4 18-06-28 18-07-12 CAMN 6 3 18-10-05 18-11-07 CAMP 10 4 18-11-08 18-11-19 CANL 4 0 18-08-01 18-09-21 CASA 0 0 18-09-27 18-10-10 CATC 6 4 18-10-02 18-11-12 CATW 1 0 18-12-07 19-01-02 CAVA 4 1 18-09-25 18-11-28 CAVV 7 3 18-09-25 18-10-12 USXU 15 8 TOTAL 78 37

NOTE: For a complete listing of CENTRE codes see www.ctg.queensu.ca/public/centre-codes

ELIGIBILITY STATUS Total patients allocated 37 Baseline Report entered 35 Ineligible 0 (0.0%) Total eligible patients 35

http://www.ctg.queensu.ca/public/centre-codes


CCTG TRIAL MA.39

PATIENT CHARACTERISTICS ARM 1 ARM 2 TOTAL # (%) # (%) # (%) TOTAL 17 (100) 18 (100) 35 (100) AGE AT ALLOCATION 40-49 1 ( 6) 5 ( 28) 6 ( 17) 50-59 5 ( 29) 7 ( 39) 12 ( 34) 60-69 10 ( 59) 3 ( 17) 13 ( 37) >= 70 1 ( 6) 3 ( 17) 4 ( 11) Median age (years) 64.0 54.0 59.0 GENDER Female 17 (100) 18 (100) 35 (100) RACE Asian 2 ( 12) 0 ( 0) 2 ( 6) Black or African American 0 ( 0) 1 ( 6) 1 ( 3) Not Reported 2 ( 12) 2 ( 11) 4 ( 11) White 13 ( 76) 15 ( 83) 28 ( 80) COUNTRY OF RESIDENCE Canada 14 ( 82) 15 ( 83) 29 ( 83) USA 3 ( 18) 3 ( 17) 6 ( 17) ETHNICITY Hispanic or Latino 1 ( 6) 1 ( 6) 2 ( 6) Not Hispanic or Latino 15 ( 88) 16 ( 89) 31 ( 89) Not reported 1 ( 6) 1 ( 6) 2 ( 6) SURGERY TYPE Breast conserving surgery 15 ( 88) 15 ( 83) 30 ( 86) Mastectomy 2 ( 12) 3 ( 17) 5 ( 14) AXILLARY DISSECTION No 13 ( 76) 13 ( 72) 26 ( 74) Yes 4 ( 24) 5 ( 28) 9 ( 26) Number of Positive Nodes 1 13 ( 76) 11 ( 61) 24 ( 69) 2 3 ( 18) 7 ( 39) 10 ( 29) 3 1 ( 6) 0 ( 0) 1 ( 3) LYMPHOVASCULAR INVASION No 8 ( 47) 10 ( 56) 18 ( 51) Yes 9 ( 53) 8 ( 44) 17 ( 49) ADJUVANT CHEMOTHERAPY No 12 ( 71) 13 ( 72) 25 ( 71) Yes 5 ( 29) 5 ( 28) 10 ( 29) PATHOLOGIC T STAGE T1 1 ( 6) 1 ( 6) 2 ( 6) T1b 1 ( 6) 1 ( 6) 2 ( 6) T1c 11 ( 65) 10 ( 56) 21 ( 60) T2 4 ( 24) 6 ( 33) 10 ( 29) PATHOLOGIC N STAGE pN1 4 ( 24) 5 ( 28) 9 ( 26) pN1a 13 ( 76) 13 ( 72) 26 ( 74)

ARM 1 ARM 2 TOTAL # (%) # (%) # (%) TUMOUR LOCATION Axillary tail 0 ( 0) 2 ( 11) 2 ( 6) Central/sub-areolar region 3 ( 18) 1 ( 6) 4 ( 11) Lower-inner quadrant 1 ( 6) 1 ( 6) 2 ( 6) Lower-outer quadrant 1 ( 6) 4 ( 22) 5 ( 14) Upper-inner quadrant 4 ( 24) 0 ( 0) 4 ( 11) Upper-outer quadrant 9 ( 53) 9 ( 50) 18 ( 51) HISTOLOGIC TYPE Invasive ductal carcinoma 10 ( 59) 14 ( 78) 24 ( 69) Invasive lobular carcinoma 1 ( 6) 2 ( 11) 3 ( 9) Invasive mammary carcinoma 2 ( 12) 0 ( 0) 2 ( 6) Invasive mixed carcinoma 2 ( 12) 0 ( 0) 2 ( 6) Other 2 ( 12) 2 ( 11) 4 ( 11) HISTOLOGIC GRADE Grade 1 (Low) 5 ( 29) 2 ( 11) 7 ( 20) Grade 2 (Intermediate) 10 ( 59) 16 ( 89) 26 ( 74) Grade 3 (High) 2 ( 12) 0 ( 0) 2 ( 6) ER STATUS Missing 0 ( 0) 2 ( 11) 2 ( 6) Greater than or equal to 1% 17 (100) 16 ( 89) 33 ( 94) HER2/NEU EXPRESSION BY IMMUNOHISTOCHEMISTRY Missing 1 ( 6) 1 ( 6) 2 ( 6) 1+ 9 ( 53) 11 ( 61) 20 ( 57) 2+ 4 ( 24) 3 ( 17) 7 ( 20) Not Done 3 ( 18) 3 ( 17) 6 ( 17) HER2 STATUS BY FISH Missing 1 ( 6) 3 ( 17) 4 ( 11) Attempted, but inadequate 1 ( 6) 0 ( 0) 1 ( 3) Not Done 7 ( 41) 9 ( 50) 16 ( 46) Not amplified (copy number <4) 1 ( 6) 0 ( 0) 1 ( 3) Not amplified (cep17 ratio <1.8) 7 ( 41) 6 ( 33) 13 ( 37) ONCOTYPE DX 0 - 10 9 ( 53) 9 ( 50) 18 ( 51) 11 - 17 8 ( 47) 9 ( 50) 17 ( 49) NUMBER OF POSITIVE SENTINEL NODES 0 1 ( 6) 0 ( 0) 1 ( 3) 1 10 ( 59) 9 ( 50) 19 ( 54) 2 2 ( 12) 8 ( 44) 10 ( 29) 3 1 ( 6) 0 ( 0) 1 ( 3) PRESENCE OF EXTRANODAL EXTENSION Missing 1 ( 6) 1 ( 6) 2 ( 6) No 10 ( 59) 12 ( 67) 22 ( 63) Yes 6 ( 35) 5 ( 28) 11 ( 31) NUMBER OF AXILLARY DISSECTION POSITIVE LYMPH NODES 0 0 ( 0) 4 ( 22) 4 ( 11) 1 2 ( 12) 1 ( 6) 3 ( 9) 2 1 ( 6) 0 ( 0) 1 ( 3) 3 1 ( 6) 0 ( 0) 1 ( 3)


CCTG TRIAL MA.39

NON-HEMATOLOGIC ADVERSE EVENTS POST BASELINE ADVERSE EVENTS - WORST EVER BY PATIENT

Arm 1 Arm 2 Evaluable patients = 8 Evaluable patients = 9 Grade* Grade* --------------------------------------------------------------------------------------------------------------------------------------- ADVERSE EVENT 1 2 3 4 5 TOTAL(%) %R** 1 2 3 4 5 TOTAL(%) %R** --------------------------------------------------------------------------------------------------------------------------------------- GASTROINTESTINAL DISORDERS Abdominal pain 1 1 ( 13) ( 0) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 6 6 ( 75) ( 50) 5 5 ( 56) ( 56) INJURY, POISONING AND PROCEDURAL COMPLICATIONS Dermatitis radiation 5 1 6 ( 75) ( 75) 2 1 1 4 ( 44) ( 44) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Chest wall pain 1 1 ( 13) ( 0) 1 1 ( 11) ( 11) Joint range of motion decreased 1 1 ( 13) ( 0) NERVOUS SYSTEM DISORDERS Peripheral sensory neuropathy 1 1 ( 13) ( 0) REPRODUCTIVE SYSTEM AND BREAST DISORDERS Breast pain 4 4 ( 50) ( 13) 2 2 4 ( 44) ( 44) Gynecomastia 1 1 ( 11) ( 11) VASCULAR DISORDERS Hot flashes 1 1 ( 11) ( 0) Hypertension 1 1 2 ( 25) ( 0) Lymphedema 2 2 ( 25) ( 13) WORST OVERALL GRADE 3 4 7 ( 88) ( 75) 3 2 1 6 ( 67) ( 67) --------------------------------------------------------------------------------------------------------------------------------------- * Adverse events graded according to CTCAE V5.0 ** Considered by investigator to be 'possibly', 'probably' or 'definitely' related to protocol treatment

OFF PROTOCOL TREATMENT (n = 14)

REASON # (%) Treatment complete 14 ( 100)

DEATHS ON TRIAL (all patients)

CAUSE OF DEATH # Patients Due to this disease 0 Due to protocol treatment 0 Due to non-study treatment 0 Due to secondary primary cancer 0 Due to other cause 0 TOTAL 0

QUALITY OF LIFE SUBMISSIONS Eligible and Form 1 Entered = 35 Patients

Period Expected Received (%) Baseline 31 30 ( 96.8) Last day of RT 14 11 ( 78.6) Month 2 1 1 (100.0)

HEALTH UTILITIES SUBMISSIONS Eligible and Form 1 Entered = 35 Patients

Period Expected Received (%) Baseline 31 29 ( 93.5) Last day of RT 14 11 ( 78.6) Month 2 1 0 ( 0.0)

TUMOUR BANKING SUMMARY N (%) Patients who have consented 37 Unrestricted tissue consent 37 ( 100)

ECOG-ACRIN Cancer Research Group EA1181 Study Progress and Safety Report Spring 2020

Page 1

EA1181 THE COMPASS TRIAL (PATHOLOGIC COMPLETE RESPONSE TO PREOPERATIVE THP TO GUIDE ADJUVANT SYSTEMIC THERAPY FOR PATIENTS WITH STAGE 2-3A HER2+ BREAST CANCER)

Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Nadine Tung Statistician Dr. Fengmin Zhao Data Specialist Michelle Azaroff Phase of Study II Type of Study NA Committee Breast Accrual Objective 1250 Patients Participating Groups ECOG-ACRIN Clinicaltrials.gov Study ID Study Status Open to Accrual Date Activated February 11, 2020 Schema

Purpose of Study The primary clinical objective of this single arm trial is to determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients with HER2-positive breast cancer who achieve pCR (ypT0 ypN0 or ypT0/Tis ypN0) after preoperative therapy with 12 weeks of a taxane, trastuzumab and pertuzumab (THP x 12). RFS is defined as the time from date of surgery until the date of the first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, recurrence of locoregional invasive breast tumor, distant recurrence, and death from any cause. Secondary objectives include evaluation of 3-year invasive disease-free survival(IDFS), distant disease-free survival (DDFS), distant recurrence-free survival (DRFS), recurrence-free interval (RFI) and overall survival (OS) in patients who achieve pCR; 3-year event-free survival (EFS) in all patients; safety and toxicity;

Eligibility: Stage II or IIIA HER2+ Invasive Breast cancer (T2-3, NO-2• cNO are eligible if T size

> 2.0 cm • cN1-2 are eligible if T size is

>1.5 cm• ER+ and ER – are eligible

1. The choice of taxane is up to the treating MD. For patients who develop hypersensitivity to paclitaxel or docetaxel, nab-paclitaxel is permitted.2. Research blood collection: 4 streck tubes (2 for cfDNA and 2 for CTCs).3. Isolated tumor cells (ITCs) or immunohistochemistry (IHC) evidence of cancer in nodes will be classified as “no pCR” (Arm B); IHC of nodes is not required.4. Follow-up: Patients will be followed every 3 months x2 years after surgery, every 6 months until 5 years after surgery and then annually until 15 years after surgery.5. Primary objective is 3y RFS for patients who achieve pCR. Secondary objectives include 3 yr RFS for those without pCR and (for all patients): EFS, iDFS, DDFS, RFI, OS.6. From patients with no pCR7. Research blood collection: 2 streck tubes for CTCs8. From patients with pCR

THP x 4 Cycles1 cycle = 3 weeks

Paclitaxel weekly x12Or

Docetaxel q3 wk x4With

Trastuzumab (H) q3 wk x4

COMPASS Part 1 (EA1181)• Complete 1 yr HP • Radiation and endocrine Rx

(if appropriate)

Preoperative Phase: all patients1

REGISTRATION

Surgery tissue collection6

Follow-up for recurrence and

survival4,5

Pre-treatment blood collection for patients who

consent2

C2D1 blood collection for patients who

consent2

Post-treatment, pre-surgery blood

collection for patients who consent7

S

U

R

G

E

R

Y

Post-surgery blood collection for patients

who consent2,8

No pCR3

pCR(ypT0/Tis ypN0)

Post-HER2 Rx blood collection for patients

who consent2,8

Standard of Care Therapy(eg, AC, T-DM1)

Additional chemotherapy and HER2-targeted therapy per individual MD

discretionPatients may enroll in other studies.

Arm A: pCR (no invasive disease)

Arm B (no-pCR; residual invasive disease)


Page 2

association between ER status with pCR and long-term survival outcomes; association of detection of CTCs at baseline with pCR and RFS. There are also several exploratory objectives about local control and correlative studies. Study Population Women or men who are >= 18 years of age and have histologically confirmed HER2-positive primary invasive breast carcinoma (clinical stage II and IIIa (T2-3/N0-2/M0) at diagnosis), as defined by the 2018 ASCO/CAP HER2 testing guideline focused update and determined by local testing, are eligible for the study. Exclusion criteria include any prior treatment for the current cancer, peripheral neuropathy of any etiology that exceeds grade 1. Summary of Study Design The primary objective of this single arm trial is to evaluate a de-escalation of standard therapy for patients with clinical stages II or IIIa (according to AJCC cancer staging manual anatomic staging table, 8th edition) HER2-positive breast cancer. Given the de-escalation nature of the trial, it will test a non-inferiority hypothesis. EA1181 has a single arm design and applies the precedent established by the single arm APT study in patients with a lower anatomic risk. In EA1181, the null hypothesis is a 3-year RFS rate for patients who achieve pCR with preoperative THP that would be considered unacceptably low given the non-inferiority hypothesis of the study. The alternative hypothesis is a 3-year RFS that would be considered good enough to forgo further chemotherapy. Rejecting the null hypothesis would provide evidence that patients who achieve a pCR with preoperative THP have a clinically acceptable prognosis with continuation of HP therapy and no further postoperative chemotherapy. Based on data from previous trials in similar patient populations and extensive discussions among the study investigators, we concluded that, for the study patients who have stage II or IIIa HER2-positive breast cancer and have achieved pCR after treatment with neoadjuvant THP x 12 weeks, the 3-year RFS will be considered unacceptable if it is 92% or less (null hypothesis), and it will be considered worthwhile if the 3-year RFS is at least 95% (alternative hypothesis). For the alternative hypothesis of 95% 3-year RFS rate, we are referencing the 3-year invasive disease-free survival (IDFS) in the node positive cohort of the APHINITY Trial for the arm that received both trastuzumab and pertuzumab and had a 3-year IDFS of 92%. A single arm trial evaluating a de-escalation of a standard of care would usually be considered a phase II study. A one-sided type I error of 0.025, however, will be used in this trial since the trial is aimed to provide a definitive answer given that its results could potentially change clinical practice if the primary clinical objective is met. With 450 HER2-positive patients with pCR after neoadjuvant therapy and 33 RFS events, the trial would have about 80% power to detect the difference in the failure hazard of 0.0171 vs. 0.0278 (i.e., 3-year RFS 95% vs 92%), assuming exponential distribution of RFS. This corresponds to a hazard ratio of 1.63 for null to alternative with a one-sided type I error rate of 0.025. The sample size/power calculation is based on Wald test for the log failure rate parameter for this design. Assuming 40% of pCR rate among HER2-positive patients and about 10% drop-out rate after registration due to some reason (e.g., rare events of progression of disease that precludes surgery, patients who achieve pCR but do not continue on de-escalation arm), the trial will enroll 1250 HER2-positive patients in about 3 years, based on an average accrual rate of 35 patients per month after study activation. Data about pCR rate and drop-out status will be collected in real time, and the two assumptions will be monitored twice a year via ECOG-ACRIN DSMC. If the observed proportions for pCR and drop-out are not consistent with the assumptions used in the design, the sample size for EA1181 will be adjusted accordingly and analysis will be conducted to explore the reasons (eg, the proportion of ER+ patients and associated pCR rate). It will take 3 years of follow up to achieve the required number of RFS events for the final analysis for the primary objective. There will be two interim harm/futility analyses at about 3.7 and 4.2 years after the enrollment of the first


Page 3

patient to the study, respectively. The final analysis will take place at about 6.5 years (3 years of accrual+ 3 years of follow-up+6 months of data cleaning) after trial activation, all HER2-positive patients who have a pCR after neoadjuvant THP therapy and do not receive any adjuvant chemotherapy will be included in the final analysis for RFS, regardless of its eligibility status. Progress to Date The study concept was approved by ECOG-ACRIN Executive Review Committee and National Cancer Institute (NCI) Breast Cancer Steering Committee (BCSC) on June 28, 2018 and May 1, 2019, respectively. The study protocol was submitted to CTEP on July 3, 2019 and approved on October 24, 2019. CIRB approved the study protocol on December 27, 2019. The study was activated on February 11, 2020. By February 12, 2020 when the report was prepared, no patients had enrolled to the trial yet.

NSABP B-51/RTOG 1304 – July, 2016

Page 1 of 10

NSABP B-51/RTOG 1304

Report Based on Data Through 04/30/2016

A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy

Chestwall and Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT in Patients with Positive Axillary Nodes Before Neoadjuvant Chemotherapy

Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy

Study Chairs: Eleftherios Mamounas, MD, MPH Julia White, MD Radiation Oncology Co-Chairs: Atif Kahn, MD Simona Shaitelman, MD Mylin Torres, MD Frank Vicini, MD Protocol Officer: Thomas Julian, MD Behavioral and Health Outcomes Officer: Patricia Ganz, MD Behavioral and Health Outcomes Co-Officer: Susan McCloskey, MD Protocol Statistician: Hanna Bandos, PhD

Protocol Pathologist: Soonmyung Paik, MD Protocol Physicist: Nilendu Gupta, PhD Protocol Co-Physicists: Allen Li, PhD

Dominic Di Costanzo, MS Activated: August 22, 2013 Status: Accruing


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NSABP PROTOCOL B-51/RTOG 1304 Schema

* Patients will be randomized to one of the following:

• Group 1 − Radiation therapy for Group 1A Whole breast irradiation + boost − No radiation therapy for Group 1B

• Group 2 − Radiation therapy for Group 2A Whole breast irradiation + boost and regional nodal irradiation − Radiation therapy for Group 2B Chest wall and regional nodal irradiation

** All patients will receive additional systemic therapy as planned (i.e., hormonal therapy for patients with hormone receptor-positive breast cancer and trastuzumab or other anti-HER2 therapy for patients with breast cancer that is HER2-positive).

Clinically T1–3, N1 Breast Cancer Documented Positive Axillary Nodes by FNA or by Core Needle Biopsy

Minimum of 12 Weeks of Standard Neoadjuvant Chemotherapy Plus Anti-HER2 Therapy for Patients with HER2-Positive Tumors

Definitive Surgery with Histologic Documentation of Negative Axillary Nodes (Either by Axillary Dissection or by Sentinel Node Biopsy ± Axillary Dissection)

STRATIFICATION • Type of surgery (mastectomy, lumpectomy) • Hormone receptor status (ER-positive and/or PgR-positive; ER- and PgR-negative) • HER2 status (negative, positive) • Adjuvant chemotherapy (yes, no) • pCR in breast (yes, no)

RANDOMIZATION

Group 1 (Groups 1A and 1B)*,** No Regional Nodal XRT

• Group 1A Lumpectomy: No regional nodal XRT with WBI

• Group 1B Mastectomy: No regional nodal XRT and no chest wall XRT

Group 2 (Groups 2A and 2B) *,**

Regional Nodal XRT • Group 2A Lumpectomy: Regional

nodal XRT with WBI • Group 2B Mastectomy: Regional

nodal XRT and chestwall XRT


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• Study description

NSABP B-51/RTOG 1304 is a Phase III, multicenter, randomized post neoadjuvant therapy trial to evaluate whether the addition of chestwall and regional nodal radiation therapy (XRT) after mastectomy or breast and regional nodal XRT after breast conserving surgery will significantly reduce the rate of events for invasive breast cancer recurrence-free interval in patients who present with histologically positive axillary nodes but convert to histologically negative axillary nodes following neoadjuvant chemotherapy. Eligible patients must have clinically T1-3, N1 breast cancer at the time of diagnosis and must have had pathologic confirmation of axillary nodal involvement at presentation (before neoadjuvant therapy) based on either a positive FNA (demonstrating malignant cells) or positive core needle biopsy (demonstrating invasive adenocarcinoma). Patients must have completed a minimum of 12 weeks of standard neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen. Patients with HER2-positive tumors must have received neoadjuvant trastuzumab or other anti-HER2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen), unless medically contraindicated. After patients complete their neoadjuvant chemotherapy, they will have either a lumpectomy or a mastectomy. At the time of definitive surgery, all removed axillary nodes must be histologically free from cancer. Patients are stratified by type of breast surgery, hormone receptor status, HER2 status, adjuvant chemotherapy, and pCR in breast.

• Patient Accrual

This protocol was opened for accrual on August 22, 2013. The first patient was accrued to the study on September 16, 2013. As of April 30, 2016, 322 (19.7%) patients had been accrued to NSABP B-51/RTOG 1304. Accrual has been slower than projected (Table 1, Figure 1). As of April 30, 2016, follow-up information was available for 148 of the 322 patients randomized. Among patients with follow-up, the median time of follow-up is 10.3 months.

• Patient and Tumor Characteristics

There have been no ineligible patients declared as of April 30, 2016 (Table 2). Of all randomized patients, 15 have withdrawn consent to be followed. Among them, six patients were randomized to the “No XRT” and nine patients were randomized to the “XRT” treatment groups. Patient and tumor characteristics of all randomized patients are presented in Table 3. The majority of patients are 50 years of age or older (61%), white (71%), and had lumpectomy performed as their definitive surgery (63%).

• Adverse Events

As of April 30, 2016, adverse event information had been received for 225 patients (114 in the “no XRT” group and 111 in the “XRT” group). One hundred and nineteen patients have experienced at least one grade 2 or higher adverse event (51 in the “No XRT” group and 68 in the “XRT” group). There were 20 patients who experienced a grade 3 adverse event as their highest (four in the “No XRT” and 16 in the “XRT” treatment group). There have been no grade 4 or 5 toxicities reported. The distribution of patients by the highest grade experienced within each system organ class is summarized in Table 4. There was one system organ class (Injury, Poisoning and Procedural Complications) with a treatment difference of three or more in grade 3 toxicities. The detailed distribution of the adverse events experienced within Injury, Poisoning and Procedural Complications class is presented in Table 5. Only terms with non-zero Grade 3 toxicities are presented.


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Table 1

NSABP B-51/RTOG 1304 Accrual Summary - Data as of 04/30/2016

Date activated to accrual: August 22, 2013 Targeted Sample Size: 1,636 Projected monthly accrual: 28 Average monthly accrual over last 6 months: 18.5 Projected accrual as of 04/30/2016: 796 Total accrual as of 04/30/2016: 322 Percent of projected accrual achieved as of 04/30/2016: 40.45% Percent of total targeted accrual as of 04/30/2016: 19.68% Projected completion date based on last 6 months accrual: March 2022


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Table 2

NSABP B-51/RTOG 1304 Consent Withdrawals and Reasons for Ineligibility - Data as of 04/30/2016

No regional Nodal XRT

Regional Nodal XRT Total

Randomized 160 162 322 Withdrew consent 6 9 15 Eligible 160 162 322 Ineligible 0 0 0


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Table 3

Patient and Tumor Characteristics for All Randomized Patients in NSABP B-51/RTOG 1304 – Data as of 04/30/2016

Patient or Tumor Characteristic No regional Nodal

XRT Regional Nodal

XRT Total

n % n % n % Age (Years)

≤ 49 63 39.4 62 38.3 125 38.8 50-59 57 35.6 54 33.3 111 34.5 ≥ 60 40 25.0 46 28.4 86 26.7

Race White 109 68.1 119 73.5 228 70.8 Black/African American 35 21.9 27 16.7 62 19.3 Other 10 6.3 13 8.0 23 7.1 Unknown 6 3.8 2 1.2 8 2.5 Multiracial 0 0.0 1 0.6 1 0.3

Ethnicity Hispanic or Latino 24 15.0 32 19.8 56 17.4 Not Hispanic or Latino 132 82.5 125 77.2 257 79.8 Unknown 4 2.5 5 3.1 9 2.8

Type of Surgery Lumpectomy 100 62.5 103 63.6 203 63.0 Mastectomy 60 37.5 59 36.4 119 37.0

Hormone Receptor Status Positive 84 52.5 82 50.6 166 51.6 Negative 76 47.5 80 49.4 156 48.4

HER2 Status Positive 84 52.5 89 54.9 173 53.7 Negative 76 47.5 73 45.1 149 46.3

Adjuvant Chemotherapy Yes 1 0.6 0 0.0 1 0.3 No 159 99.4 162 100.0 321 99.7

pCR in breast Yes 127 79.4 123 75.9 250 77.6 No 33 20.6 39 24.1 72 22.4

Consented to PRO/QOL collection Yes 138 86.3 133 82.1 271 84.2 No 22 13.7 29 17.9 51 15.8

Total 160 100.0 162 100.0 322 100.0


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Table 4

Distribution of NSABP-B-51/RTOG 1304 Patients by Highest Grade Adverse Event by System Organ Class – Data as of 04/30/2016

For All Reported Adverse Events without Regard to Attribution

No regional Nodal XRT (N=114)

Regional Nodal XRT (N=111)

System Organ Class

n and (%) of Patients by Grade

n and (%) of Patients by Grade 0-1 2 3 4 5 0-1 2 3 4 5

Overall Highest Grade

63 47 4 0 0

43 52 16 0 0 (55.3) (41.2) (3.5) (0.0) (0.0) (38.7) (46.8) (14.4) (0.0) (0.0)

Blood and Lymphatic System Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Cardiac Disorders

112 1 1 0 0

111 0 0 0 0 (98.2) (0.9) (0.9) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Congenital, Familial and Genetic Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Ear and Labyrinth Disorders

114 0 0 0 0

110 1 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (99.1) (0.9) (0.0) (0.0) (0.0)

Endocrine Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Eye Disorders

114 0 0 0 0

110 0 1 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (99.1) (0.0) (0.9) (0.0) (0.0)

Gastrointestinal Disorders

113 1 0 0 0

103 7 1 0 0 (99.1) (0.9) (0.0) (0.0) (0.0) (92.8) (6.3) (0.9) (0.0) (0.0)

General Disorders and Administration Site Conditions

102 12 0 0 0

93 18 0 0 0

(89.5) (10.5) (0.0) (0.0) (0.0) (83.8) (16.2) (0.0) (0.0) (0.0) Hepatobiliary Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Immune System Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Infections and Infestations

111 3 0 0 0

107 4 0 0 0 (97.4) (2.6) (0.0) (0.0) (0.0) (96.4) (3.6) (0.0) (0.0) (0.0)

Injury, Poisoning and Procedural Complications

80 31 3 0 0

61 38 12 0 0 (70.2) (27.2) (2.6) (0.0) (0.0) (55.0) (34.2) (10.8) (0.0) (0.0)

Investigations

114 0 0 0 0

110 1 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (99.1) (0.9) (0.0) (0.0) (0.0)

Metabolism and Nutrition Disorders

114 0 0 0 0

109 1 1 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (98.2) (0.9) (0.9) (0.0) (0.0)

Musculoskeletal and Connective Tissue Disorders

110 4 0 0 0

106 4 1 0 0 (96.5) (3.5) (0.0) (0.0) (0.0) (95.5) (3.6) (0.9) (0.0) (0.0)


Page 8 of 10



System Organ Class



Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)

114 0 0 0 0

111 0 0 0 0

(100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0) Nervous System Disorders

111 3 0 0 0

108 3 0 0 0 (97.4) (2.6) (0.0) (0.0) (0.0) (97.3) (2.7) (0.0) (0.0) (0.0)

Pregnancy, Puerperium and Perinatal Conditions

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Psychiatric Disorders

112 2 0 0 0

110 1 0 0 0 (98.2) (1.8) (0.0) (0.0) (0.0) (99.1) (0.9) (0.0) (0.0) (0.0)

Renal and Urinary Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Reproductive System and Breast Disorders

105 9 0 0 0

109 2 0 0 0 (92.1) (7.9) (0.0) (0.0) (0.0) (98.2) (1.8) (0.0) (0.0) (0.0)

Respiratory, Thoracic and Mediastinal Disorders

111 3 0 0 0

107 3 1 0 0 (97.4) (2.6) (0.0) (0.0) (0.0) (96.4) (2.7) (0.9) (0.0) (0.0)

Skin and Subcutaneous Tissue Disorders

100 14 0 0 0

90 21 0 0 0 (87.7) (12.3) (0.0) (0.0) (0.0) (81.1) (18.9) (0.0) (0.0) (0.0)

Social Circumstances

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Surgical and Medical Procedures

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Vascular Disorders

112 2 0 0 0

106 3 2 0 0

(98.2) (1.8) (0.0) (0.0) (0.0) (95.5) (2.7) (1.8) (0.0) (0.0) Adverse events were graded with CTCAE version 4.0


Page 9 of 10

Table 5

Distribution of NSABP-B-51/RTOG 1304 Patients by Highest Grade Adverse Event by Specific Adverse Event Term– Data as of 04/30/2016

For Selected Adverse Events without Regard to Attribution



System Organ Class/Term




Dermatitis radiation

84 27 3 0 0

66 33 12 0 0 (73.7) (23.7) (2.6) (0.0) (0.0) (59.5) (29.7) (10.8) (0.0) (0.0)

Adverse events were graded with CTCAE version 4.0 Only terms with non-zero Grade 3-5 toxicities from the System Organ Classes with the difference of 3 or more in Grade 3-5 are presented.


Page 10 of 10

0

300

600

900

1200

1500

1800

Cum

ulat

ive

Num

ber o

f Pat

ient

s R

ando

miz

ed

Month and Year

Figure 1

Cumulative Accrual for NSABP B-51 - Data as of 04/30/2016

Projected Accrual

Observed Accrual

322

1,636

796


Page 1

EA1131 A RANDOMIZED PHASE III POST-OPERATIVE TRIAL OF PLATINUM BASED CHEMOTHERAPY VS. CAPECITABINE IN PATIENTS WITH RESIDUAL TRIPLE-NEGATIVE BREAST CANCER FOLLOWING NEOADJUVANT CHEMOTHERAPY

Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Ingrid Mayer Statistician Dr. Fengmin Zhao Data Specialist Keith Slade Phase of Study III Type of Study Therapeutic Committee Breast Accrual Objective 750 Patients Participating Groups ECOG-ACRIN, CTSU NSC# 119875, 241240, 712807 Clinicaltrials.gov Study ID NCT02445391 Study Status Open to Accrual Date Proposed January 16, 2014 Date Activated April 29, 2015 Date Suspended December 28, 2015 Date Reactivated June 22, 2016 Date Suspended January 7, 2019 Date Reactivated January 15, 2019 Schema


Page 2

Purpose of Study The purpose of study is to compare the IDFS in TNBC patients with residual basal-like disease after neoadjuvant chemotherapy who are randomized to post-preoperative platinum-based chemotherapy with those who are randomized to capecitabine. Secondary objectives include 1) To evaluate OS and RFS in the two arms in patients with TNBC with residual basal-like disease after neoadjuvant chemotherapy, 2) To characterize the side effects and tolerability of each platinum agent (cisplatin and carboplatin) as well as capecitabine in patients with TNBC with residual disease after neoadjuvant chemotherapy, 3) To identify the rate of basal-like gene expression using PAM50 analysis by digital mRNA quantitation amongst drug-resistant residual TNBC after neoadjuvant chemotherapy, 4) To compare the IDFS in TNBC patients with residual non-basal-like disease after neoadjuvant chemotherapy who are randomized to post-preoperative platinum based chemotherapy with those who are randomized to capecitabine (exploratory analysis), 5) To assess the difference in health-related quality of life (HRQL) between the platinum based and capecitabine chemotherapy arms, and 6) To describe the rate of neurotoxicity over time in the platinum arm, the rate of medication adherence in the capecitabine arm and the rates of amenorrhea in both arms (exploratory). The study also has exploratory tobacco use objectives and correlative biomarker objectives (i.e., association of genomic alterations identified via profiling of the surgical tumor specimen with RFS). Study Population Eligible patients must have residual invasive disease at the time of definitive surgery following preoperative chemotherapy (taxane +/- anthracycline) for their histologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, stage II-III at diagnosis (AJCC 8th edition). Patients must not have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen. Patients must be randomized within 24 weeks from surgery, and Cycle 1/ Day 1 chemotherapy must start within 1 week (5 working days) following randomization. Radiotherapy may be given before or after protocol treatment per standard of care guidelines. Patients have to be >/= 18 years of age and have ECOG PS of 0-1. Summary of Study Design The primary objective of this multi-institutional, open-label, randomized phase III study is to compare the two treatment arms, platinum and capecitabine, with respect to invasive disease-free survival (IDFS) in patients with triple-negative breast cancer (TNBC) treated with taxane +/- anthracycline-based neoadjuvant chemotherapy (NAC) who do not achieve a pathologic complete response (pCR) with a residual disease of more than 1.0 cm and with basal-like gene expression via PAM50 analysis by digital mRNA quantitation (NanoString) in the residual surgical specimen. IDFS is defined to be time from randomization to the earliest of documented disease recurrence (local, regional and/or distant), invasive contralateral breast cancer, invasive any other second primary cancer, or death. Cases with incomplete follow up or without adequate disease evaluations will be censored at the date last documented to be free of IDFS events. The primary population for the primary endpoint is the basal-like subtype. Regardless of molecular subtype, all patients will be randomized according to the permuted block algorithm with a 1:1 randomization ratio to platinum and capecitabine arms. Stratification factors include 1) clinical stage at diagnosis (II or III), 2) residual cancer burden after NAC (1~3 cm or > 3 cm), 3) planned platinum agent (cisplatin or carboplatin), 4) anthracycline exposure in the neoadjuvant setting (yes or no), 5) administration of radiotherapy (yes or no), and 6) basal-like subtype (yes or no). A non-inferiority design with a superiority alternative is used for this trial. The primary analysis for the primary endpoint will test the null hypothesis of inferiority of platinum. The sample size would be calculated based on a modest superiority alternative hypothesis. If the hypothesis of inferiority of


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platinum is rejected in the primary analysis, the secondary hypothesis of no difference vs. superiority of platinum will be tested. Due to the closed testing procedure, no multiple-comparison adjustment is required for the two hypothesis tests. The null hypothesis for testing non-inferiority of platinum is defined as that the hazard ratio (HR) for platinum/ capecitabine ≥ 1.154 (ie, HR of 1.154 is used as the non-inferiority margin). This corresponds to a 4-year IDFS rate of ≤63% on platinum if the 4-year IDFS rate is 67% on capecatibine arm. With a total accrual of 562 patients (281 on each arm) and full information of 196 IDFS events, this non-inferiority test would have about 83% power, with a one-sided 0.025 significance level, to reject the null hypothesis of inferiority of platinum under the alternative hypothesis of HR=0.754 for platinum/ capecitabine, ie, the 4-year IDFS rate for platinum is expected to be 73.9%. If inferiority of platinum is rejected at an interim analysis or the final analysis, the primary hypothesis is answered, and a superiority test of platinum (ie, the secondary hypothesis) is then performed at an overall one-sided type I error rate of 0.025, using the same RCIs used for the above non-inferiority test. For the superiority test, the null hypothesis is that HR=1 for platinum/capecitabine. Assuming the alternative hypothesis is HR=0.653 for platinum/ capecitabine for the superiority test, with 562 basal-like TNBC patients and total information of 196 IDFS events, there would be at least 82% power to detect a 34.7% reduction in the IDFS failure hazard rate using stratified log rank test with an overall one-sided type I error rate of 0.025, if the trial continues regardless of the results of non-inferiority test. This reduction in IDFS failure hazard rate corresponds to an improvement in 4-year IDFS rate from 67% on the capecitabine arm to 77% on the platinum arm, under the assumption of exponential distribution of IDFS. ECOG-ACRIN DSMC will monitor the IDFS endpoint for early stopping for efficacy according to the principles of group-sequential methods using the Jennison and Turnbull repeated confidence interval (RCI) methodology. Early stopping for inferiority of platinum would also be monitored using conditional power and the above RCI methods. For the IDFS endpoint, the primary analysis will compare treatment groups defined by the randomized treatment assignment (intent-to-treat analysis, ITT). A secondary analysis will be performed comparing groups defined by treatment received. The results will be creditable only if the two analyses are reasonably consistent. With an average annual accrual rate of 144 patients with basal-like TNBC, about 3.9 years of accrual will be needed with an additional 3 years of follow up to reach the expected number of IDFS failures. The final analysis for IDFS comparison in the basal-like TNBC patients is expected to be conducted at about 7.5 years after study activation. It is expected at least 75% of the residual post-NAC TNBC screened would fall within the basal-like subtype. Hence, at least 750 patients with residual TNBC at the time of surgery will be enrolled to obtain the 562 patients with basal-like TNBC. All patients will be followed for disease recurrence and survival through 10 years. Progress to Date This study opened on April 29, 2015. As of January 7, 2020, 445 patients had been screened (entered step 0) and 314 patients had been randomized to the study (entered step 1). Detailed information about accrual is shown in Table 1a (accrual by ECOG-ACRIN institution), 1b (accrual by cooperative group) and 1c (projected accrual). Expected and actual cumulative accrual is shown in Figure 1. Table 2 summarizes patient status as of January 7, 2020. Of the randomized 314 patients, 3 patients were ineligible and fifteen patients did not start protocol therapy for the reasons listed under Table 2. Table 3 summarizes patient demographics. Record status is displayed in Table 4. Two hundred and sixty-three patients have discontinued protocol treatment and the reasons off treatment are displayed in Table 5. Table 6 shows treatment-related adverse events. Two non-treatment related lethal adverse event has been reported via CTEP-AERS as summarized in Table 7. Second primary cancers are summarized in Table 8. A summary of the collection of quality of life data is presented in Table 9.


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Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 0 Step 1 Atlantic NCORP 2 1 Aurora NCORP 3 3 Baptist Memorial Health Care/Mid South MU NCORP 3 3 Beth Israel Deaconess Medical Center 2 1 CROWN NCORP 4 3 Cancer Research Consortium of West Michigan NCORP 3 2 Cancer Research for the Ozarks NCORP 5 2 Carle Cancer Center NCORP 2 2 Case Western Reserve University 10 8 Catholic Health Initiatives NCORP 17 11 Columbus NCORP 12 9 Danbury Hospital 1 1 Dartmouth Hitchcock Medical Center 1 1 Dayton NCORP 2 1 Delaware/Christiana Care NCORP 9 8 Emory University/Winship Cancer Institute 1 1 Fox Chase Cancer Center 1 1 Geisinger Cancer Institute NCORP 2 1 Georgia Cares Minority Underserved NCORP 6 5 Georgia NCORP 6 5 Gulf South MU NCORP 11 9 Hackensack University Medical Center 4 4 Heartland Cancer Research NCORP 10 7 Indiana Univ/Melvin and Bren Simon Cancer Center 1 0 Iowa-Wide Oncology Research Coalition NCORP 7 5 Johns Hopkins Univ/Sidney Kimmel Cancer Center 10 5 Lankenau Medical Center 3 1 Mayo Clinic 5 3 Medical University of South Carolina MU NCORP 4 2 Metro Minnesota Community Oncology Res Consortium 15 11 Michigan Ca Res Consortium NCORP 12 9 Mobile Infirmary Medical Center 4 2 Montana Cancer Consortium NCORP 1 1 Montefiore MU NCORP 15 13 Nevada Cancer Research Foundation NCORP 6 3 New Mexico MU NCORP 6 5 Northwestern University 12 7 Pacific Cancer Research Consortium NCORP 4 4 Penn State Milton S Hershey Medical Center 2 2 Saint Luke's University Hospital-Bethlehem Campus 4 2 Stony Brook University Medical Center 1 0 Stroger Hospital of Cook County MU NCORP 4 4 UMass Memorial Medical Center - University Campus 3 3 UT Southwestern/Simmons Cancer Center-Dallas 7 6 University Of Pretoria 1 1 University of Oklahoma Health Sciences Center 5 0 University of Pennsylvania/Abramson Cancer Center 3 2 University of Pittsburgh Cancer Institute (UPCI) 10 7 University of Wisconsin Hospital and Clinics 7 6 VCU Massey Cancer Center MU NCORP 4 4


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Institution Name Step 0 Step 1 Vanderbilt University/Ingram Cancer Center 9 6 Western States Cancer Research NCORP 8 4 Wichita NCORP 5 3 Yale University 1 0 Total 296 210

Table 1b. Accrual by Group

Step 0 Step 1 ECOG-ACRIN 296 210 SWOG 35 21 ALLIANCE 51 38 NRG 63 45 Total 445 314

Table 1c. Projected Accrual

Accrual goal 750 Planned accrual rate 192/yr Accrual to date 314 Annual accrual rate Overall 75/yr Last 6 months 86/yr Projected date of closure January 2025

Note: Planned accrual rate was 144 patients per year (12 basal-like patients/month) before activation of amendment #3 (activated in June 2016), and it was 192 patients per year (16 TNBC patients/month) after that. Accrual was suspended between December 2015 and June 2016.


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Table 2. Patient Status

Before Amendment

#3&

After Amendment #3-

Basal like

After Amendment #3-

Non basal like

Total

Cases Entered 5 238 71 314 Ineligible 0 2 1 3 Never Started Assigned Therapy 0 12 3 15

&: Only basal-like patients were eligible to register to step 1 before Amendment #3.

Reasons for ineligibility (n=3): Blood work did not meet the eligibility requirements (11045) All baseline labs for step 1 outside protocol window (11207) ER was deemed 10.4% and as per protocol not eligible (11193)

Reasons never started assigned therapy (n=15): Patient ineligible (11045, 11178, 11193, 11290) Patient withdrawal/refusal before beginning protocol therapy (11089, 11127, 11274, 11314, 11353, 11401), Medication cannot be obtained (11100), Surgery to randomization window expired (11065) Patient moved to another facility due to insurance (11319) Patient’s insurance company denied her medicine. The appeal approval did not come through in time for her to start the study (11352) Patient did not receive protocol medication within the 3 week time period per protocol due to multiple issues with her insurance company, despite staff working diligently to get it to her on time (11422).

Duplicate registrations (n=2): 11033, 11104

Table 3. Demographics

Variable Level Arm A

(n=3) Arm B

(n=150) Arm C

(n=161) Total

(n=314) Sex Male 0 (0.0) 1 (0.7) 0 (0.0) 1 (0.3)

Female 3 (100.0) 149 (99.3) 161 (100.0) 313 (99.7) Race White 3 (100.0) 105 (75.5) 118 (77.1) 226 (76.6)

African-American 0 (0.0) 31 (22.3) 29 (19.0) 60 (20.3) Asian 0 (0.0) 3 (2.2) 6 (3.9) 9 (3.1) Unknown/Unreported 0 11 8 19

Ethnicity Hispanic 0 (0.0) 18 (12.4) 16 (10.7) 34 (11.4) Non-Hispanic 3 (100.0) 127 (87.6) 134 (89.3) 264 (88.6) Unknown/Missing 0 5 11 16

Age Median 53 52 54 53 Minimum 41 28 26 26 Maximum 58 75 76 76


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Table 4. Record Status

Form Name Forms Due

Forms Received %

Adverse Event Form 1289 1278 99.1% Baseline Adverse Event Form 309 306 99.0% Disease Follow-Up Status 2267 2255 99.5% Follow-Up Distant Recurrence Evaluation Form 1579 1579 100.0% Follow-Up Hematology/Chemistry 2269 2261 99.6% Follow-Up Local/Regional Recurrence Evaluation Form 1554 1554 100.0% Hematology/Chemistry 336 334 99.4% Late Adverse Event Form 14 14 100.0% Other Adverse Event Form 86 86 100.0% Off Treatment (Step 1) 262 262 100.0% Off Treatment - No Start (Step 1) 14 14 100.0% Patient Characteristics 2603 2593 99.6% Report Period and Vital Status Form 2439 2394 98.2% Treatment Agent: Capecitabine 806 801 99.4% Treatment Form 487 484 99.4%

Table 5. Reasons Off Treatment

(Includes all patients who started treatment and for whom off-treatment data have been received)

Reasons N %

Adverse event/side effects/complications 19 7.2 Alternative therapy 1 0.4 Disease progression- relapse during active treatment 22 8.4 Other 6 2.3 Patient off-treatment for other complicating disease 1 0.4 Patient withdrawal/refusal after beginning protocol therapy 6 2.3 Treatment completed per protocol criteria 208 79.1 Total off treatment 263 100.0


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Table 6. Toxicity Incidence

Toxicity Type

Treatment Arm B (n=131) C (n=153)

Grade Grade 1,2 3 4 5 1,2 3 4 5 (%) (%) (%) (%) (%) (%) (%) (%)

Anemia 54 6 - - 29 - - - Blood and lymphatic system disorders - Other, specify - 1 - - - - - - Febrile neutropenia - - - - - 1 - - Thrombotic thrombocytopenic purpura - 1 - - - - - - Cardiac disorders - Other, specify - - - - - - 1 - Hearing impaired - 1 - - - - - - Colitis - - - - - 1 - - Constipation 21 - - - 11 - - - Diarrhea 8 - - - 42 5 - - Mucositis oral - - - - 1 1 - - Nausea 47 2 - - 40 1 - - Vomiting 15 - - - 10 - - - Fatigue - 2 - - - 1 - - Allergic reaction 1 - - - 1 - - - Breast infection - 1 - - - - - - Sepsis - - - - - - 1 - Bruising 6 - - - 2 - - - Blood bilirubin increased - - - - 1 - - - Lymphocyte count decreased 1 2 - - 1 - - - Neutrophil count decreased 1 2 1 - - - 1 - Platelet count decreased - 4 3 - - - - - White blood cell decreased 50 11 1 - 22 2 - - Hypokalemia - - - - - 1 - - Headache - 1 - - - - - - Peripheral sensory neuropathy 25 1 - - 27 - - - Syncope - - - - - 1 - - Alopecia 3 - - - 4 - - - Purpura 1 - - - 1 - - - Palmar-plantar erythrodysesthesia syndrome - - - - 51 6 - - Thromboembolic event - - - - - 1 - - WORST DEGREE 55 21 4 - 71 14 1 - Note: Only adverse events with a treatment relation of 3 or higher (possible, probably, or definitely related) were included in the table.

Table 7. Lethal Adverse Events

Case Arm Description of Event

11034 B The death of the patient was unrelated to carboplatin, definitely related to breast cancer, and probably related to respiratory distress bilateral: pleural effusions.

11175 B Per site assessment, the death of the patient was unrelated to carboplatin, and it was definitely related to invasive breast cancer. NCI assessment is not available yet.


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Table 8. Second Primary Cancers

Site Arm B Arm C

Melanoma 1 1 Non-Hodgkins Lymphoma - 1 Pancreas - 1

Table 9. QOL Table

QOL Timepoint

Patients Reaching

Timepoint % Forms

Completed Baseline 224 85.7 Before Cycle 3 Chemotherapy 213 69.5 6 Months After Start of Chemotherapy 133 63.9 15 Months After Start of Chemotherapy 51 76.5

Note: QOL endpoint was added to the study in Amendment #4 which was activated on 9/20/2017. A total of 229 patients enrolled to the study between 9/20/2017 and 1/7/2020.



Alliance Study A011202 – A Randomized Phase III Trial Evaluation the Role of Axillary Lymph Node Dissection in Breast Cancer Patients (cT1-3 N1) who have Positive Sentinel Lymph Node Disease

after Neoadjuvant Chemotherapy

Data as of 09/11/2019

Committee: Breast Study Statistician: Vera Suman, PhD Study Chair: Judy C. Boughey, MD 1.0 OBJECTIVES

Primary Objective

1. To evaluate whether radiation to the undissected axilla and regional lymph nodes is not inferior to axillary lymph node dissection with radiation to the regional lymph nodes but not to the dissected axilla in terms of invasive breast cancer recurrence-free interval in patients with positive SLN(s) after completion of neoadjuvant chemotherapy..

Primary endpoint: Invasive breast cancer recurrence-free interval (IBC-RFI) will be defined as time from

randomization to the first of the following events: invasive ipsilateral, local, regional, or distant recurrence; and death due to breast cancer or treatment

Secondary Objectives

1. To evaluate whether radiation to the undissected axilla and regional lymph nodes is not

inferior to axillary lymph node dissection with radiation to the regional lymph nodes but not to the dissected axilla in terms of the incidence of invasive loco-regional recurrences in patients with a positive SLN(s) after completion of neoadjuvant chemotherapy.

2. For each treatment arm,

To obtain an estimate of the distribution of residual disease burden scores. To estimate the distribution of overall survival.

Secondary endpoints:

• Overall survival (defined as time from randomization to death due to any cause). • Ipsilateral/local/regional invasive breast cancer recurrence (ILR-REC) - includes the

following events: Invasive breast cancer involving the same breast parenchyma as the original

primary Invasive breast cancer in the axilla, regional lymph nodes, chest wall or skin

of the ipsilateral breast • A patient will be considered to have developed arm lymphedema if there is a 10 %

increase in the volume of her ipsilateral arm from its pre-surgery volume. A patient will be considered to have mild lymphedema if she has symptomatic arm swelling or heaviness with less than a 10% increase in volume of the ipsilateral arm from pre-surgery volume.

• Breast lymphedema (in BCT patients) • Adequacy of radiation fields; dose delivered to supraclavicular and axillary nodes • Residual Cancer Burden (RCB)

Correlative Science Objectives



1. To estimate the incidence of arm lymphedema.

2. To estimate the incidence of breast lymphedema for patients who underwent breast conserving surgery based on the specific treatment rendered to the axilla.

2.0 CURRENT SCHEMA* Schema for patients who pre-register prior to SLN surgery:

Schema for patients who pre-register AFTER surgery* (where SLN was performed but ALND was NOT performed):

3.0 ELIGIBILITY CRITERIA Pre-registration eligibility criteria:



• Patients > 18 years of age. • Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant

chemotherapy) by AJCC staging 7th edition. • No inflammatory breast cancer. • No other malignancy within 5 years of registration with the exception of basal cell or squamous

cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix. • All patients must have had an axillary ultrasound with FNA or core needle biopsy of axillary

lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy. Note: Biopsy of intra-mammary nodes does not fulfill eligibility criteria.

• Patients must have had estrogen receptor, progesterone receptor and HER2 status (by IHC and/or ISH) evaluated on diagnostic core biopsy prior to start of neoadjuvant chemotherapy. Note: If HER2 status has not been clearly determined (i.e. equivocal/indeterminate), then patients should not be enrolled.

• Patients must have completed all chemotherapy prior to surgery. Sandwich chemotherapy is not allowed (i.e. chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes. Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.

• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab, or trastuzumab + pertuzumab, or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be FDA-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an IRB-approved clinical trial.

• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy. Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.

• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.

• No neoadjuvant radiation therapy. • No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or

during neoadjuvant chemotherapy. • No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast

disease is allowed. • No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of

hidradenitis. • No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease,

LCIS or DCIS of contralateral breast is allowed. • Patients must not be pregnant or nursing. Note: Peri-menopausal women must be amenorrheic

for > 12 months to be considered not of childbearing potential. • ECOG (Zubrod) Performance Status 0-1.

Intra-operative registration/randomization criteria

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 56 days of the completion of the last dose of neoadjuvant chemotherapy.

• A minimum of 1 sentinel node and a maximum of 6 total nodes (sentinel + non-sentinel) are identified and excised by the surgeon. Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.

• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment. Note: Isolated tumor



cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+). Note: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study (see Section 14.0) ALND is not to be performed prior to Registration/Randomization.

Post-operative registration/randomization criteria: For cases where ALND has not been performed and one of the following is true: 1) intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm. OR 2) lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 56 days of the completion of the last dose of neoadjuvant chemotherapy. Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink.

• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).

• Among the minimum of 1 and the maximum of 6 nodes (sentinel + non-sentinel) identified and excised by the surgeon, no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised. Note: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).

• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

4.0 TREATMENT SCHEDULE Protocol mandated axillary surgery:

• For those patients who pre-register prior to sentinel lymph node surgery, sentinel lymph node surgery is to be performed at most 28 days following pre-registration.

• For those patients who pre-register after sentinel lymph node surgery, pre-registration must occur at most 28 days after sentinel lymph node surgery.

Patients who are clinically node negative after neoadjuvant chemotherapy by physical examination will undergo clinically indicated breast surgery (mastectomy or lumpectomy) with sentinel lymph node (SLN) surgery. Sentinel lymph node surgery must be performed within 8 weeks (56 days) after completion of the last dose of neoadjuvant chemotherapy. For patients randomized to ALND (Arm 1), the ALND surgery should occur within 56 days of sentinel lymph node surgery.

• Radiation therapy is to be performed no sooner that 3 weeks following surgery and no later than

12 weeks following surgery.

Patients randomized to Arm 1 : For both lumpectomy and mastectomy patients radiation is to be delivered using dose specifications provided below to: the breast/chest wall, undissected axilla*, supraclavicular nodes and internal mammary nodes in the first 3 intercostal spaces. Patients randomized to Arm 2 : For both lumpectomy and mastectomy patients radiation is to be delivered using dose specifications provided below to: the breast/chest wall, full axilla including Levels I, II, III, supraclavicular nodes and internal mammary nodes in the



first 3 intercostal spaces. In this arm the full axilla should be included in the supraclavicular/axillary field. A posterior axillary boost field may be used if necessary to assure coverage of the level 1, 2, and 3 nodes in accordance with the specified target doses outlined below.

Dose specifications

• Post lumpectomy breast + boost: Breast: 50 Gy in 2 Gy daily (5 days a week) fractions over 5-6 weeks. Lumpectomy cavity boost: 10 - 14 Gy in 2 Gy daily (5 days a week) fractions over 1-2 weeks to total tumor bed dose of 60-64 Gy. • Post mastectomy radiation: Chest wall, undissected axilla, supraclavicular nodes, and internal mammary nodes: 50 Gy in 2 Gy daily fractions over 5-6 weeks. Boost: Boost to the chest wall/scar of 10 - 14 Gy in 2 Gy fractions is required on all post mastectomy patients. • Regional Nodal Irradiation: Undissected axilla, supraclavicular nodes, and internal mammary nodes: 46 –50 Gy in 2 Gy daily fractions over 5-6 weeks.

5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors A randomized Phase III clinical trial is being conducted to assess whether radiation to the undissected axilla and regional lymph nodes is not inferior to axillary lymph node dissection with radiation to the regional lymph nodes but not to the dissected axilla in terms of the incidence of invasive loco-regional recurrences in patients with a positive SLN(s) after completion of neoadjuvant chemotherapy. A dynamic allocation procedure will be used to allocate an equal number of patients to each of the treatment arms. This procedure will balance the marginal distributions of the stratification factors, namely, histologic subtype (triple negative vs. Her2 positive vs. ER and/or PR and Her2 negative); cT stage at diagnosis (1,2 vs. 3), type of surgery (lumpectomy vs mastectomy); and intention to undergo adjuvant chemotherapy (yes vs. no).

The sample size was calculated under the assumptions that: • Forty patients per month must pre-register to the trial in order to obtain 22 patients per

month who fulfill the eligibility criterion of at least one positive lymph node among the 1-6 lymph nodes removed at sentinel lymph node surgery.

• 5 year IBC-RFI rate is 63% among women with positive sentinel lymph node disease following neoadjuvant chemotherapy who undergo ALND with radiation to the regional lymph nodes but not to the dissected axilla.

• Enrollment period of 6 years • Follow-up period after close of enrollment of 5 years • One sided alpha =0.05

With a sample size of 788 per arm, a test of the non-inferiority will have 87% power to reject the null hypothesis of inferiority of radiation to the undissected axilla and regional lymph nodes to axillary lymph node dissection with radiation to the regional lymph nodes but not to the dissected axilla in terms of recurrence-free interval when the average annual hazard rate is 0.0923 among those receiving radiation to the regional lymph nodes but not to the dissected axilla following ALND and the true hazard ratio is 1.0. The expected number of local, regional, and distant breast recurrences at the time of final analysis is 814. Assuming the nodal response rate after neoadjuvant chemotherapy is 40%, and 10% of the remaining patients are such that they have positive surgical margins, or have more than six



sentinel lymph nodes removed, or a sentinel node, which cannot be identified or receive adjuvant chemotherapy, then a total of 3350 women would need to be pre-registered in order to obtain 1576 women with sentinel node positive disease after neoadjuvant chemotherapy, who meet the criteria for inclusion in the primary analysis.


The primary endpoint of this study is invasive breast cancer recurrence-free interval (IBC-RFI) which is defined as time from randomization to the first of the following events: invasive ipsilateral, local, regional, or distant recurrence; and death due to breast cancer or treatment 5.3 Target Accrual Target enrollment rate for preregistered patients is 40 per month. As such we expect the target accrual rate for patients who will fulfill the eligibility criterion of at least one positive lymph node at sentinel lymph node surgery will be 22 per month

6.0 CURRENT ACCRUAL

Study Activation Date 02/07/2014

PRE-REGISTRATION

Target pre-registration accrual 3350*

Actual number of patients pre-registered 3249

Expected pre-registration accrual rate 40/month

Pre-registration Accrual Rate – Since activation 53.1/month

Pre-registration accrual Rate – Past 12 months** 82.8/month

Pre-registration accrual Rate – Past 6 months** 76.8/month

REGISTRATION

Target registration accrual 1576

Actual number of patients registered 1543

Expected registration accrual rate 22/month

Registration Accrual Rate – Since activation 24.4/month

Registration accrual Rate – Past 12 months 40.8/month

Registration accrual Rate – Past 6 months 39.5/month

*The protocol was updated (update #8) 9/18/2018 to increase in the sample size at the pre-registration phase to accommodate a smaller number of patients than expected going on to study registration. **Temporarily suspended to new patient pre-registration April 18, 2019.



The following accrual chart was for all pre-registered patients.

The following accrual chart was created for registered patients.




This study was activated on February 7, 2014, and temporarily closed to enrollment on 04/18/2019 having met its registration cap. An addendum is being drafted to allow additional enrollments to meet study objectives.

8.0 PATIENT CHARACTERISTICS

Table 8a. Demographics

Frequencies of Age Race and Gender

Arm 1 (ALND+Nodal RT)

(N=772)

Arm 2 (Axilla+ Nodal RT)

(N=771) Total

(N=1543) Age N 772 771 1543 Mean (SD) 51.2 (11.0) 51.2 (11.4) 51.2 (11.2) Median 51.0 51.0 51.0 Q1, Q3 43.0, 59.0 42.0, 60.0 43.0, 59.0 Range (19.0-86.0) (20.0-87.0) (19.0-87.0) Race White 560 (72.5%) 557 (72.2%) 1117 (72.4%) Black or African American 121 (15.7%) 129 (16.7%) 250 (16.2%) Native Hawaiian or Other Pacific Islander 2 (0.3%) 1 (0.1%) 3 (0.2%) Asian 32 (4.1%) 31 (4.0%) 63 (4.1%) American Indian or Alaska Native 6 (0.8%) 0 (0.0%) 6 (0.4%) Not reported: patient refused or not available 27 (3.5%) 29 (3.8%) 56 (3.6%) Unknown: Patient unsure 24 (3.1%) 24 (3.1%) 48 (3.1%) Gender Female 767 (99.4%) 769 (99.7%) 1536 (99.5%) Male 5 (0.6%) 2 (0.3%) 7 (0.5%)

Table 8b. Stratification Factors

Arm 1 (ALND + Nodal RT)

(N=772)


(N=771) Total

(N=1543) Clinical T Stage At Diagnosis T1-2 591 (76.6%) 591 (76.7%) 1182 (76.6%) T3 181 (23.4%) 180 (23.3%) 361 (23.4%) Hormone Receptor Status At Diagnosis ER Neg./PgR Neg./HERS Negative 110 (14.2%) 111 (14.4%) 221 (14.3%) HER2 positive 158 (20.5%) 158 (20.5%) 316 (20.5%) ER pos. +/- PgR pos. and HER2 neg. 504 (65.3%) 502 (65.1%) 1006 (65.2%)



Arm 1 (ALND + Nodal RT)

(N=772)


(N=771) Total

(N=1543) Type of Surgery at Diagnosis Lumpectomy 363 (47.0%) 365 (47.3%) 728 (47.2%) Mastectomy 409 (53.0%) 406 (52.7%) 815 (52.8%) Intent to Administer Adjuvant Chemotherapy Missing 165 163 328 Yes 58 (9.6%) 58 (9.5%) 116 (9.5%) No 549 (90.4%) 550 (90.5%) 1099 (90.5%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary Adverse event data are available for 1532 patients (Arm 1: 768, Arm 2: 764). There have been no treatment related deaths. Arm 1 (ALND + Nodal RT): Commonly occurring grade 3+ AE include: I Wound infection 3.0%, and dermatitis radiation 5.0%.

Arm 2 (Axillary and Nodal RT): Commonly occurring grade 3+ AE include: wound infection 3.0%, and dermatitis radiation 4.0%. There were two grade 5 events reported on Arm 1 not related to study treatment – a death due to respiratory failure, and death due to disease. There were two grade 5 events reported on Arm 2 due to disease.

Summary of Grade 3+Adverse Events Regardless of Attribution



Grade 3 Event 1 105 (13.7%)

2 96 (12.6%)


2 7 (0.9%)


2 2 (0.3%)



2 9 (1.2%)




Patients with a maximum: Arm n (%)


2 1 (0.1%)


2 0 (0.0%)


Grade 3 Event 1 103 (13.4%)

2 92 (12.0%)


2 6 (0.8%)


2 2 (0.3%)







Anemia 1 3 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 0 ( 0%) 0 ( 0%) Blood and lymph sys disorders - Oth Spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 5 ( 1%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 1 ( 0%) 0 ( 0%) White blood cell decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events Cardiac disorders

Myocardial infarction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)







Restrictive cardiomyopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Sinus tachycardia 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Congenit, famil, genet disord Congen, family, genetic disord -Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Eye disorders

Cataract 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Gastrointestinal disorders Abdominal pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Diarrhea 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Esophagitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Nausea 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Vomiting 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Gen disord and admin site cond Death NOS 1 0 ( 0%) 0 ( 0%) 1 ( 0%) 2 0 ( 0%) 0 ( 0%) 2 ( 0%) Fatigue 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 0%) 0 ( 0%) 0 ( 0%) Fever 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Gen disord and admin site conds-Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Non-cardiac chest pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Pain 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 0%) 0 ( 0%) 0 ( 0%)







Hepatobiliary disorders Cholecystitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Infections and infestations Breast infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Device related infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Duodenal infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Enterocolitis infectious 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec

1 6 ( 1%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Kidney infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Sepsis 1 0 ( 0%) 3 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Skin infection 1 5 ( 1%) 1 ( 0%) 0 ( 0%) 2 5 ( 1%) 0 ( 0%) 0 ( 0%) Urinary tract infection 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Vaginal infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Wound infection 1 23 ( 3%) 0 ( 0%) 0 ( 0%) 2 24 ( 3%) 0 ( 0%) 0 ( 0%)

Inj, pois and proced complic Dermatitis radiation 1 41 ( 5%) 0 ( 0%) 0 ( 0%) 2 31 ( 4%) 1 ( 0%) 0 ( 0%) Fracture 1 3 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Postoperative hemorrhage 1 1 ( 0%) 1 ( 0%) 0 ( 0%)







2 2 ( 0%) 0 ( 0%) 0 ( 0%) Seroma 1 6 ( 1%) 0 ( 0%) 0 ( 0%) 2 8 ( 1%) 0 ( 0%) 0 ( 0%) Vascular access complication 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Wound complication 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 1 ( 0%) 0 ( 0%) Wound dehiscence 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Investigations Investigations - Other, specify 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Weight gain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 0%) 0 ( 0%) 0 ( 0%)

Metabol and nutrition disord Dehydration 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperglycemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Hyperkalemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Hypokalemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) Hyponatremia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 1 ( 0%) 0 ( 0%) Metabolism, nutrition disord - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 1 ( 0%) 0 ( 0%) Musculosk and conn tiss disord

Back pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Bone pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Fibrosis deep connective tissue 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)







Generalized muscle weakness 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Joint range of motion decreased 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Musculoskeletal, conn tissue - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Myalgia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Neck pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Osteoporosis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Pain in extremity 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Superficial soft tissue fibrosis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Neoplsm benign, mal and unspec Neoplasms benign, mal, uncpec - Oth spec

1 5 ( 1%) 1 ( 0%) 0 ( 0%)

2 2 ( 0%) 0 ( 0%) 0 ( 0%) Nervous system disorders

Dizziness 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Nervous system disorders - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Peripheral sensory neuropathy 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Seizure 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Syncope 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Vasovagal reaction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Psychiatric disorders







Insomnia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Psychiatric disorders - Other, specify

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Psychosis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Renal and urinary disorders Acute kidney injury 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) Renal and urinary disorders - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Renal calculi 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Reprod sys and breast disord Breast pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 0 ( 0%) 0 ( 0%) Premature menopause 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Reproductive system and breast -Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Vaginal dryness 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Respirat, thor, mediast disord Adult respiratory distress syndrome

1 0 ( 0%) 1 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Cough 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspnea 1 3 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypoxia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Pneumonitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%)







2 0 ( 0%) 0 ( 0%) 0 ( 0%) Pneumothorax 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Productive cough 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Resp, thoracic, mediastinal - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Respiratory failure 1 0 ( 0%) 1 ( 0%) 1 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Skin and subcutan tiss disord Bullous dermatitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Erythroderma 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Skin and subcut tissue disord - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Skin induration 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Skin ulceration 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%)

Surgical and medical proced Surgical and medical proced - Oth spec

1 2 ( 0%) 0 ( 0%) 0 ( 0%)

2 2 ( 0%) 0 ( 0%) 0 ( 0%) Vascular disorders

Hematoma 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 0 ( 0%) 0 ( 0%) Hot flashes 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 0%) 0 ( 0%) 0 ( 0%) Hypertension 1 7 ( 1%) 0 ( 0%) 0 ( 0%) 2 3 ( 0%) 0 ( 0%) 0 ( 0%) Hypotension 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Lymphedema 1 2 ( 0%) 0 ( 0%) 0 ( 0%)







2 2 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 2 ( 0%) 2 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES

Incidence of arm and breast lymphedema (A011202-SI1): The objectives of this companion study are: • To estimate the incidence of arm lymphedema by treatment arm. • To estimate the incidence of breast lymphedema for patients who underwent

breast conserving surgery by treatment arm. • To assess whether the incidence of arm lymphedema is decreased for those

patients who receive radiation therapy alone relative to those who receive both axillary lymph node dissection and radiation therapy.

NSABP BR003 - July, 2017

Page 1 of 10

NRG BR003

Report Based on Data through 4/30/2017

A Randomized Phase III Trial of Adjuvant Therapy Comparing Doxorubicin Plus

Cyclophosphamide Followed by Weekly Paclitaxel with or without Carboplatin for

Node-Positive or High-Risk Node-Negative Triple-Negative Invasive Breast Cancer

Study Chair: Vicente Valero, MD

Protocol Officer: Priya Rastogi, MD

Protocol Statistician: Gong Tang, PhD

Protocol Pathologist: Soonmyung Paik, MD

Activated: June 26, 2015

Status: Accruing


Page 2 of 10

NRG BR003 Schema


• Arm 1

− Doxorubicin (A) 60 mg/m2 IV + cyclophosphamide (C) 600 mg/m2 IV every 2 weeks for 4 cycles

(dose-dense schedule)

− Followed by paclitaxel 80 mg/m2 IV weekly for 12 doses

Arm 2

− Doxorubicin (A) 60 mg/m2 IV + cyclophosphamide (C) 600 mg/m2 IV every 2 weeks for 4 cycles

(dose-dense schedule)

− Followed by paclitaxel 80 mg/m2 IV weekly for 12 doses plus carboplatin AUC of 5 IV every 3

weeks for 4 cycles

Patients with Resected Node-Positive or High-Risk Node-

Negative HER2-Negative, ER- and PgR-Negative Invasive

Breast Cancer Diagnosed by Core Needle Biopsy

STRATIFICATION

Number of positive nodes (0, 1–3, 4–9, 10+)

BRCA mutation status (positive; negative or unknown)

RANDOMIZATION

Arm 1

ACWP*

Arm 2

ACWP + Carboplatin*


Page 3 of 10

Study description

NRG BR003 is a Phase III, multicenter, randomized adjuvant therapy trial to evaluate whether the

addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed

by paclitaxel will improve the invasive disease-free survival (IDFS) compared to

doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-

positive or high-risk node-negative triple-negative breast cancer. Eligible patients must have clinically

T1-3, pathologically N1-3 breast cancer or N0 breast cancer with the primary tumor > 3.0 cm at staging.

Tumors must have been determined to be ER-negative and PgR-negative and HER2-negative, assessed by

current ASCO/CAP Guidelines. Patients must have undergone either a mastectomy (total, skin-sparing, or

nipple-sparing) or lumpectomy. For patients who undergo lumpectomy, the margins of the resected

specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist.

For patients who undergo mastectomy, the margins must be free of residual gross tumor. LVEF

assessment must be performed within 90 days prior to randomization. The LVEF must be 50%

regardless of the cardiac imaging facility's lower limit of normal.

Patient Accrual

This protocol was opened for accrual on June 26, 2015. The first patient was accrued to the study on July

10, 2015. As of April 30, 2016, 310 (31.3%) patients had been accrued to NRG BR003. Accrual has been

slower than projected (Table 1, Figure 1). As of April 30, 2017, follow-up information was available from

273 of the 313 patients randomized. Among patients with follow-up, the median time of follow-up is 10.9

months. The protocol has been amended to allow the inclusion of patients with 1-10% ER and PgR

staining by IHC to improve the patient accrual.

The first interim analysis is planned when 82 IDFS events are observed. The projected date for the first

interim analysis based on the current data is December 2019. This projection is based on current accrual

pattern and anticipated event and loss to follow-up rates.

Patient and Tumor Characteristics

There have been no ineligible patients declared as of April 30, 2017 (Table 2). Of all randomized patients,

seven patients withdrew consent from the study. Four of them were randomized to Arm 1 and the other

three were randomized to Arm 2. Patient and tumor characteristics of all randomized patients are

presented in Table 3. The majority of patients are 50 years of age or older (59%) at entry, white (73%),

node-positive (74%), and had mastectomy as their primary surgery (55%).

Off-protocol Carboplatin in the ACWP Group

As of April 30, 2017, four out of 155 patients who were randomized to the ACWP group received

carboplatin off-protocol. The cross-in from the control arm is less than 3% and does not pose a serious

issue.


Page 4 of 10

Adverse Events

As of April 30, 2017, adverse event information had been received for 294 patients (148 in the ACWP

group and 146 in the ACWP + Carboplatin group). There were 133 patients who experienced a grade 3

adverse event as their highest (58 in the ACWP group and 75 in the ACWP + Carboplatin group).

Another 25 patients had at least a grade 4 adverse event as their highest (12 in the ACWP group and 13

in the ACWP + Carboplatin group). No grade 5 toxicities have been reported. The distribution of

patients by the highest grade experienced within each system organ class is summarized in Table 4.

Toxicities with a treatment difference of three or more in grade 3 toxicities are listed and presented in

table 5.


Page 5 of 10

Table 1

NRG BR003 Accrual Summary - Data as of 4/30/2017

Date activated to accrual: June 26, 2015

Targeted Sample Size: 990

Projected monthly accrual: 57

Average monthly accrual over last 3 months: 12

Projected accrual as of 4/30/2017: 990

Total accrual as of 4/30/2017: 310

Percent of projected accrual achieved as of 4/30/2017: 31.3%

Percent of total targeted accrual as of 4/30/2017: 31.3%

Projected completion date based on last 3 months accrual: January 2022

Table 2

NRG BR003 Consent Withdrawals and Reasons for Ineligibility - Data as of 4/30/2017

ACWP

ACWP

+Carboplatin Total

Randomized 155 155 310

Withdrew consent 4 3 7

Eligible 155 155 310

Ineligible 0 0 0


Page 6 of 10

Table 3

Patient and Tumor Characteristics for All Randomized Patients in

NRG BR003 – Data as of 4/30/2017

Patient or Tumor Characteristic ACWP

ACWP

+Carboplatin Total

n % n % n %

Age (Years)

≤ 49 59 38.0 69 44.5 128 41.3

50-59 44 28.4 47 30.3 91 29.4

≥ 60 52 33.6 39 25.2 91 29.4

Race

White 113 72.9 114 73.6 227 73.2

Black/African American 31 20.0 31 20.0 62 20.0

Other 7 4.5 6 3.9 13 4.2

Unknown 4 2.6 4 2.6 8 2.6

Ethnicity

Hispanic or Latino 12 7.7 14 9.0 26 8.4

Not Hispanic or Latino 137 88.4 138 89.0 275 88.7

Unknown 6 3.9 3 1.9 9 2.9

Type of Surgery

Lumpectomy 71 45.8 70 45.2 141 45.5

Mastectomy 84 54.2 85 54.8 169 54.5

Number of Positive Nodes

0 40 25.8 41 26.5 81 26.1

1-3 90 58.1 89 57.4 179 57.7

4-9 21 13.6 18 11.6 39 12.6

10+ 4 1.3 7 4.5 11 3.6

BRCA Mutation

Yes 10 6.4 11 7.1 21 6.8

No 44 28.4 57 36.8 101 32.6

Unknown 101 65.2 87 56.1 188 60.7

Total 155 100.0 155 100.0 310 100.0


Page 7 of 10

Table 4

Distribution of NRG BR003 Patients by Highest Grade Adverse Event

by System Organ Class – Data as of 4/30/2017


ACWP (N=148)

ACWP+Carboplatin (N=146)

System Organ Class



0-1 2 3 4 5 0-1 2 3 4 5


13 65 58 12 0

8 50 75 13 0

(8.8) (43.9) (39.2) (8.1) (0) (5.5) (34.2) (51.4) (8.9) (0.0)

Blood and Lymphatic

System Disorders

94 32 20 2 0

74 48 24 0 0

(63.5) (21.6) (13.5) (1.4) (0) (50.7) (32.9) (16.4) (0) (0)

Cardiac Disorders

141 7 0 0 0

144 2 0 0 0

(95.3) (4.7) (0) (0) (0) (98.6) (1.4) (0) (0) (0)

Congenital, Familial and

Genetic Disorders

148 0 0 0 0

146 0 0 0 0

(100) (0) (0) (0) (0) (100) (0) (0) (0) (0)

Ear and Labyrinth

Disorders

146 2 0 0 0

145 1 0 0 0

(98.6) (1.4) (0) (0) (0) (99.3) (0.7) (0) (0) (0)

Endocrine Disorders

148 0 0 0 0

146 0 0 0 0

(100) (0) (0) (0) (0) (100) (0) (0) (0) (0)

Eye Disorders

146 2 0 0 0

146 0 0 0 0

(98.6) (1.4) (0) (0) (0) (100) (0) (0) (0) (0)


77 57 14 0 0

71 57 18 0 0

(52) (38.5) (9.5) (0) (0) (48.6) (39) (12.3) (0) (0)

General Disorders and

Administration Site

Conditions

79 65 4 0 0

92 48 6 0 0

(53.4) (43.9) (2.7) (0) (0) (63) (32.9) (4.1) (0) (0)

Hepatobiliary Disorders

148 0 0 0 0

146 0 0 0 0

(100) (0) (0) (0) (0) (100) (0) (0) (0) (0)


146 2 0 0 0

146 0 0 0 0

(98.6) (1.4) (0) (0) (0) (100) (0) (0) (0) (0)


106 36 6 0 0

106 37 3 0 0

(71.6) (24.3) (4.1) (0) (0) (72.6) (25.3) (2.1) (0) (0)

Injury, Poisoning and

Procedural Complications

146 2 0 0 0

142 3 1 0 0

(98.6) (1.4) (0) (0) (0) (97.3) (2.1) (0.7) (0) (0)

Investigations

105 21 14 8 0

80 15 39 12 0

(70.9) (14.2) (9.5) (5.4) (0) (54.8) (10.3) (26.7) (8.2) (0)

Metabolism and Nutrition

Disorders

115 23 9 1 0

110 26 9 1 0

(77.7) (15.5) (6.1) (0.7) (0) (75.3) (17.8) (6.2) (0.7) (0)

Musculoskeletal and

Connective Tissue

Disorders

119 26 3 0 0

113 29 4 0 0

(80.4) (17.6) (2) (0) (0) (77.4) (19.9) (2.7) (0) (0)


Page 8 of 10

ACWP (N=148)


System Organ Class



0-1 2 3 4 5 0-1 2 3 4 5

Neoplasms Benign,

Malignant and Unspecified

(Incl Cysts and Polyps)

148 0 0 0 0

146 0 0 0 0

(100) (0) (0) (0) (0) (100) (0) (0) (0) (0)

Nervous System Disorders

108 31 9 0 0

97 43 6 0 0

(73) (20.9) (6.1) (0) (0) (66.4) (29.5) (4.1) (0) (0)

Pregnancy, Puerperium and

Perinatal Conditions

148 0 0 0 0

146 0 0 0 0

(100) (0) (0) (0) (0) (100) (0) (0) (0) (0)


132 16 0 0 0

124 19 2 1 0

(89.2) (10.8) (0) (0) (0) (84.9) (13) (1.4) (0.7) (0)

Renal and Urinary

Disorders

146 1 1 0 0

146 0 0 0 0

(98.6) (0.7) (0.7) (0) (0) (100) (0) (0) (0) (0)

Reproductive System and

Breast Disorders

145 3 0 0 0

144 2 0 0 0

(98) (2) (0) (0) (0) (98.6) (1.4) (0) (0) (0)

Respiratory, Thoracic and

Mediastinal Disorders

124 21 2 1 0

117 28 1 0 0

(83.8) (14.2) (1.4) (0.7) (0) (80.1) (19.2) (0.7) (0) (0)

Skin and Subcutaneous

Tissue Disorders

84 63 1 0 0

81 62 3 0 0

(56.8) (42.6) (0.7) (0) (0) (55.5) (42.5) (2.1) (0) (0)


148 0 0 0 0

146 0 0 0 0

(100) (0) (0) (0) (0) (100) (0) (0) (0) (0)

Surgical and Medical

Procedures

147 1 0 0 0

146 0 0 0 0

(99.3) (0.7) (0) (0) (0) (100) (0) (0) (0) (0)

Vascular Disorders

114 25 9 0 0

119 19 8 0 0

(77) (16.9) (6.1) (0) (0) (81.5) (13) (5.5) (0) (0)

Adverse events were graded with CTCAE version 4.0


Page 9 of 10

Table 5

Distribution of NRG BR003 Patients by Highest Grade Adverse Event

by Specific Adverse Event Term– Data as of 4/30/2017


ACWP (N=148)





0-1 2 3 4 5 0-1 2 3 4 5

Blood and Lymphatic

System Disorders

104 33 11 0 0 79 50 17 0 0

Anemia (70.3) (22.3) (7.4) 0 0 (54.1) (34.2) (11.6) 0 0


Nausea

112 34 2 0 0

101 36 9 0 0

(75.7) (23) (1.4) (0) (0) (69.2) (24.7) (6.2) (0) (0)

136 11 1 0 0 121 19 6 0 0

Vomiting (91.9) (7.4) (0.7) (0) (0) (82.9) (13) (4.1) (0) (0)

General Disorders and

Administration Site

Fatigue 98 47 0 0 0 97 44 5 0 0

(66.2) (31.8) (0) (0) (0) (66.4) (30.1) (3.4) (0) (0)


Other Infections and 140 8 0 0 0 137 6 3 0 0

infestations (94.6) (5.4) (0) (0) (0) (93.8) (4.1) (2.1) (0) (0)

Investigations

Lymphocyte count 133 6 7 2 0 132 9 5 0 0

decreased (89.9) (4.1) (4.7) (1.4) (0) (90.4) (6.2) (3.4) (0) (0)

Neutrophil count 131 7 4 6 0 97 15 26 8 0

decreased (89.9) (4.7) (2.7) (4.1) (0) (66.4) (10.3) (17.8) (5.5) (0)

Platelet count decreased 145 2 0 1 0 128 10 8 0 0

(98) (1.4) (0) (0.7) (0) (87.7) (6.8) (5.5) (0) (0)

White blood cell 134 10 3 1 0 99 19 24 4 0

decreased (90.5) (6.8) (2) (0.7) (0) (67.8) (13) (16.4) (2.7) (0)

Nervous System Disorders

Peripheral sensory 125 19 4 0 0 120 5 0 0 0

neuropathy (84.5) (12.8) (2.7) (0) (0) (96.6) (3.4) (0) (0) (0) Adverse events were graded with CTCAE version 4.0

Only toxicities with the difference of 3 or more in Grade 3-5 are presented.


Page 10 of 10

Figure 1

Cumulative Accrual for NRG BR003 – Data as of 4/30/2017

0200

400

600

800

1000

Month and Year of Accrual

Cum

ula

tive N

um

ber

of

Patients

Random

ized

Jun-

15

Jul-1

5

Aug-1

5

Sep-1

5

Oct-1

5

Nov-

15

Dec-

15

Jan-

16

Feb-1

6

Mar

-16

Apr-1

6

May

-16

Jun-

16

Jul-1

6

Aug-1

6

Sep-1

6

Oct-1

6

Nov-

16

Dec-

16

Jan-

17

Feb-1

7

Mar

-17

Apr-1

7

Projected Accrual

Observed Accrual

990

310


Page 1 of 10

NSABP B-51/RTOG 1304

Report Based on Data Through 04/30/2016

A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy

Chestwall and Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT in Patients with Positive Axillary Nodes Before Neoadjuvant Chemotherapy

Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy

Study Chairs: Eleftherios Mamounas, MD, MPH Julia White, MD Radiation Oncology Co-Chairs: Atif Kahn, MD Simona Shaitelman, MD Mylin Torres, MD Frank Vicini, MD Protocol Officer: Thomas Julian, MD Behavioral and Health Outcomes Officer: Patricia Ganz, MD Behavioral and Health Outcomes Co-Officer: Susan McCloskey, MD Protocol Statistician: Hanna Bandos, PhD

Protocol Pathologist: Soonmyung Paik, MD Protocol Physicist: Nilendu Gupta, PhD Protocol Co-Physicists: Allen Li, PhD

Dominic Di Costanzo, MS Activated: August 22, 2013 Status: Accruing


Page 2 of 10

NSABP PROTOCOL B-51/RTOG 1304 Schema


• Group 1 − Radiation therapy for Group 1A Whole breast irradiation + boost − No radiation therapy for Group 1B

• Group 2 − Radiation therapy for Group 2A Whole breast irradiation + boost and regional nodal irradiation − Radiation therapy for Group 2B Chest wall and regional nodal irradiation

** All patients will receive additional systemic therapy as planned (i.e., hormonal therapy for patients with hormone receptor-positive breast cancer and trastuzumab or other anti-HER2 therapy for patients with breast cancer that is HER2-positive).

Clinically T1–3, N1 Breast Cancer Documented Positive Axillary Nodes by FNA or by Core Needle Biopsy

Minimum of 12 Weeks of Standard Neoadjuvant Chemotherapy Plus Anti-HER2 Therapy for Patients with HER2-Positive Tumors

Definitive Surgery with Histologic Documentation of Negative Axillary Nodes (Either by Axillary Dissection or by Sentinel Node Biopsy ± Axillary Dissection)

STRATIFICATION • Type of surgery (mastectomy, lumpectomy) • Hormone receptor status (ER-positive and/or PgR-positive; ER- and PgR-negative) • HER2 status (negative, positive) • Adjuvant chemotherapy (yes, no) • pCR in breast (yes, no)

RANDOMIZATION

Group 1 (Groups 1A and 1B)*,** No Regional Nodal XRT

• Group 1A Lumpectomy: No regional nodal XRT with WBI

• Group 1B Mastectomy: No regional nodal XRT and no chest wall XRT

Group 2 (Groups 2A and 2B) *,**

Regional Nodal XRT • Group 2A Lumpectomy: Regional

nodal XRT with WBI • Group 2B Mastectomy: Regional

nodal XRT and chestwall XRT


Page 3 of 10

• Study description

NSABP B-51/RTOG 1304 is a Phase III, multicenter, randomized post neoadjuvant therapy trial to evaluate whether the addition of chestwall and regional nodal radiation therapy (XRT) after mastectomy or breast and regional nodal XRT after breast conserving surgery will significantly reduce the rate of events for invasive breast cancer recurrence-free interval in patients who present with histologically positive axillary nodes but convert to histologically negative axillary nodes following neoadjuvant chemotherapy. Eligible patients must have clinically T1-3, N1 breast cancer at the time of diagnosis and must have had pathologic confirmation of axillary nodal involvement at presentation (before neoadjuvant therapy) based on either a positive FNA (demonstrating malignant cells) or positive core needle biopsy (demonstrating invasive adenocarcinoma). Patients must have completed a minimum of 12 weeks of standard neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen. Patients with HER2-positive tumors must have received neoadjuvant trastuzumab or other anti-HER2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen), unless medically contraindicated. After patients complete their neoadjuvant chemotherapy, they will have either a lumpectomy or a mastectomy. At the time of definitive surgery, all removed axillary nodes must be histologically free from cancer. Patients are stratified by type of breast surgery, hormone receptor status, HER2 status, adjuvant chemotherapy, and pCR in breast.

• Patient Accrual

This protocol was opened for accrual on August 22, 2013. The first patient was accrued to the study on September 16, 2013. As of April 30, 2016, 322 (19.7%) patients had been accrued to NSABP B-51/RTOG 1304. Accrual has been slower than projected (Table 1, Figure 1). As of April 30, 2016, follow-up information was available for 148 of the 322 patients randomized. Among patients with follow-up, the median time of follow-up is 10.3 months.

• Patient and Tumor Characteristics

There have been no ineligible patients declared as of April 30, 2016 (Table 2). Of all randomized patients, 15 have withdrawn consent to be followed. Among them, six patients were randomized to the “No XRT” and nine patients were randomized to the “XRT” treatment groups. Patient and tumor characteristics of all randomized patients are presented in Table 3. The majority of patients are 50 years of age or older (61%), white (71%), and had lumpectomy performed as their definitive surgery (63%).

• Adverse Events

As of April 30, 2016, adverse event information had been received for 225 patients (114 in the “no XRT” group and 111 in the “XRT” group). One hundred and nineteen patients have experienced at least one grade 2 or higher adverse event (51 in the “No XRT” group and 68 in the “XRT” group). There were 20 patients who experienced a grade 3 adverse event as their highest (four in the “No XRT” and 16 in the “XRT” treatment group). There have been no grade 4 or 5 toxicities reported. The distribution of patients by the highest grade experienced within each system organ class is summarized in Table 4. There was one system organ class (Injury, Poisoning and Procedural Complications) with a treatment difference of three or more in grade 3 toxicities. The detailed distribution of the adverse events experienced within Injury, Poisoning and Procedural Complications class is presented in Table 5. Only terms with non-zero Grade 3 toxicities are presented.


Page 4 of 10

Table 1

NSABP B-51/RTOG 1304 Accrual Summary - Data as of 04/30/2016

Date activated to accrual: August 22, 2013 Targeted Sample Size: 1,636 Projected monthly accrual: 28 Average monthly accrual over last 6 months: 18.5 Projected accrual as of 04/30/2016: 796 Total accrual as of 04/30/2016: 322 Percent of projected accrual achieved as of 04/30/2016: 40.45% Percent of total targeted accrual as of 04/30/2016: 19.68% Projected completion date based on last 6 months accrual: March 2022


Page 5 of 10

Table 2

NSABP B-51/RTOG 1304 Consent Withdrawals and Reasons for Ineligibility - Data as of 04/30/2016

No regional Nodal XRT

Regional Nodal XRT Total

Randomized 160 162 322 Withdrew consent 6 9 15 Eligible 160 162 322 Ineligible 0 0 0


Page 6 of 10

Table 3

Patient and Tumor Characteristics for All Randomized Patients in NSABP B-51/RTOG 1304 – Data as of 04/30/2016

Patient or Tumor Characteristic No regional Nodal

XRT Regional Nodal

XRT Total

n % n % n % Age (Years)

≤ 49 63 39.4 62 38.3 125 38.8 50-59 57 35.6 54 33.3 111 34.5 ≥ 60 40 25.0 46 28.4 86 26.7

Race White 109 68.1 119 73.5 228 70.8 Black/African American 35 21.9 27 16.7 62 19.3 Other 10 6.3 13 8.0 23 7.1 Unknown 6 3.8 2 1.2 8 2.5 Multiracial 0 0.0 1 0.6 1 0.3

Ethnicity Hispanic or Latino 24 15.0 32 19.8 56 17.4 Not Hispanic or Latino 132 82.5 125 77.2 257 79.8 Unknown 4 2.5 5 3.1 9 2.8

Type of Surgery Lumpectomy 100 62.5 103 63.6 203 63.0 Mastectomy 60 37.5 59 36.4 119 37.0

Hormone Receptor Status Positive 84 52.5 82 50.6 166 51.6 Negative 76 47.5 80 49.4 156 48.4

HER2 Status Positive 84 52.5 89 54.9 173 53.7 Negative 76 47.5 73 45.1 149 46.3

Adjuvant Chemotherapy Yes 1 0.6 0 0.0 1 0.3 No 159 99.4 162 100.0 321 99.7

pCR in breast Yes 127 79.4 123 75.9 250 77.6 No 33 20.6 39 24.1 72 22.4

Consented to PRO/QOL collection Yes 138 86.3 133 82.1 271 84.2 No 22 13.7 29 17.9 51 15.8

Total 160 100.0 162 100.0 322 100.0


Page 7 of 10

Table 4

Distribution of NSABP-B-51/RTOG 1304 Patients by Highest Grade Adverse Event by System Organ Class – Data as of 04/30/2016




System Organ Class




63 47 4 0 0

43 52 16 0 0 (55.3) (41.2) (3.5) (0.0) (0.0) (38.7) (46.8) (14.4) (0.0) (0.0)

Blood and Lymphatic System Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Cardiac Disorders

112 1 1 0 0

111 0 0 0 0 (98.2) (0.9) (0.9) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Congenital, Familial and Genetic Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Ear and Labyrinth Disorders

114 0 0 0 0

110 1 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (99.1) (0.9) (0.0) (0.0) (0.0)

Endocrine Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Eye Disorders

114 0 0 0 0

110 0 1 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (99.1) (0.0) (0.9) (0.0) (0.0)


113 1 0 0 0

103 7 1 0 0 (99.1) (0.9) (0.0) (0.0) (0.0) (92.8) (6.3) (0.9) (0.0) (0.0)

General Disorders and Administration Site Conditions

102 12 0 0 0

93 18 0 0 0

(89.5) (10.5) (0.0) (0.0) (0.0) (83.8) (16.2) (0.0) (0.0) (0.0) Hepatobiliary Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)


114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)


111 3 0 0 0

107 4 0 0 0 (97.4) (2.6) (0.0) (0.0) (0.0) (96.4) (3.6) (0.0) (0.0) (0.0)


80 31 3 0 0

61 38 12 0 0 (70.2) (27.2) (2.6) (0.0) (0.0) (55.0) (34.2) (10.8) (0.0) (0.0)

Investigations

114 0 0 0 0

110 1 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (99.1) (0.9) (0.0) (0.0) (0.0)

Metabolism and Nutrition Disorders

114 0 0 0 0

109 1 1 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (98.2) (0.9) (0.9) (0.0) (0.0)

Musculoskeletal and Connective Tissue Disorders

110 4 0 0 0

106 4 1 0 0 (96.5) (3.5) (0.0) (0.0) (0.0) (95.5) (3.6) (0.9) (0.0) (0.0)


Page 8 of 10



System Organ Class



Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)

114 0 0 0 0

111 0 0 0 0

(100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0) Nervous System Disorders

111 3 0 0 0

108 3 0 0 0 (97.4) (2.6) (0.0) (0.0) (0.0) (97.3) (2.7) (0.0) (0.0) (0.0)

Pregnancy, Puerperium and Perinatal Conditions

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)


112 2 0 0 0

110 1 0 0 0 (98.2) (1.8) (0.0) (0.0) (0.0) (99.1) (0.9) (0.0) (0.0) (0.0)

Renal and Urinary Disorders

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Reproductive System and Breast Disorders

105 9 0 0 0

109 2 0 0 0 (92.1) (7.9) (0.0) (0.0) (0.0) (98.2) (1.8) (0.0) (0.0) (0.0)

Respiratory, Thoracic and Mediastinal Disorders

111 3 0 0 0

107 3 1 0 0 (97.4) (2.6) (0.0) (0.0) (0.0) (96.4) (2.7) (0.9) (0.0) (0.0)

Skin and Subcutaneous Tissue Disorders

100 14 0 0 0

90 21 0 0 0 (87.7) (12.3) (0.0) (0.0) (0.0) (81.1) (18.9) (0.0) (0.0) (0.0)


114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Surgical and Medical Procedures

114 0 0 0 0

111 0 0 0 0 (100.0) (0.0) (0.0) (0.0) (0.0) (100.0) (0.0) (0.0) (0.0) (0.0)

Vascular Disorders

112 2 0 0 0

106 3 2 0 0

(98.2) (1.8) (0.0) (0.0) (0.0) (95.5) (2.7) (1.8) (0.0) (0.0) Adverse events were graded with CTCAE version 4.0


Page 9 of 10

Table 5

Distribution of NSABP-B-51/RTOG 1304 Patients by Highest Grade Adverse Event by Specific Adverse Event Term– Data as of 04/30/2016








Dermatitis radiation

84 27 3 0 0

66 33 12 0 0 (73.7) (23.7) (2.6) (0.0) (0.0) (59.5) (29.7) (10.8) (0.0) (0.0)

Adverse events were graded with CTCAE version 4.0 Only terms with non-zero Grade 3-5 toxicities from the System Organ Classes with the difference of 3 or more in Grade 3-5 are presented.


Page 10 of 10

0

300

600

900

1200

1500

1800

Cum

ulat

ive

Num

ber o

f Pat

ient

s R

ando

miz

ed

Month and Year

Figure 1

Cumulative Accrual for NSABP B-51 - Data as of 04/30/2016

Projected Accrual

Observed Accrual

322

1,636

796



Alliance Study A011106 – Alternate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant Treatment (ALTERNATE) in postmenopausal women: A

Phase III Study

Data as of 10/02/2019

Committee: Breast Study Statisticians: Vera Suman, PhD. Study Chair: Cynthia X. Ma, MD, PhD Travis Dockter, M.S 1.0 OBJECTIVES

Primary objectives

1. To determine whether fulvestrant administered for 24 weeks as neoadjuvant endocrine treatment increases the proportion of endocrine sensitive tumors relative to patients treated with anastrozole.

2. To determine whether fulvestrant in combination with anastrozole, administered for 24 weeks as neoadjuvant endocrine treatment, increases the proportion of endocrine sensitive tumors* relative to patients treated with anastrozole.

3. If both of the fulvestrant containing arms are found to have an endocrine sensitive disease rate at least 10% higher than that of the anastrozole arm, we will assess whether the endocrine sensitive disease rate is greater with the combination of anastrozole and fulvestrant than with fulvestrant alone.

4. To assess whether the 5-year RFS rate among women treated with anastrozole with a modified preoperative endocrine prognostic index (PEPI) score of 0 following 24 weeks of neoadjuvant treatment is at most 90%.

5. For the fulvestrant containing regimens, a point and interval estimate of the 5 year RFS will be obtained.

Secondary objectives

1. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between the fulvestrant arm and the anastrozole arm.

2. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between patients randomized to fulvestrant in combination with anastrozole and those randomized to anastrozole.

3. To examine the rate of pathologic complete response (pCR) of 12 weeks of neoadjuvant paclitaxel in patients with endocrine resistant disease following 4-weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole).

4. To examine the rate of pathologic complete response (pCR) among those patients with endocrine resistant disease, following 4 weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole), who choose not to receive neoadjuvant paclitaxel, but another standard neoadjuvant taxane and /or anthracycline containing regimen or CMF.

5. To summarize the frequency of severe (NCI CTCAE grade > 3) adverse events encountered with administration of paclitaxel in the neoadjuvant setting.

6. To assess time to breast cancer recurrence for patients with endocrine resistant tumors defined by tumor 1) Ki67 >10% at week 4; 2) Ki67 >10% at week 12; and 3) modified PEPI score of non-zero on neoadjuvant endocrine therapy, with all three groups combined or separated.

2.0 CURRENT SCHEMA




A patient will be eligible for inclusion in this study only if ALL of the following criteria apply:

1. Female ≥ 18 years of age. 2. ECOG performance status 0-2. 3. Postmenopausal, verified by:

- Post bilateral surgical oophorectomy, or - No spontaneous menses > 1 year or - No menses for < 1 year with FSH and estradiol levels in postmenopausal range,

according to institutional standards 4. Pathologic confirmation of invasive breast cancer diagnosed by core needle biopsy.

5. Clinical T2-T4c, any N, M0 invasive breast cancer, by AJCC 7th edition clinical staging, with the goal being surgery to complete excision of the tumor in the breast and the lymph node. 6. Primary lesion must be:

- palpable - its size can be measured bidimensional by tape, ruler or caliper technique, and - its largest tumor diameter is at least 2.0 cm by physical examination or by radiological assessment.

7. Invasive breast cancer is estrogen receptor positive with an Allred score of 6, 7 or 8 by local institution standard protocol. 8. Invasive breast cancer is HER2 negative defined as (1) 0 or 1+ by IHC and ISH not done. (2) 0 or 1+ by IHC or ISH ratio (HER2 gene copy/chromosome 17) < 2 (3) 2+ by IHC and ISH ratio (HER2 gene copy/chromosome 17) < 2



9. Documentation of mammogram and ultrasound (including DCIS and invasive cancer) of the diseased breast preformed within 42 days prior to registration. Mammogram for the unaffected contralateral breast is required within 12 months prior to registration.

10. Laboratory values (≤14 days prior to registration) Absolute Neutrophil Count (ANC) > 1,000/mm3 Platelet Count > 100,000/mm3 Total Bilirubin < 1.5 x upper limits of normal (ULN) Creatinine <1.5 x upper limits of normal (ULN) Serum ALT < 2.5 x upper limits of normal (ULN)

11. Tissue acquisition: Patient must agree to provide the required research biopsies at baseline, week 4 and at surgery for biomarker and correlative studies.

Contradictions to study registration:

1. Premenopausal status 2. Inflammatory breast cancer defined as clinically significant erythema of the breast

and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau d’orange without erythema).

3. An excisional biopsy of this breast cancer 4. Hormone replacement therapy of any type, megestrol acetate, or raloxifene within one week prior to registration. 5. Tumor ER Allred score between 0-5 or HER2 positive by IHC (3+) or amplified by FISH > 2.0 6. Surgical axillary staging procedure prior to study entry. Note: FNA or core needle biopsy of axillary node is permitted. 7. Clinical or radiographic evidence of metastatic disease. Metastatic workup is not required, but is recommended for patients with clinical stage III disease. Note: isolated ipsilateral supraclavicular node involvement is permitted 8. Breast implants are contraindicated only if the implant precludes the required research biopsies. Patients who have previously had implants removed within 6 weeks prior to registration are eligible. 9. Treatment for this cancer including surgery, radiation therapy, chemotherapy,

biotherapy, hormonal therapy or investigational agent prior to study entry. 10. Patients with bilateral ductal carcinoma in situ and/or invasive breast cancer are not eligible.




Treatment/follow-up decision: If a patient is found to have a 4 week Ki67 > 10%, it is recommended that the patient be switched to neoadjuvant chemotherapy. If the patient refuses to switch to neo-adjuvant chemotherapy, or is not a candidate for neoadjuvant chemotherapy, decides to start neoadjuvant treatment with another regimen, or decides to undergo immediate surgery, submit on-line data indicating whether the patient will go immediately to surgery or begin other anti-neoplastic approaches. These patients will go to extended follow-up where further treatment is at the discretion of her treating physician.

Treatment/follow-up decision during neo-adjuvant phase: • If no evidence of clinical progression, continue to follow protocol procedures. • If there is physical evidence for clinical progression with clinical assessment of the lymph node mass, an ultrasound of the axilla should be done to confirm/rule out progressive disease.

1) If progression is confirmed by ultrasound OR mammographic imaging, treatment is at the investigator’s discretion, operate as soon as possible or begin other anti-neoplastic approaches such as chemotherapy or radiation therapy.



2) If disease progression is not confirmed by ultrasound or mammographic imaging, study drug may be continued at the investigator’s discretion, and the protocol should be followed. If the study drug is to be discontinued, the patient will go to the extended follow-up

phase. 3) Clinical progression outside the primary site (i.e., the development of a new breast mass or the development of clinical suspicion for advanced disease) should lead to further imaging evaluation and if confirmed, study drug will be discontinued after correlative samples of the primary tumor have been obtained. Subsequent management is at the investigator’s discretion. The patient will go to the extended follow-up phase

Surgery: Surgery should be scheduled during the last 3 weeks (days 7 to 28) of the 6th cycle

of neoadjuvant endocrine therapy (Arms I, II and III) or 3-6 weeks following the last dose of neoadjuvant paclitaxel or other NCCN regimen (Neoadjuvant Chemotherapy Group). Patients who refuse to undergo surgery or are unable to undergo surgery due to co-morbid conditions will go to extended follow-up phase of the trial. Patients may be treated at the physician’s discretion. The type of breast surgery is determined by the treating surgeon according to institutional standard, with the goal to completely excise the tumor.

Postoperative systemic therapy Arm I:

• Modified PEPI 0 Group: Adjuvant anastrozole 1 mg PO daily for 54 cycles

(approximately 4.5 years). Patient may not participate in other adjuvant trials of pharmaceutical interventions.

Arm II:

• Modified PEPI 0 Group: Adjuvant fulvestrant 500 mg IM day 1 for 18 cycles followed by anastrozole 1 mg PO daily for 36 cycles (approximately 3 years). If the last

dose of neoadjuvant fulvestrant was administered more than 4 weeks prior to beginning adjuvant fulvestrant, a reload with fulvestrant (500mg IM on days 1 and 15) during the first cycle is needed.

Arm III: • Modified PEPI 0 Group:

Adjuvant anastrozole 1 mg PO daily in combination with fulvestrant 500 mg IM day 1 for 18 cycles, followed by anastrozole 1 mg PO daily for 36

cycles (approximately 3 years). If the last dose of neoadjuvant fulvestrant was administered more than 4 weeks prior to beginning adjuvant fulvestrant, a reload

with fulvestrant (500mg IM on days 1 and 15) during the first cycle is needed. Patient may not participate in other adjuvant trials of pharmaceutical

interventions. Adjuvant radiation therapy

• The administration of adjuvant radiation to the breast and draining lymph nodes is according to institutional standard. • Whole breast radiation rather than partial breast or brachytherapy, is recommended for patients where adjuvant radiation is indicated.

The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report).

5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors



This clinical trial was designed to address two issues: (1) whether the endocrine resistance rate with either of the fulvestrant containing regimens is significantly less than the endocrine resistance rate with anastrozole, and (2) whether the 5 year recurrence-free survival rate (RFS) among women with a modified PEPI score of 0 following treatment with the neoadjuvant anastrozole is at most 90%. The Pocock - Simon dynamic allocation procedure will be used to allocate an equal number of patients to each of the 3 treatment strategies. The stratification factors are clinical tumor stage, clinical lymph node status, and performance status.


First Phase (Neoadjuvant question)

The primary endpoint of the neoadjuvant portion of this trial is the rate of endocrine resistant disease. A patient is considered to have endocrine resistant disease if any of the following holds true: • Ki67 > 10% after 4 weeks on neoadjuvant endocrine therapy; • Ki67 > 10% after 12 weeks on neoadjuvant endocrine therapy (note: week 12

sample collection was discontinued in Update #07); • Progressive disease is documented anytime during neoadjuvant endocrine

therapy; • Surgical findings at 24-26 weeks post neoadjuvant endocrine therapy are such

that: pT stage is 3/4, positive lymph nodes (except N1mi) are present or Ki67 > 2.7% (i.e. non-zero modified PEPI score of not being 0); or

• Discontinued study treatment for any reason without completing surgery (to preserve the intent to treat principle).

Note: A patient who does not meet any of the criteria for endocrine resistant disease will be referred to as having endocrine sensitive disease.

Second Phase (Adjuvant question)

The second phase of this clinical trial is designed to examine whether 5 year RFS rate is at most 90% among the women randomized to anastrozole who had a modified PEPI score of 0 and continue to receive protocol treatment for an additional 4.5 years after surgery. Recurrence-free survival is defined as the time of surgery to the first of the following events: Invasive ipsilateral breast tumor recurrence, local/regional invasive breast cancer recurrence, distant recurrence or death from breast cancer.

5.3 Target Accrual

Neoadjuvant Phase: A total of 1275 eligible patients were to be randomized in equal numbers to each of the 3 treatment arms. Adjuvant Phase: Enrollment will continue approximately 9-12 months after the 1275 patients required to complete the neoadjuvant phase of the trial are enrolled. Approximately 1455 patients will be enrolled. The target accrual rate is 20 patients per month.

6.0 CURRENT ACCRUAL

Study Activation Date 12/13/2013 Temporary Closure Date* 08/30/2016



Reopened to Accrual 9/15/2016 Closure Date for Arms 2 and 3 11/1/2018 Temporary Closure Date for Arm 1 11/1/2018 Arm 1 reopened to Accrual 11/30/2018 Temporary Closure Date for Arm 1 05/09/2019 Closed to enrollment 7/15/2019 Maximum Target Accrual (n) [depends upon the number of treatment arms carried forward to adjuvant phase]

1275 (complete for the neo-adjuvant phase) 1455 (complete for the adjuvant phase)

Current Accrual (n) 1473 Expected Accrual Rate** 20/month Accrual Rate – Since activation 22.3/month Accrual Rate – Past 12 months*** 29.1/month Accrual Rate – Past 6 months 23.2/month Projected closure date for a trial open for more than one year (based on accrual rate from past 12 months)

4/11/2019

*Due to a shortage of supply of the study drug, this study was temporarily suspended on August 30th, 2016 and re-opened on September 15th, 2016. Due to completion of the 1st phase, enrollment was temporarily suspended on November 1st, 2018. Enrollment resumed on November 30, 2018 to Anastrozole (arm 1) for the 2nd phase of this trial.

**Reduced to 20 per month on April 15th, 2017 ***Temporary closure for Arm 1 May, 9th 2019. Permanently closed 07/15/2019.


This study was activated on 12/13/2013. The enrollment goal for the neoadjuvant portion of this trial (1275 eligible patients; 425 patients per arm) was met as of November 1, 2018. On May 9, 2019 enrollment was temporarily suspended to Arm 1 on May 9, 2019 and then permanently closed on July15, 2019.

8.0 PATIENT CHARACTERISTICS Table 8a. Demographics


1(Anastrozole)

(N=563) 2(Fulvestrant)

(N=454) 3(A+F) (N=456)

Total (N=1473)

Age N 563 454 456 1473 Mean (SD) 64.9 (8.2) 64.8 (8.2) 64.2 (8.4) 64.7 (8.2) Median 65.0 64.0 63.0 64.0 Q1, Q3 59.0, 71.0 59.0, 70.0 58.0, 70.0 58.0, 70.0 Range (46.0-92.0) (46.0-87.0) (45.0-87.0) (45.0-92.0) Race White 465 (82.6%) 378 (83.3%) 387 (84.9%) 1230 (83.5%) Black or African American 53 (9.4%) 43 (9.5%) 27 (5.9%) 123 (8.4%) Native Hawaiian or Other Pacific Islander

1 (0.2%) 2 (0.4%) 1 (0.2%) 4 (0.3%)

Asian 10 (1.8%) 8 (1.8%) 13 (2.9%) 31 (2.1%) American Indian or Alaska Native 7 (1.2%) 1 (0.2%) 2 (0.4%) 10 (0.7%) Not reported: patient refused or not available

16 (2.8%) 16 (3.5%) 12 (2.6%) 44 (3.0%)




1(Anastrozole)


(N=454) 3(A+F) (N=456)

Total (N=1473)

Unknown: Patient unsure 11 (2.0%) 6 (1.3%) 14 (3.1%) 31 (2.1%) Gender Female 563 (100.0%) 454 (100.0%) 456 (100.0%) 1473 (100.0%)


1(Anastrozole)


(N=454) 3(A+F) (N=456)

Total (N=1473)

Clinical Lymph Node Status Positive 242 (43.0%) 194 (42.7%) 195 (42.8%) 631 (42.8%) Negative 321 (57.0%) 260 (57.3%) 261 (57.2%) 842 (57.2%) Clinical T Stage 1 326 (57.9%) 257 (56.6%) 259 (56.8%) 842 (57.2%) T2 191 (33.9%) 155 (34.1%) 156 (34.2%) 502 (34.1%) T3 42 (7.5%) 37 (8.1%) 37 (8.1%) 116 (7.9%) T4a-c 4 (0.7%) 5 (1.1%) 4 (0.9%) 13 (0.9%) Performance Status 0-1 554 (98.4%) 447 (98.5%) 448 (98.2%) 1449 (98.4%) 2 9 (1.6%) 7 (1.5%) 8 (1.8%) 24 (1.6%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for toxicity and adverse event (AE) reporting. There is no safety stopping rule for this trial. Arm 1(Anastrozole): Among the 554 patients randomized to anastrozole with toxicity data

available, the grade 4 adverse events reported that were at least possibility related include a neutrophil count decrease ( 3 pts). Other grade 4 toxicities reported as unrelated to study treatment included: intracranial hemorrhage (1 pt.), and hyponatremia (1 pt.). There were no grade 5 adverse events that were at least possibly related to treatment. However, one patient died during the end of her 5th cycle of treatment. She presented to the ED with a intracranial hemorrhage. Comfort measures were administered until her death later that day. There were also two women who died shortly after surgery due to AE. One woman who completed neo-adjuvant therapy, lumpectomy and a single cycle of adjuvant docetaxel and cytoxan developed a necrotic bowel. She underwent a hemicolectomy and died one day later due to sepsis. The seond woman who had a history of pulmonary hypertension, diabetes, hyperlipidemia and hypothyroidism completed NAC and surgery but required a re-operation the night of surgery for evacuation of a hematoma. She was followed for persistent elevated plumonary artery pressures secondary to volume overload. She continued to gain fluid weight and develop more hypoxemia. She become oliguric and was intubated. She went into bradycardiac arrest. CPR was performed with ECMO. She was found the next morning to be unresponsive and died later that day.



Arm 2(Fulvestrant): Among the 445 patients randomized to fulvestrant with toxicity data available, the grade 4 adverse events at least possibly related to treatment included a neutrophil count decrease (1 pt.) and white blood cell decrease (1 pt.). Other grade 4 toxicities reported as unrelated to study treatment included: anemia (1 pt.); myocardial infarction (1 pt.); hypertriglyceridemia (1 pt.); seziure (1pt); and hypertension (1pt.). There was one death on study among the women randomized to this treatment arm. It was a 60 year old woman who had switched to neo-adjuvant chemotherapy with doxorubicin and cyclophamide and then died after one month of NAC due to general discorders (queries are underway to obtain more information concerning this death).

Arm 3(A+F): Among the 443 patients randomized to anastrozole plus fulvestrant with toxicity data available, there was one death on study. A 64 years old woman with a history of type 2 diabetes, morbid obesity, hypertension, non-schemic dilated cardiomyopahty and coronary artery disease had a LVEF of 15-20% on pre-surgical cardiac evaluation died 10 days after breast surgery due to cardiac arrest that was considered to be not related to the study treatment. The grade 4 adverse events at least possibly related to treatment was neutrophil count decreased (1 pt.). Other grade 4 toxicities reported as unrelated to study treatment included febrile neutropenia (1 pt.); and obesity (1 pt.).

Number of Evaluable Patients:

Arm 1: Anastrozole (n=554) Arm 2: Fulvestrant (n=445)

Arm 3: Anastrozole + Fulvestrant (n=443)


Grade 2 Event 1 189 (34.1%)

2 139 (31.2%)

3 145 (32.7%)


2 45 (10.1%)

3 57 (12.9%)


2 6 (1.3%)

3 3 (0.7%)


2 1 (0.2%)

3 1 (0.2%)



2 5 (1.1%)

3 6 (1.4%)




2 1 (0.2%)

3 1 (0.2%)


2 2 (0.4%)

3 1 (0.2%)


2 0 (0.0%)

3 0 (0.0%)


Grade 2 Event 1 192 (34.7%)

2 138 (31.0%)

3 144 (32.5%)


2 46 (10.3%)

3 58 (13.1%)


2 4 (0.9%)

3 2 (0.5%)


2 1 (0.2%)

3 1 (0.2%)


Max Grade Per Patient Per Event Regardless of Attribution Number of Evaluable Patients:

Arm 1: Anastrozole (n=554) Arm 2: Fulvestrant (n=445) Arm 3: Anastrozole + Fulvestrant (n=443) Grade of Adverse Event

Arm 2- Mod 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%) n (%)


Anemia 1 4 ( 1%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 1 ( 0%) 1 ( 0%) 0 ( 0%) 3 4 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Blood and lymph sys disorders - Oth Spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






Lymphocyte count decreased 1 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphocyte count increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased 1 1 ( 0%) 1 ( 0%) 3 ( 1%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 1 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 1 ( 0%) 0 ( 0%) White blood cell decreased 1 1 ( 0%) 5 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 1 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events Blood and lymphatic sys disord

Febrile neutropenia 1 0 ( 0%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 0%) 0 ( 0%) Lymph node pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Cardiac disorders Acute coronary syndrome 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Atrial fibrillation 1 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Atrial flutter 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Atrioventricular block first degree

1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Cardiac arrest 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 0%)






Cardiac disorders - Other, specify

1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Chest pain - cardiac 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Heart failure 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Myocardial infarction 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 1 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Palpitations 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Pericardial effusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Restrictive cardiomyopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Sinus bradycardia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Sinus tachycardia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Ear and labyrinth disorders Ear and labyrinth disorders - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Ear pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hearing impaired 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%)






2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Vertigo 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Endocrine disorders Endocrine disorders - Other, specify

1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperparathyroidism 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperthyroidism 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypothyroidism 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Eye disorders Blurred vision 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Cataract 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Dry eye 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Eye disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Eye pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Retinal tear 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal disorders

Abdominal pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Bloating 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Cecal hemorrhage 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Colitis 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Constipation 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Diarrhea 1 6 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 6 ( 1%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 3 5 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspepsia 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Flatulence 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastric hemorrhage 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastric ulcer 1 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastritis 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastroesophageal reflux disease

1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal disorders - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hemorrhoids 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis oral 1 4 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Nausea 1 16 ( 3%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 19 ( 4%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 3 18 ( 4%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Oral pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Pancreatitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Vomiting 1 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Gen disord and admin site cond Death NOS 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Edema limbs 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Edema trunk 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






Fatigue 1 67 ( 12%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 2 51 ( 11%) 5 ( 1%) 0 ( 0%) 0 ( 0%) 3 58 ( 13%) 4 ( 1%) 0 ( 0%) 0 ( 0%) Fever 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Flu like symptoms 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gait disturbance 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gen disord and admin site conds-Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Infusion site extravasation 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Injection site reaction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Localized edema 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Malaise 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Non-cardiac chest pain 1 2 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Pain 1 5 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 7 ( 2%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 3 7 ( 2%) 1 ( 0%) 0 ( 0%) 0 ( 0%)

Hepatobiliary disorders Gallbladder pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Immune system disorders

Allergic reaction 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Infections and infestations Appendicitis 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Bladder infection 1 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Breast infection 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Bronchial infection 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Conjunctivitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Gum infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec

1 2 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 0%)

2 4 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 4 ( 1%) 4 ( 1%) 0 ( 0%) 0 ( 0%) Laryngitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 3 ( 1%) 0 ( 0%) 0 ( 0%) Mucosal infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






Otitis media 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Pharyngitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Sinusitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Skin infection 1 4 ( 1%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 3 ( 1%) 0 ( 0%) 0 ( 0%) Tooth infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Upper respiratory infection 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 11 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary tract infection 1 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 8 ( 2%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Uterine infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Vaginal infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Wound infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Inj, pois and proced complic Ankle fracture 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Bruising 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Fall 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Fracture 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hip fracture 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Infusion related reaction 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 7 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 6 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Seroma 1 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Wound dehiscence 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%)

Investigations Alanine aminotransferase increased

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Aspartate aminotransferase increased

1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Creatinine increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) ECG QT corrected interval prolonged

1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Investigations - Other, specify 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Weight loss 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Metabol and nutrition disord Anorexia 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 7 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Dehydration 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Hyperglycemia 1 3 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 4 ( 1%) 0 ( 0%) 0 ( 0%) Hyperkalemia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypertriglyceridemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 1 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypoalbuminemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypoglycemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Hypokalemia 1 0 ( 0%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Hyponatremia 1 0 ( 0%) 1 ( 0%) 1 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Metabolism, nutrition disord - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Obesity 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%)






2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 1 ( 0%) 0 ( 0%)

Musculosk and conn tiss disord Arthralgia 1 62 ( 11%) 6 ( 1%) 0 ( 0%) 0 ( 0%) 2 46 ( 10%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 3 51 ( 12%) 6 ( 1%) 0 ( 0%) 0 ( 0%) Arthritis 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Back pain 1 5 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 7 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Bone pain 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Buttock pain 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Chest wall pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Flank pain 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Generalized muscle weakness 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Joint range of motion decreased

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Muscle weakness lower limb 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Muscle weakness upper limb 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






Musculoskeletal, conn tissue - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Myalgia 1 35 ( 6%) 4 ( 1%) 0 ( 0%) 0 ( 0%) 2 25 ( 6%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 3 20 ( 5%) 3 ( 1%) 0 ( 0%) 0 ( 0%) Neck pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Pain in extremity 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 7 ( 2%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 5 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%)


1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Nervous system disorders Amnesia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Concentration impairment 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Dizziness 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Dysgeusia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Headache 1 11 ( 2%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 6 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Intracranial hemorrhage 1 0 ( 0%) 0 ( 0%) 1 ( 0%) 1 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






Memory impairment 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Nervous system disorders - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Neuralgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Paresthesia 1 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Peripheral sensory neuropathy 1 22 ( 4%) 4 ( 1%) 0 ( 0%) 0 ( 0%) 2 19 ( 4%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 12 ( 3%) 2 ( 0%) 0 ( 0%) 0 ( 0%) Phantom pain 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Presyncope 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Seizure 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 1 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Stroke 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Syncope 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 3 ( 1%) 0 ( 0%) 0 ( 0%) Transient ischemic attacks 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Psychiatric disorders Agitation 1 10 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 6 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%)






3 8 ( 2%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Anxiety 1 39 ( 7%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 27 ( 6%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 22 ( 5%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Confusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Delirium 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Depression 1 30 ( 5%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 20 ( 5%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 3 10 ( 2%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Euphoria 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Insomnia 1 6 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 11 ( 2%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 9 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Personality change 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Renal and urinary disorders Acute kidney injury 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Chronic kidney disease 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal and urinary disorders - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal calculi 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal colic 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary frequency 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary incontinence 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary tract obstruction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Urinary urgency 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Reprod sys and breast disord Breast pain 1 9 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 8 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 6 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspareunia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Pelvic pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Reproductive system and breast -Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Vaginal dryness 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Respirat, thor, mediast disord Allergic rhinitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Cough 1 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






3 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspnea 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hoarseness 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Nasal congestion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Postnasal drip 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Productive cough 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Pulmonary hypertension 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Resp, thoracic, mediastinal - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Sinus pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Sleep apnea 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Wheezing 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Skin and subcutan tiss disord Alopecia 1 13 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 7 ( 2%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 6 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Dry skin 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)






2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Erythema multiforme 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperhidrosis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Pain of skin 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Palmar-plantar erythrodysesthesia syndrm

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Photosensitivity 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Rash maculo-papular 1 3 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Skin and subcut tissue disord - Oth spec

1 4 ( 1%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 2 ( 0%) 0 ( 0%) 0 ( 0%) 3 4 ( 1%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Skin ulceration 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Urticaria 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)


1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

Vascular disorders






Hematoma 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 0%) 2 ( 0%) 0 ( 0%) 0 ( 0%) Hot flashes 1 48 ( 9%) 3 ( 1%) 0 ( 0%) 0 ( 0%) 2 45 ( 10%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 41 ( 9%) 3 ( 1%) 0 ( 0%) 0 ( 0%) Hypertension 1 11 ( 2%) 18 ( 3%) 0 ( 0%) 0 ( 0%) 2 8 ( 2%) 13 ( 3%) 1 ( 0%) 0 ( 0%) 3 10 ( 2%) 16 ( 4%) 0 ( 0%) 0 ( 0%) Hypotension 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) Phlebitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Superficial thrombophlebitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 2 ( 0%) 0 ( 0%) 0 ( 0%) Vascular disorders - Other, specify

1 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 1 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES CORRELATIVE RESEARCH STUDIES

Correlative science objectives (Week 12 sample collection discontinued in Update #07)

1. To assess whether the degree of tumor Ki67 suppression at week 4 and surgery differs between patients randomized to fulvestrant and those randomized to anastrozole.

2. To assess whether the degree of tumor Ki67 suppression at week 4 and surgery differs between patients randomized to fulvestrant in combination with anastrozole and those randomized to anastrozole.

3. To examine the impact of tumor ER expression level post-neoadjuvant endocrine therapy on RFS in each treatment arm separately.



4. To examine whether RFS differs with respect to pathologic tumor stage (T1 vs. T2) post-neoadjuvant endocrine therapy in the subgroup of women with a modified PEPI score of 0.

5. To examine whether rate of endocrine resistant tumors or RFS differs with respect to the degree of week 4 Ki67 suppression.

6. To examine whether the rate of week 4 Ki67 level > 10%, the rate of endocrine resistant tumors or RFS differs with respect to pre-treatment gene expression profile.

7. To examine whether gene expression profiles at week 4 can further refine the patient population who have modified PEPI score non-0 or shorter RFS.

8. To assess the pCR/RCB-1 rate in each of the following cohorts: a. Those who chose to switch to paclitaxel after finding their week 4 Ki67 was > 10%. b. Those who chose to switch to paclitaxel after finding their week 12 Ki67 was > 10%. c. Those patients who chose to switch to a standard neoadjuvant taxane and/or

anthracycline containing regimen or CMF (rather than paclitaxel) after finding their week 4 Ki67 was > 10%.

d. Those patients who chose to switch to a standard neoadjuvant taxane and/or anthracycline containing regimen or CMF (rather than paclitaxel) after finding their week 12 Ki67 was > 10%.

9. To evaluate Cycle 1, day 2 tumor biopsy following the initiation of paclitaxel to develop early molecular markers of tumor response to paclitaxel.

10. To evaluate tumor tissue, serum, and plasma specimens collected at baseline, on-therapy, and at surgery, and blood collected during follow-up and at recurrence for biomarker discovery (through methods such as gene expression profiling, patterns of gains or losses of DNA, tumor whole genome and targeted DNA and RNA sequencing and proteomics) in studies that aim to understand signaling pathways associated with endocrine therapy and taxane therapy sensitivity and resistance.



Alliance Study A011502 – A Randomized Phase III Double Blinded Placebo Controlled Trial of Aspirin as Adjuvant Therapy for Node Positive Her2 Negative Breast Cancer:

The ABC Trial

Data as of 09/18/2019 Committee: Breast Study Statisticians: Karla Ballman, Ph.D. Study Chair: Wendy Y. Chen, M.D., M.P.H. Linda McCall, M.S. 1.0 OBJECTIVES

Primary To compare the effect of aspirin (300 mg daily) versus placebo upon invasive disease free survival (iDFS) in early stage node-positive HER2 negative breast cancer patients.

Secondary

1. To compare the effect of aspirin versus placebo in early stage node-positive HER2 negative breast cancer patients upon:

a) Distant disease-free survival b) Overall survival c) Cardiovascular disease

2. To compare the toxicity of aspirin versus placebo in early stage node-positive HER2 negative breast cancer patients.

3. To assess adherence to aspirin and placebo among early stage node-positive HER2 negative breast cancer patients.

4. To bank tumor and germline deoxyribonucleic acid (DNA), plasma and urine collected at baseline and sequential plasma and urine collected 2 years later for future measurement of inflammatory markers.

5. To determine if there are subgroups of participants characterized by lifestyle factors associates with greater inflammation for whom there is greater benefit of aspirin versus placebo upon iDFS.

2.0 CURRENT SCHEMA


• Histologic documentation of women or men with node positive, HER2 negative, anatomic stage II or III breast carcinoma within one year of diagnosis and free of recurrence. If neoadjuvant therapy was received, either initial clinical stage (determined by physical and or radiologic examination) or post-operative pathologic stage can be used for eligibility purposes, with the higher stage determining eligibility. Histologic documentation of node positivity is required.

• Any ER/PgR status allowed. • Prior adjuvant treatment with chemotherapy and/or endocrine therapy, as determined the

treating physician, is allowed. The last dose of chemotherapy or radiation therapy must be at least 60 days prior to study registration. Concurrent hormonal therapy will be allowed.



• Regular NSAID/aspirin use (defined as ≥ 5 days per week) is allowed if aspirin and/or NSAIDs are stopped for one year prior to study entry and throughout the study period. Participants will be encouraged to use acetaminophen for minor pain and fever.

• Patients must be enrolled within 1 year after diagnosis. • Age > 18 and < 70 years of age. • ECOG performance status 0-2. • Patients with a prior history of gastric/duodenal ulcers documented on endoscopy can be

enrolled as long as the ulcers did not cause bleeding requiring a blood transfusion/major intervention. For patients who are Helicobacter pylori positive, a course of Helicobacter pylori eradication treatment must have been completed.

• No history of GI bleeding requiring a blood transfusion, endoscopic or operative intervention. • No history of any prior stroke (hemorrhagic or ischemic). • No concurrent anticoagulation with warfarin or heparin or clopidogrel or oral direct thrombin

inhibitors. • No history of atrial fibrillation or myocardial infarction. • No history of grade 4 hypertension, defined as hypertension resulting in life-threatening

consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis).

• No chronic (duration >30 days) daily use of oral steroids. • No known allergy to aspirin. • No prior malignancy of any type within the past 5 years other than breast cancer, basal or

squamous cell carcinoma of the skin or carcinoma in situ of the cervix. • Concurrent enrollment on a non-chemotherapy treatment trial will be allowed, as long as that

trial allows concurrent daily aspirin use. • Platelet count ≥ 100,000/mm3


The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report). 5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors This is a randomized double-blind placebo-controlled phase III trial of aspirin (300 mg daily) in early stage node-positive HER2 negative breast cancer patients. Patients will be randomized 1:1 within stratum defined by: Hormone Receptor status (HR positive vs HR negative), body mass index (<30 vs ≥ 30 kg/m2) and stage (Stage II vs III). 5.2 Primary Endpoint The primary endpoint of this trial is invasive disease-free survival (iDFS), defined as time from randomization to the first occurrence of any one of the following events for invasive disease: Distant recurrence, locoregional recurrence, ipsilateral or contralateral breast cancer, second primary (non-breast) invasive cancer or death from any cause. Censoring will occur on the date the patient was last known to be alive and free from all invasive breast cancer and second invasive primaries. 5.3 Target Accrual The target accrual for this study is 2936 patients using a 1:1 randomization. The target accrual rate is 108 patients per month with a 6 month ramp-up period to the target rate.

6.0 CURRENT ACCRUAL

The study opened on 12/8/2016. As of 9/7/2018, 664 of the targeted 2936 patients have been accrued.

Study Activation Date 12/08/2016



Target Accrual (n) 2936 Current Accrual (n) 1878 Expected Accrual Rate 108/month Accrual Rate – Since activation 55.2/month Accrual Rate – Past 12 months 99.2/month Accrual Rate – Past 6 months 100.7/month

0 3 10 16 24 25 35 14 39 31 31 31 32 52 38 50 4758 47 33 40 51

8599 72

103126

111118 82

102 111

100 57

Dec16 Mar17 Jun17 Sep17 Dec17 Mar18 Jun18 Sep18 Dec18 Mar19 Jun19 Sep19

Month

0

500

1000

1500

2000

2500

Tota

l Num

ber o

f Pat

ients

Expected Accrual 2396 PatientsActual Accrual

A011502 Cumulative Accrual: Actual Versus ExpectedNumbers on the Accrual Line are M onthly Accrual


This study is currently open to accrual. 8.0 PATIENT CHARACTERISTICS

All patients registered through 9/7/2017 are included in the patient characteristics tables below.

Table 8a. Demographics

Aspirin

(N=940) Placebo (N=938)

Total (N=1878)

Age N 940 938 1878 Mean (SD) 52.5 (9.1) 52.2 (9.1) 52.4 (9.1)



Aspirin

(N=940) Placebo (N=938)

Total (N=1878)

Median 53.0 52.0 53.0 Q1, Q3 46.0, 59.0 46.0, 59.0 46.0, 59.0 Range (23.0-69.0) (25.0-69.0) (23.0-69.0) Race White 775 (82.4%) 756 (80.6%) 1531 (81.5%) Black or African American 89 (9.5%) 89 (9.5%) 178 (9.5%) Native Hawaiian or Other Pacific Islander 4 (0.4%) 4 (0.4%) 8 (0.4%) Asian 40 (4.3%) 36 (3.8%) 76 (4.0%) American Indian or Alaska Native 5 (0.5%) 10 (1.1%) 15 (0.8%) Not reported: patient refused or not available 13 (1.4%) 24 (2.6%) 37 (2.0%) Unknown: Patient unsure 14 (1.5%) 19 (2.0%) 33 (1.8%) Gender Female 933 (99.3%) 934 (99.6%) 1867 (99.4%) Male 7 (0.7%) 4 (0.4%) 11 (0.6%)


Aspirin

(N=940) Placebo (N=938)

Total (N=1878)

Hormone Receptor Status Not expected(Accrued prior to strat factor) 327 326 653 Positive and <= 18 months since diagnosis 267 (43.6%) 268 (43.8%) 535 (43.7%) Positive and > 18 months since diagnosis 280 (45.7%) 278 (45.4%) 558 (45.6%) Negative 66 (10.8%) 66 (10.8%) 132 (10.8%) Body Mass Index Less than 30 520 (55.3%) 519 (55.3%) 1039 (55.3%) Greater than or equal to 30 420 (44.7%) 419 (44.7%) 839 (44.7%) Breast Cancer Stage Stage II 648 (68.9%) 646 (68.9%) 1294 (68.9%) Stage III 292 (31.1%) 292 (31.1%) 584 (31.1%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary As of 9/18/2019, there are 1125 patients evaluable for adverse event (AE) analysis (note that the first AE assessment takes place six months after study treatment begins). 88 patients have experienced a grade 3, 4, or 5 adverse event. 6 patients experienced grade 4+ events. One patient had a grade 4 wound complication deemed not related to treatment. Another patient suffered a grade 4 dyspnea and thromboembolic event, both deemed unlikely to be related to treatment. One patient had unrelated grade 4 depression. Another patient had unrelated grade 4 sepsis and respiratory failure. A patient had grade 4 neoplasim deemed probably related. Another



patient had unrelated grade 4 gallbladder infection, gallbladder perforation, sepsis, and hypertriglyceridemia. Lastly, one patient had an unrelated grade 5 myocardial infarction and one patient had an unrelated grade 5 death from a house fire.





2 42 (7.3%)


2 3 (0.5%)


2 2 (0.3%)



2 6 (1.0%)


2 0 (0.0%)


2 0 (0.0%)

Non-Hematologic Adverse Events Grade 3 Event 1 41 (7.5%)

2 37 (6.4%)


2 3 (0.5%)


2 2 (0.3%)













Blood/Bone Marrow Anemia 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Blood and lymph sys disorders - Oth Spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased 1 8 ( 2%) 0 ( 0%) 0 ( 0%) 2 5 ( 1%) 0 ( 0%) 0 ( 0%) White blood cell decreased 1 4 ( 1%) 0 ( 0%) 0 ( 0%) 2 3 ( 1%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events Blood and lymphatic sys disord

Febrile neutropenia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Cardiac disorders Cardiac disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Myocardial infarction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 1 ( 0%)

Ear and labyrinth disorders Vertigo 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Eye disorders Cataract 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Gastrointestinal disorders Abdominal pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Colitis 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal disorders - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 2 ( 0%) 0 ( 0%) 0 ( 0%)







Nausea 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Small intestinal obstruction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Upper gastrointestinal hemorrhage 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Vomiting 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Gen disord and admin site cond Edema limbs 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Fatigue 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Flu like symptoms 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Non-cardiac chest pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Hepatobiliary disorders Gallbladder perforation 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hepatobiliary disorders - Other, specify

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 0%) 0 ( 0%) 0 ( 0%) Infections and infestations

Breast infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Device related infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Gallbladder infection 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec

1 2 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%)







Sepsis 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) Skin infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Urinary tract infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Vaginal infection 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Wound infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Inj, pois and proced complic Fall 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Fracture 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Inj, pois and proced complic - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 1 ( 0%) Wound complication 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 1 ( 0%) 0 ( 0%) Wrist fracture 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Investigations Alanine aminotransferase increased

1 3 ( 1%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Aspartate aminotransferase increased

1 2 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Cholesterol high 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Weight loss 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Metabol and nutrition disord Hyperglycemia 1 3 ( 1%) 0 ( 0%) 0 ( 0%)







2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperkalemia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypertriglyceridemia 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypokalemia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Obesity 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Musculosk and conn tiss disord Arthralgia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Arthritis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Back pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Bone pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Flank pain 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Generalized muscle weakness 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Musculoskeletal, conn tissue - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Pain in extremity 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%)


1 1 ( 0%) 1 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Nervous system disorders

Dizziness 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Headache 1 1 ( 0%) 0 ( 0%) 0 ( 0%)







2 1 ( 0%) 0 ( 0%) 0 ( 0%) Peripheral sensory neuropathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Seizure 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Syncope 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Vasovagal reaction 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Psychiatric disorders Anxiety 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Depression 1 0 ( 0%) 1 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Suicidal ideation 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Renal and urinary disorders Acute kidney injury 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal and urinary disorders - Oth spec

1 1 ( 0%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal calculi 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Renal colic 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary tract obstruction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Reprod sys and breast disord Breast pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Dyspareunia 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Vaginal dryness 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)







Respirat, thor, mediast disord Dyspnea 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) Respiratory failure 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 0%) 0 ( 0%) Sleep apnea 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

Skin and subcutan tiss disord Pruritus 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)


1 4 ( 1%) 0 ( 0%) 0 ( 0%)

2 2 ( 0%) 0 ( 0%) 0 ( 0%) Vascular disorders

Hematoma 1 1 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypertension 1 4 ( 1%) 0 ( 0%) 0 ( 0%) 2 2 ( 0%) 0 ( 0%) 0 ( 0%) Hypotension 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 2 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 1 ( 0%) 0 ( 0%) Vascular disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 0%) 0 ( 0%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES Not Applicable

breast committee 2020/ros book... · 2020. 9. 9. · s1007 phase iii ... most recent progress...

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