leukemia committee - swog 2017/leukemia.pdfoctober 11 - 14, 2017 swog leukemia 4 patient...

OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 1

LEUKEMIA COMMITTEE


CONTENTS

S0919 Phase II ............................................................................................................................................................... 6

S1204 Surveillance ...................................................................................................................................................... 12

S1312 Phase I .............................................................................................................................................................. 13

S1318 Phase II ............................................................................................................................................................. 19

S1612 Phase II-III ........................................................................................................................................................ 25


Patient Registrations to Studies

By 12 Month Intervals

LEUKEMIA COMMITTEE

Screening registrations and registrations to Biologic only studies are excluded.

SWOG LAPS MEMBER NCORP NON-SWOG

183

280

564549

244

88

0

100

200

300

400

500

600

Time of Registration

Jul 2011Jun 2012

Jul 2012Jun 2013

Jul 2013Jun 2014

Jul 2014Jun 2015

Jul 2015Jun 2016

Jul 2016Jun 2017

40

76

33

34

46

66

36

132

139

106

61

258

125

140

73

211

45

101

48

50

46


Patient Registrations by Study and Arm LEUKEMIA COMMITTEE

Jan 2017

Jun 2017

Jul 2016

Dec 2016

Jan 2016

Jun 2016

All

Patients

S0919 Rel AML: Pravastatin+Ida+Ara-C

Induction

Pravastatin+Idarubicin+Ara-C 1 10 4 115

Consolidation

Pravastatin+Idarubicin+Ara-C 0 1 0 15

S1312 ALL, CD22+, REL/REF, Inotuzumab+CVP

Initial Registration

CVP + Inotuzumab dose level 1 0 0 0 5





6 8 3 36

S1318 ALL, Age 65+, Ph±, Blinatumomab

Initial registration

Induction: Ph- 14 6 4 27

Induction: Ph+/Ph-like 9 5 2 16

23 11 6 43

A041202 CLL, 65+, Ben+Rtx vs Ibrut±Rtx*

Total Registrations 0 0 4 99

E1910 BCR-ABL-neg, B ALL, Blinatumomab*


E1912 CLL, Age 18-70, Ibrutinib vs FCR*


E2905 MDS, Len vs Len + Epo*


NHLBIMDS LEUK, National MDS Study*


* For non-SWOG coordinated studies only SWOG registrations are shown.


Non-SWOG Studies with SWOG-Credited Registrations LEUKEMIA COMMITTEE

Studies with Accrual from January 2016 - June 2017

SWOG

Champion

Date

Activated

Date

Closed

Total

Accrued

A041202 CLL, 65+, Ben+Rtx vs Ibrut±Rtx S Coutre 12/15/13 05/16/16 548

Most Recent Progress Report

E1910 BCR-ABL-neg, B ALL, Blinatumomab M Liedtke 12/23/13 227


E1912 CLL, Age 18-70, Ibrutinib vs FCR S O’Brien 02/07/14 06/09/16 529


E2905 MDS, Len vs Len + Epo C Schiffer 02/09/09 05/13/16 240


NHLBIMDS LEUK, National MDS Study D Hill, C Yi 04/05/16 216

No Progress Report Available


S0919/II

S0919 Phase II

Coordinating Group: SWOG

A Phase II Study of Idarubicin and Ara-C in Combination with Pravastatin

for Poor-risk Acute Myelogenous Leukemia (AML)

Participants:

SWOG, CTSU (Supported by ECOG-ACRIN)

Study Chairs:

A Advani, L Michaelis, E Attallah (ECOG-ACRIN)

Statisticians:

M Othus, A Moseley

Data Coordinator:

L Highleyman

Date Activated:

08/15/2009

Objectives To test whether the complete remission (CR) rate

(including CR with incomplete recovery [CRi]) in

poor-risk patients with acute myeloid leukemia

(AML) treated with a combination of chemotherapy

and pravastatin is sufficiently high to warrant Phase

III investigation. This will be tested independently in

two groups of patients: (1) patients with MDS

transformed to AML, and (2) refractory or relapsed

patients with previous remission < 6 months.

To estimate relapse-free survival and overall survival

rates in these two groups of patients.

To estimate the frequency and severity of toxicities

of this regimen in these two groups of patients.

To evaluate in a preliminary manner whether

prestudy cytogenetic features correlate with response

in these two groups of patients.

Patient Population MDS transformed to AML cohort (Cohort 1):

Patients must have a previous morphologically

confirmed diagnosis of MDS/CMML. Patients may

have received previous non-intensive therapy (e.g.

azacitidine, decitabine, low-dose cytarabine (LDAC),

lenalidomide) given for treatment of MDS/CMML

(with up to 20% blasts). At the time of registration

patients must have a morphologically confirmed

diagnosis of acute myeloid leukemia (AML).

Relapsed/Refractory Cohort (Cohort 2):

Patients must have a previous morphologically

confirmed diagnosis of acute myeloid leukemia

(AML). Relapse or refractory disease must be

documented by a bone marrow examination

demonstrating > 5% blasts in the bone marrow not

attributable to another cause.

Patients must have received at least one prior

induction chemotherapy regimen for their AML and

they may have received any type of chemotherapy.

Patients must not have received chemotherapy within

14 days prior to registration. Relapsed patients must

have achieved CR or CRi, lasting less than six

months with their last induction regimen. Primary

refractory patients are eligible if, on Day 14 of their

previous chemotherapy regimen, they have

significant residual disease. Refractory patients who

received only hypomethylating agent or low dose

therapy for induction are not eligible.

All patients:


S0919/II

Patients with acute promyelocytic leukemia (APL,

FAB M3) or blastic transformation of chronic

myelogenous leukemia are not eligible.

Patients who have received autologous or allogeneic

stem cell transplantation are not eligible.

Patients must have adequate cardiac function as

defined in the protocol. Patients must be at least 18

years of age, must have a Zubrod performance status

of 0, 1, or 2, and must have adequate renal and

hepatic function. Patients must not have clinical

evidence of leptomeningeal disease and must not

have a systemic fungal, bacterial, viral or other

infection that is not controlled. Patients who are

known to be HIV+ may be eligible providing they

meet all of the criteria in the protocol.

Stratification/Descriptive Factors Patients will be stratified according to disease status:

patients with MDS transformed to AML vs refractory

or relapsed patients with previous remission less than

6 months.

Accrual Goals Seventy-four eligible patients will be accrued to the

two additional poor-risk cohorts, 37 in each cohort.

Summary Statement On July 1, 2012, the study was temporarily closed to

accrual to relapsed patients with previous remission

of longer than three months. Final results for this

cohort of 36 patients were reported in the Spring

2013 Report of Studies and are not included in this

report. On April 1, 2013, the study was re-opened to

two additional poor-risk cohorts: patients with MDS

transformed AML, and refractory or relapsed patients

with previous remission less than six months. The

following tables, other than 'Registration by

Institution' show accrual for these two poor-risk

cohorts only.

Relapsed/Refractory Cohort:

The study was closed to accrual for

refractory/relapsed AML patients on November 24,

2014, after meeting the accrual goal with 50 patients

registered. Three patients are ineligible: one due to

prior stem cell transplantation and two due to

previous remission longer than six months. One

patient had a cardiac event prior to starting treatment

causing a decline in performance status. This patient

did not receive any protocol therapy and is not

included in any analyses. A major protocol deviation

is coded for one patient who received an extra dose

of Ara-C.

Forty-six relapsed/refractory AML patients have been

assessed for adverse events. Four treatment-related

deaths occurred: one due to sepsis (reported as Inf,

Unk ANC: blood), another due to hypotension, a

third due to beta strep Group B (reported as Inf, 3-4

ANC: blood), and a fourth due to respiratory failure

(reported as DLCO). An additional 11 patients

experienced treatment-related Grade 4 non-

hematologic toxicities.

Two patients accrued to the refractory/relapsed

cohort were ineligible for consolidation therapy

because they were ineligible for induction. An

additional patient who relapsed prior to consolidation

treatment began is not evaluable for toxicities. No

Grade 3 or higher treatment-related non-hematologic

toxicity has been reported during consolidation

therapy.

MDS Transformed to AML Cohort:

As of June 30, 2017, 29 patients have been accrued to

the MDS transformed to AML cohort. Three patients

went off treatment for reasons not specified in the

protocol: two were induction refractory and one went

on to receive transplant after achieving a complete

response. Among the 26 patients assessed for adverse

events, there were five deaths that were possibly

related to treatment: one due to respiratory failure

(reported as DLCO), one due to lung infection and

respiratory failure (coded as Lung Inf, Unk ANC:

lung), one due to hypoxia and respiratory failure

(reported as DLCO), one due to DLCO, and one due

to clostridium difficile (coded as GI Inf, Unk ANC:

sm bowel NOS) and infectious colitis. This last

patient also experienced Grade 4 multi-organ failure

(coded as Constitutional Symptoms-other). Three

additional patients reported treatment-related Grade 4

non-hematologic toxicities, including one instance of

Grade 4 respiratory failure (coded as Pulmonary-

other).


S0919/II

Registration by Institution


Registrations ending June 30, 2017

Institutions

Total

Reg Institutions

Total

Reg

Stanford University 24 Loyola University 4

Cleveland Clinic OH 23 Birmingham, U of AL 3

Rochester, Univ of 15 PCRC NCORP 2

H Lee Moffitt CC 11 Tulane University 2

Colorado, U of 6 LSU-Shreveport/Gulf South MU-NCORP 1

Oregon Hlth Sci Univ 6 Mississippi, Univ of 1

Wichita NCORP 6 Tulane Univ MBCCOP 1

Baylor College 5 Total (16 Institutions) 115

New Mexico MU-NCORP 5

Registration, Eligibility, and Evaluability


Registrations from April 1, 2013 through June 30, 2017; Data as of July 25, 2017

TOTAL

MDS

transformed to

AML

Refractory or

relapsed with

previous

remission < 6

months

NUMBER REGISTERED 79 29 50

INELIGIBLE 3 0 3

ELIGIBLE 76 29 47

Analyzable, Pend. Elig. 1 1 0

Not Analyzable 1 0 1

RESPONSE ASSESSMENT

Determinable 65 25 40

Not Determinable 9 3 6

Too Early 1 1 0

ADVERSE EVENT ASSESSMENT

Evaluable 75 29 46


S0919/II

Patient Characteristics



MDS

transformed to

AML

(n=29)

Refractory or

relapsed with

previous

remission < 6

months

(n=46)

AGE

Median 64.9 57.3

Minimum 21.8 23.1

Maximum 77.1 75.0

SEX

Males 16 55% 24 52%

Females 13 45% 22 48%

HISPANIC

Yes 0 0% 4 9%

No 28 97% 38 83%

Unknown 1 3% 4 9%

RACE

White 28 97% 35 76%

Black 1 3% 2 4%

Asian 0 0% 6 13%

Multi-Racial 0 0% 3 7%

Treatment Summary

Induction


TOTAL

MDS

transformed to

AML

Refractory or

relapsed with

previous

remission < 6

months

NUMBER ON PROTOCOL TREATMENT 0 0 0

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

75 29 46

Treatment completed as planned 59 20 39

Adverse Event or side effects 2 1 1

Refusal unrelated to adverse event 1 0 1

Progression/relapse 0 0 0

Death 10 5 5

Other - not protocol specified 3 3 0

Reason under review 0 0 0

MAJOR PROTOCOL DEVIATIONS 1 0 1


S0919/II

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

Induction

Adverse Events Unlikely or Not Related to Treatment Excluded

Non-Hematologic Adverse Events Only

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


MDS transformed to AML

(n=29)

Grade

Refractory or relapsed with

previous remission < 6

months

(n=46)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5

ALT 27 1 1 0 44 2 0 0

AST 26 2 1 0 45 1 0 0

Acidosis 28 1 0 0 46 0 0 0

Alkaline phosphatase 29 0 0 0 45 1 0 0

Alkalosis 28 1 0 0 46 0 0 0

Anorexia 28 1 0 0 46 0 0 0

Bilirubin 27 2 0 0 46 0 0 0

Cardiac ischemia/infarction 28 0 1 0 46 0 0 0

Colitis, infectious 28 0 0 1 45 1 0 0

Constitutional Symptoms-other 27 1 1 0 46 0 0 0

Creatinine 26 3 0 0 44 2 0 0

DLCO 25 0 1 3 45 0 0 1

Diarrhea 25 3 1 0 38 8 0 0

Distension 27 2 0 0 46 0 0 0

Dry mouth 28 1 0 0 46 0 0 0

Dyspnea 28 1 0 0 44 1 1 0

Edema-limb 27 2 0 0 46 0 0 0

Fatigue 27 2 0 0 44 2 0 0

Febrile neutropenia 11 18 0 0 14 27 5 0

GI Hemorrhage: duodenum 28 1 0 0 46 0 0 0

GI Inf, 3-4 ANC: stomach 29 0 0 0 45 1 0 0

GI Inf, Unk ANC: sm bowel NOS 28 0 0 1 46 0 0 0

GI Necrosis: small bowel 28 0 1 0 46 0 0 0

GI Obstruction: small bowel 28 1 0 0 46 0 0 0

GI Pain: abdomen 26 3 0 0 46 0 0 0

GI Pain: esophagus 29 0 0 0 45 1 0 0

GI Pain: oral cavity 29 0 0 0 43 3 0 0

GI Pain: peritoneum 28 0 1 0 46 0 0 0

GI Ulcer: duodenum 28 1 0 0 46 0 0 0

GU Inf, 3-4 ANC: kidney 29 0 0 0 45 1 0 0

Hyperglycemia 27 2 0 0 46 0 0 0

Hyperkalemia 27 1 1 0 46 0 0 0

Hypermagnesemia 28 1 0 0 46 0 0 0

Hypoalbuminemia 26 3 0 0 40 6 0 0

Hypocalcemia 24 5 0 0 43 2 1 0

Hypokalemia 26 3 0 0 43 3 0 0

Hyponatremia 29 0 0 0 45 1 0 0

Hypophosphatemia 25 4 0 0 44 2 0 0


S0919/II

MDS transformed to AML

(n=29)

Grade

Refractory or relapsed with

previous remission < 6

months

(n=46)

Grade


Hypotension 27 0 2 0 45 0 0 1

Hypoxia 27 0 1 1 43 3 0 0

Ileus 27 2 0 0 46 0 0 0

Inf, 3-4 ANC: blood 25 0 4 0 39 1 5 1

Inf, Unk ANC: blood 26 0 3 0 42 0 3 1

Infection-other 28 1 0 0 46 0 0 0

Lung Hemorrhage: bronchopulm. 29 0 0 0 45 0 1 0

Lung Hemorrhage: nose 29 0 0 0 45 1 0 0

Lung Inf, 3-4 ANC: bronchus 29 0 0 0 45 1 0 0

Lung Inf, 3-4 ANC: lung 27 1 1 0 40 5 1 0

Lung Inf, Unk ANC: lung 28 0 0 1 46 0 0 0

Lung Inf, Unk ANC: mucosa 29 0 0 0 45 1 0 0

Mucositis, clin: oral cavity 29 0 0 0 45 1 0 0

Mucositis, clin: pharynx 29 0 0 0 45 0 1 0

Mucositis, funct: oral cav. 29 0 0 0 45 1 0 0

Musculo. Pain: bone 29 0 0 0 45 1 0 0

Musculo. Pain: limb 29 0 0 0 45 1 0 0

Musculoskeletal-other 28 1 0 0 46 0 0 0

Nausea 28 1 0 0 43 3 0 0

Neuro Inf, 3-4 ANC: mening. 29 0 0 0 45 0 1 0

Opportunistic infection 29 0 0 0 44 2 0 0

Pleural effusion 28 1 0 0 46 0 0 0

Pulmonary-other 28 0 1 0 46 0 0 0

Rash 29 0 0 0 45 1 0 0

Renal failure 29 0 0 0 44 0 2 0

Renal-other 28 1 0 0 46 0 0 0

Skin Inf, 3-4 ANC: skin 28 1 0 0 46 0 0 0

Supra Arrhyth: Atrial Fib. 28 0 1 0 46 0 0 0

Typhlitis 29 0 0 0 45 1 0 0

Ulceration 29 0 0 0 45 1 0 0

Vomiting 27 2 0 0 46 0 0 0

Weight Loss 29 0 0 0 44 2 0 0

MAX. GRADE ANY ADVERSE

EVENT

4 17 3 5 3 28 11 4


S1204

S1204 Surveillance

A Sero-Epidemiologic Survey and Cost-Effectiveness Study of Screening for

Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and

Hepatitis C Virus (HCV) Among Newly Diagnosed Cancer Patients

Study Chairs:

S Ramsey, D Hershman

Statisticians:

J Unger, K Arnold

Data Coordinators:

H Dong, M Yee

Date Activated:

08/29/2013

Date Closed:

02/15/2017

Objectives Among newly diagnosed cancer patients presenting

to SWOG-affiliated community and academic

oncology clinics, estimate the prevalence of human

immunodeficiency virus (HIV), hepatitis B (HBV),

and hepatitis C (HCV) infection.

Evaluate known sociodemographic, clinical, and

behavioral factors that are significantly associated

with previously undiagnosed HIV, HBV, and/or

HCV infection in a population of people with newly

diagnosed cancer

Among patients who are identified as having HIV,

HBV, and/or HCV, evaluate the timing and type of

treatments received, both for the viral infections and

the cancers.

Evaluate type and rate of cancer treatment-related

adverse events in patients with HIV, HBV, and/or

HCV infection.

Determine the cost-effectiveness of (1) routine,

universal screening and (2) risk factor-directed

screening of newly diagnosed cancer patients for

HIV, HBV and/or HCV versus current care.

Patient Population Patients must be presenting for evaluation or

treatment for the first diagnosis of a new solid or

hematologic cancer malignancy. Confirmed diagnosis

date must be within 120 days prior to first clinic visit

as a newly diagnosed cancer patient at the registering

clinic. Patients presenting for "second opinions" of

confirmed malignancies are eligible, including those

who have started cancer treatment at other facilities.

Patients must be registered within 90 days after their

first clinic visit. Patients must not have been

diagnosed with a malignancy other than the current

malignancy within the past five years, with the

exception of basal cell or squamous cell skin cancer,

in situ cervical cancer, or in situ breast cancer.

Patients must have no evidence of disease for a prior

malignancy for at least five years prior to

randomization except as noted above.

Patients must be 18 years of age or older. Patients

must have had their blood drawn for viral status

testing for HIV, HBV and HCV or provide

acceptable viral status documentation prior to

registration, as defined in the protocol. Note that

patients must have blood drawn for testing prior to

registration for any of the three viruses not covered

by the documentation. Patients are allowed to

participate in other clinical trials.

Accrual Goals A total of 3,061 patients will be accrued to achieve

3,000 eligible patients.

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

Cancer Care Delivery chapter.


S1312/I

S1312 Phase I

A Phase I Study of Inotuzumab (NSC-772518) in Combination with CVP

(Cyclophosphamide, Vincristine, Prednisone) for Patients with

Relapsed/Refractory CD22-Positive Acute Leukemia (including B-ALL,

Mixed Phenotypic Leukemia, and Burkitt's Leukemia)

Study Chairs:

A Advani, M Liedtke

Statisticians:

M Othus, A Moseley

Data Coordinator:

L Highleyman

Date Activated:

04/01/2014

Objectives To assess the safety of inotuzumab in combination

with cyclophosphamide, vincristine and prednisone

(CVP) and to determine the maximum tolerated dose

(MTD) of inotuzumab in this regimen for patients

with relapsed or refractory CD22-positive acute

leukemia (B-ALL, mixed phenotype, and Burkitt's).

To estimate the preliminary activity [response rate:

complete remission (CR) + complete remission with

incomplete count recovery (CRi)] of this combination

in the expansion cohort.


of this combination in this patient population.

Patient Population Patients must have a diagnosis of relapsed or

refractory CD22-positive acute leukemia including

B-ALL, mixed phenotype leukemia (bilineal and

biphenotypic), or Burkitt's leukemia based on WHO

classification. Patients with bilineal leukemia are

excluded. Patients must have evidence of acute

leukemia in their peripheral blood or bone marrow.

Patients must have ≥ 5% blasts in the peripheral

blood or bone marrow. At least ≥ 20% of those blasts

must be CD22-positive (surface) based on local

immunophenotyping and histopathology. Patients

must be refractory or have relapsed following prior

induction therapy.

Patients may have received prior allogeneic

transplant or autologous transplant. Patients with

prior allogeneic bone marrow transplant will be

eligible only if the conditions stated in the protocol

are met. Patients known to have Ph+ ALL must have

either failed treatment or been intolerant to treatment

with at least one second or third generation tyrosine

kinase inhibitor. Patients must not have received

prior treatment with inotuzumab. Previous treatment

with other anti-CD22 antibodies must have been

completed at least 90 days prior to registration.

Patients must not have received any chemotherapy,

investigational agents, or undergone major surgery

within 14 days prior to registration with the following

exceptions: (1) Monoclonal antibodies must not have

been received for one week prior to registration; (2)

Chimeric antigen receptor (CAR) T-cells must not

have been received for 28 days prior to registration;

(3) Steroids, hydroxyurea, vincristine, 6-

mercaptopurine, methotrexate, thioguanine and

intrathecal chemotherapy are permitted within any

time frame prior to registration. FDA-approved

tyrosine kinase inhibitors may also be administered

until one day prior to start of study therapy (C1, D1).

All drug-related toxicities must have resolved to ≤

Grade 2. Treatment with hydroxyurea and steroids is

permitted to bring down peripheral blast count.

Patients must be at least 18 years of age and have

Zubrod performance status of 0-2. Patients must not

have a systemic bacterial, fungal, or viral infection

that is not controlled. Patients must not have active


S1312/I

CNS involvement. Patients must have < Grade 2

neuropathy (sensory/motor). Patients must not have a

history of chronic or active hepatitis B or C infection.

Patients must not have evidence or history of veno-

occlusive disease or sinusoidal obstruction syndrome.

Patients who are known to be HIV+ are eligible

providing they meet all of the criteria in the protocol.

Patients with a history of a serious allergic or

anaphylactic reaction to humanized monoclonal

antibodies are not eligible. Patients must have

adequate hematologic, renal, hepatic and cardiac

function.

Accrual Goals Patient enrollment will follow the traditional "3+3"

algorithm until the MTD for inotuzumab is reached

or the highest dose tested is judged tolerable. This

study will accrue 3-30 eligible and evaluable patients

in the Phase I portion and six additional eligible

patients in the expansion cohort.

Summary Statement The study will evaluate up to five dose levels of

inotuzumab.

The initial dose level of 0.4 mg/m2 inotuzumab closed

on November 1, 2014 with five eligible patients

registered, three of whom were evaluable for dose

limiting toxicities (DLT). The second dose level of

inotuzumab at 0.6 mg/m2 on day 1 and 0.4 mg/m

2 on

day 15 closed on May 15, 2015 with five patients

registered, three of whom were evaluable for DLT.

One patient was ineligible due to inadequate liver

function, leaving four eligible patients in this dose

level. There were no DLTs in either the first or

second dose level.

The third dose level of inotuzumab at 0.8 mg/m2

on

day 1 and 0.4 mg/m2 on day 15 closed on April 15,

2016 with 11 patients registered. One patient was

ineligible due to inadequate liver function. Four

patients were not evaluable for DLT: two went off

treatment before their counts recovered and before

prolonged myelosuppression could be ruled out, one

died before receiving a full cycle of treatment, and

one continued to take tyrosine kinase inhibitor (TKI)

while on protocol and is coded as a major protocol

deviation. Six of the 10 eligible patients were

evaluable for DLT. One of the first three evaluable

patients experienced DLT (prolonged

myelosuppression), so three additional patients were

evaluated at this dose level. None of these additional

patients experienced a DLT. Among 10 patients

assessed for toxicity, one patient experienced Grade 4

hyperglycemia and another experienced Grade 4

hyperglycemia and oral mucositis.

The fourth dose level of inotuzumab at 0.8 mg/m2

on

day 1 and 0.4 mg/m2 on days 8 and 15 closed on

August 22, 2016 with five patients registered. Two

patients were not evaluable for DLT because they

went off treatment before their counts recovered and

before prolonged myelosuppression could be ruled

out. There were no DLTs and no Grade 4 or Grade 5

non-hematological toxicities related to treatment at

dose level 4.

The fifth dose level of inotuzumab at 0.8 mg/m2

on

day 1 and 0.5 mg/m2 on days 8 and 15 opened on

October 5, 2016 and as of June 30, 2017 had accrued

ten patients. Five patients went off treatment before

their counts recovered and before prolonged

myelosuppression could be ruled out and are

therefore not evaluable for DLT. One patient

experienced DLT: Grade 3 ascites, an event

considered clinically significant regardless of

duration. There have been no Grade 4 or Grade 5

non-hematological toxicities related to treatment at

dose level 5.

Twenty patients went off treatment for non-protocol

specified reasons, due to lack of treatment benefit,

physician decision, or transplant.


S1312/I




Institutions Total Reg

City of Hope Med Ctr 13

Cleveland Clinic OH 10

Rochester, Univ of 7

Baylor College 4

Stanford University 2

Total (5 Institutions) 36



Registrations ending June 30, 2017; Data as of July 25, 2017

TOTAL

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

NUMBER REGISTERED 36 5 5 11 5 10

INELIGIBLE 2 0 1 1 0 0

ELIGIBLE 34 5 4 10 5 10

RESPONSE ASSESSMENT

Determinable 31 5 4 8 5 9

Not Determinable 2 0 0 2 0 0

Too Early 1 0 0 0 0 1


Evaluable 34 5 4 10 5 10

DLT ASSESSMENT

Evaluable 20 3 3 6 3 5

Not Evaluable 14 2 1 4 2 5


S1312/I




CVP +

Inotuzumab

dose level 1

(n=5)

CVP +

Inotuzumab

dose level 2

(n=4)

CVP +

Inotuzumab

dose level 3

(n=10)

CVP +

Inotuzumab

dose level 4

(n=5)

CVP +

Inotuzumab

dose level 5

(n=10)

AGE

Median 48.9 42.3 42.8 49.6 39.4

Minimum 22.4 20.7 22.4 33.1 25.2

Maximum 73.7 56.4 75.4 50.2 58.7

SEX

Males 4 80% 0 0% 6 60% 3 60% 5 50%

Females 1 20% 4 100% 4 40% 2 40% 5 50%

HISPANIC

Yes 2 40% 2 50% 2 20% 4 80% 2 20%

No 3 60% 2 50% 7 70% 1 20% 6 60%

Unknown 0 0% 0 0% 1 10% 0 0% 2 20%

RACE

White 4 80% 3 75% 6 60% 5 100% 6 60%

Black 1 20% 1 25% 2 20% 0 0% 1 10%

Asian 0 0% 0 0% 0 0% 0 0% 1 10%

Unknown 0 0% 0 0% 2 20% 0 0% 2 20%

Treatment Summary


TOTAL

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

NUMBER ON PROTOCOL TREATMENT 0 0 0 0 0 0



34 5 4 10 5 10

Treatment completed as planned 4 1 2 1 0 0

Adverse Event or side effects 3 0 0 2 0 1

Refusal unrelated to adverse event 0 0 0 0 0 0

Progression/relapse 6 1 1 4 0 0

Death 1 0 0 1 0 0

Other - not protocol specified 20 3 1 2 5 9

Reason under review 0 0 0 0 0 0

MAJOR PROTOCOL DEVIATIONS 1 0 0 1 0 0


S1312/I




Hematologic Adverse Events Only



CVP +

Inotuzumab

dose level 1

(n=5)

Grade

CVP +

Inotuzumab

dose level 2

(n=4)

Grade

CVP +

Inotuzumab

dose level 3

(n=10)

Grade

CVP +

Inotuzumab

dose level 4

(n=5)

Grade

CVP +

Inotuzumab

dose level 5

(n=10)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Anemia 3 1 1 0 2 1 1 0 3 7 0 0 2 3 0 0 5 5 0 0

Lymphocyte count decreased 3 0 2 0 3 1 0 0 7 2 1 0 2 1 2 0 5 2 3 0

Neutrophil count decreased 2 0 3 0 1 0 3 0 1 0 9 0 1 2 2 0 3 3 4 0

Platelet count decreased 3 0 2 0 2 0 2 0 3 1 6 0 1 1 3 0 5 1 4 0

White blood cell decreased 2 0 3 0 0 1 3 0 0 1 9 0 0 0 5 0 5 0 5 0


EVENT

2 0 3 0 0 0 4 0 0 0 10 0 0 0 5 0 1 2 7 0







CVP +

Inotuzumab

dose level 1

(n=5)

Grade

CVP +

Inotuzumab

dose level 2

(n=4)

Grade

CVP +

Inotuzumab

dose level 3

(n=10)

Grade

CVP +

Inotuzumab

dose level 4

(n=5)

Grade

CVP +

Inotuzumab

dose level 5

(n=10)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Ascites 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 9 1 0 0

Dysphagia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0

Encephalopathy 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0

Enterocolitis 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 9 1 0 0

Fatigue 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0

Febrile neutropenia 5 0 0 0 2 2 0 0 8 2 0 0 2 3 0 0 9 1 0 0

Fever 4 1 0 0 3 1 0 0 9 1 0 0 5 0 0 0 10 0 0 0

GI disorders-Other, specify 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 10 0 0 0

Gastric hemorrhage 3 2 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 0 0 0

Headache 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 10 0 0 0

Hyperglycemia 5 0 0 0 4 0 0 0 6 2 2 0 1 4 0 0 8 2 0 0

Hypertension 5 0 0 0 4 0 0 0 9 1 0 0 4 1 0 0 10 0 0 0

Hypoalbuminemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0

Hypocalcemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0


S1312/I

CVP +

Inotuzumab

dose level 1

(n=5)

Grade

CVP +

Inotuzumab

dose level 2

(n=4)

Grade

CVP +

Inotuzumab

dose level 3

(n=10)

Grade

CVP +

Inotuzumab

dose level 4

(n=5)

Grade

CVP +

Inotuzumab

dose level 5

(n=10)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Hypokalemia 5 0 0 0 4 0 0 0 10 0 0 0 4 1 0 0 10 0 0 0

Infections/infestations-Other 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 9 1 0 0

Intracranial hemorrhage 4 1 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 0 0 0

Lung infection 5 0 0 0 4 0 0 0 10 0 0 0 3 2 0 0 10 0 0 0

Mucositis oral 5 0 0 0 4 0 0 0 9 0 1 0 5 0 0 0 10 0 0 0

Skin infection 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0


EVENT

1 4 0 0 2 2 0 0 3 5 2 0 0 5 0 0 7 3 0 0


S1318/II

S1318 Phase II


A Phase II Study of Blinatumomab and POMP (Prednisone, Vincristine,

Methotrexate, 6-Mercaptopurine) for Elderly Patients (≥ 65 Years of Age)

with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

Participants:

SWOG, CTSU (Supported by Alliance and ECOG-

ACRIN)

Study Chairs:

A Advani, K O'Dwyer, M Wiedewult (Alliance), J Park

(ECOG-ACRIN)

Statisticians:

M Othus, A Moseley

Data Coordinator:

T Maher

Date Activated:

01/12/2015

SCHEMA

REGISTRATION Step 1

D28 CR/CRi?

Dasatinib / Prednisone Induction

Continue Induction Cycle

YES

Blinatumomab

Re-induction 1

Ph-positive Patients:

NO

Until intolerance or progression for up to 10 years from registration, then

Protocol Therapy Complete

CR/CRi?

YES

NO

Off Protocol Therapy

REGISTRATION Step 2: Post-remission therapy

Blinatumomab/Dasatinib

REGISTRATION Step 3: Maintenance

Dasatinib/Prednisone

Ph-negative Patients:

Blinatumomab Induction

CR/CRi?

REGISTRATION Step 1

YES NO

REGISTRATION Step 2:

Post-remission therapy

Blinatumomab

Continued CR/Cri?

REGISTRATION Step 3:

Maintenance

POMP Chemotherapy

Protocol Therapy Complete

Blinatumomab

Re-induction

D56 CR/CRi?

YESNO

Continue Dasatinib

to Day 84

Continued CR/Cri?

YES

Blinatumomab

Re-induction 2

CR/CRi?

NO

YESYES

Continued CR/Cri?

NO

NO

CR/CRi?

YES NO

Off Protocol Therapy

YES NO


S1318/II

Objectives To evaluate the three-year survival rate in elderly

patients with newly diagnosed Philadelphia

chromosome (Ph) negative ALL treated with

blinatumomab followed by POMP maintenance.

To evaluate in a preliminary manner (feasibility

study) the safety of dasatinib-steroid based induction

followed by blinatumomab treatment in combination

with dasatinib followed by dasatinib-based

maintenance in elderly patients with newly diagnosed

Ph-positive ALL, relapsed/refractory Ph-positive

ALL, and Ph-like DSMKF ALL (newly-diagnosed

relapsed or refractory).

To evaluate toxicities in these patient populations

treated with these regimens.

To estimate the rates of complete response (CR),

complete response with incomplete count recovery

(CRi), and disease-free survival in Ph-negative

patients.

To estimate disease-free and overall survival in Ph-

positive ALL and Ph-like DSMKF ALL.

To estimate in each cohort the rate of minimal

residual disease (MRD) negativity, and the time to

achieve MRD negativity (exploratory analysis).

To determine whether anti-idiotype antibodies

directed against blinatumomab develop with

blinatumomab treatment in this study.

Patient Population Patients must have a new morphologic diagnosis of

precursor B cell acute lymphoblastic leukemia (ALL)

(non-T cell) based on WHO criteria as defined in

protocol. Patients with Burkitts (L3) are not eligible

for this study. Patients with Ph-positive or Ph-like

ALL with dasatinib-sensitive mutations or kinase

fusions (DSMKF) may have relapsed or refractory

diagnoses. Patients must have a diagnosis of Ph-

negative ALL or Ph-positive ALL by cytogenetics,

FISH or polymerase chain reaction (PCR). If not

already known, BCR-ABL status (p190 or p210)

must be evaluated in Ph-positive patients by PCR. To

be registered under the Ph-like DSMKF criterion, the

patient must have a known or presumed activating

Ph-like signature and dasatinib-sensitive mutation or

kinase fusion as defined in the protocol. Patients must

have evidence of ALL in their marrow or peripheral

blood with at least 20% lymphoblasts (at least 5% for

relapsed/refractory patients) within 14 days prior to

registration. At registration, relapsed/refractory

patients must submit pathology and cytogenetics

reports from time of original diagnosis.

Immunophenotyping of the blood or marrow

lymphoblasts must be performed to determine lineage

within 14 days prior to registration. Patients with

only extramedullary disease in the absence of bone

marrow or blood involvement are not eligible.

Patients must not have testicular involvement.

Patients must not have received any prior

chemotherapy, radiation therapy, or other therapy for

the treatment of ALL (other than those noted below)

and must not be receiving any immunosuppressive

therapy. Patients must not have received any prior

investigational therapy within 28 days prior to

registration. Patients may have received the following

within any time prior to registration: low dose

chemotherapy, TKI therapy, steroids, hydroxyurea,

leukapheresis, intrathecal chemotherapy, or

vincristine. Patients must not have received any

monoclonal antibody therapy within 42 days of

registration.

Patients must be at least 65 years of age and have a

Zubrod performance status of 0-2. Patients must have

adequate hepatic, cardiac and renal function. Patients

must not have a history or presence of clinically

relevant CNS pathology and must have a lumbar

puncture to determine CNS involvement of ALL

within 14 days prior to registration. Patients must not

have systemic fungal, bacterial, viral or other

infection that is not controlled. Patients must not have

Grade 2 or higher neuropathy (cranial, motor or

sensory) within 14 days prior to registration. Patients

known to be positive for HIV may be eligible,

providing they meet the criteria in the protocol.

Patients must not be candidates for allogeneic

hematopoietic stem cell transplant. Patients must not

have any known autoimmune disease. Ph-negative

patients must have PT/PTT/INR/fibrinogen and

neurologic assessment tests within 28 days prior to

registration. Ph-positive patients must not have active

pericardial effusion, ascites or pleural effusion of any

grade.

Stratification/Descriptive Factors Patients are stratified by Registration Cohort: Ph-

negative vs Ph-positive/Ph-like DSMKF.

Accrual Goals This study will accrue up to 26 eligible Ph-negative

patients. An interim analysis will be performed

among the first 11 patients. If at least five complete

remissions (CR or CRi) are observed, then the study


S1318/II

will continue to full accrual. The study will continue

accruing while the remission data is being reviewed.

This study will initially accrue six eligible and

evaluable Ph-positive/Ph-like DSMKF patients. If the

regimen is considered safe, then the study will accrue

nine additional eligible Ph-positive/Ph-like DSMKF

patients.

Summary Statement The study was activated on January 12, 2015. The

Ph-positive/Ph-like DSMKF cohort was temporarily

closed to Step 1 accrual on April 15, 2017 to assess

the safety profile of this cohort. The Ph-negative

cohort remains open to accrual.

As of June 30, 2017, 27 patients were enrolled to the

Ph-negative cohort and 16 were enrolled to the Ph-

positive/Ph-like DSMKF cohort. Two patients in the

Ph-negative cohort were ineligible: one due to

elevated alkaline phosphatase and another due to a

final diagnosis of follicular lymphoma.

Of the 32 patients evaluable for toxicities, one patient

in the Ph-negative cohort died of respiratory failure

related to treatment and this patient also experienced

treatment-related Grade 4 dyspnea. Another patient in

the Ph-negative cohort experienced treatment-related

Grade 4 lung infection. Two patients in the Ph-

positive/Ph-like DSMKF cohort experienced

treatment-related non-hematologic Grade 4 toxicities:

one had febrile neutropenia and the other had sepsis

and lung infection.

There have been no Grade 4 or higher treatment-

related non-hematologic toxicities reported on post-

remission or maintenance.




Institutions

Total

Reg Institutions

Total

Reg

City of Hope Med Ctr 4 New Mexico MU-NCORP 1

Cleveland Clinic OH 4 Rochester, Univ of 1

Irvine, U of CA 3 San Diego, U of CA 1

So Calif, U of 3 UF Cancer Center/Arkansas, U of 1

Birmingham, U of AL 1 Wichita NCORP 1

Greenville NCORP 1 ALLIANCE 13

Heartland NCORP 1 ECOG-ACRIN 6

Loma Linda Univ 1 Total (16 Institutions) 43

Michigan, U of 1


S1318/II




TOTAL

Induction:

Ph-

Induction:

Ph+/Ph-like

NUMBER REGISTERED 43 27 16

INELIGIBLE 2 2 0

ELIGIBLE 41 25 16

Analyzable, Pend. Elig. 6 6 0

RESPONSE ASSESSMENT

Determinable 26 15 11

Not Determinable 2 1 1

Too Early 13 9 4


Evaluable 32 20 12

Too Early 9 5 4




Induction:

Ph-

(n=25)

Induction:

Ph+/Ph-like

(n=16)

AGE

Median 75.6 73.3

Minimum 66.3 48.2

Maximum 84.0 87.3

SEX

Males 19 76% 3 19%

Females 6 24% 13 81%

HISPANIC

Yes 2 8% 3 19%

No 23 92% 12 75%

Unknown 0 0% 1 6%

RACE

White 24 96% 12 75%

Asian 1 4% 2 13%

Unknown 0 0% 2 13%


S1318/II

Treatment Summary

Induction


TOTAL

Induction:

Ph-

Induction:

Ph+/Ph-like

NUMBER ON PROTOCOL TREATMENT 14 10 4



27 15 12

Treatment completed as planned 19 11 8

Adverse Event or side effects 3 1 2

Refusal unrelated to adverse event 1 1 0

Progression/relapse 1 1 0

Death 3 1 2

Other - not protocol specified 0 0 0

Reason under review 0 0 0

MAJOR PROTOCOL DEVIATIONS 0 0 0


Induction





Induction: Ph-

(n=20)

Grade

Induction: Ph+/Ph-like

(n=12)

Grade


ALT increased 19 1 0 0 12 0 0 0

Confusion 19 1 0 0 12 0 0 0

Cytokine release syndrome 19 1 0 0 12 0 0 0

Dehydration 20 0 0 0 11 1 0 0

Diarrhea 20 0 0 0 11 1 0 0

Dyspnea 18 1 1 0 11 1 0 0

Edema limbs 20 0 0 0 11 1 0 0

Febrile neutropenia 18 2 0 0 11 0 1 0

Generalized muscle weakness 20 0 0 0 11 1 0 0

Heart failure 20 0 0 0 11 1 0 0

Hematoma 20 0 0 0 11 1 0 0

Hyperglycemia 19 1 0 0 12 0 0 0

Hypertension 19 1 0 0 12 0 0 0

Hypocalcemia 19 1 0 0 12 0 0 0

Hypotension 19 1 0 0 12 0 0 0

Hypoxia 20 0 0 0 11 1 0 0

Infections/infestations-Other 19 1 0 0 11 1 0 0

Infusion related reaction 19 1 0 0 12 0 0 0


S1318/II

Induction: Ph-

(n=20)

Grade

Induction: Ph+/Ph-like

(n=12)

Grade


Lung infection 19 0 1 0 10 1 1 0

Nausea 20 0 0 0 11 1 0 0

Pneumonitis 19 1 0 0 12 0 0 0

Respiratory failure 19 0 0 1 12 0 0 0

Sepsis 20 0 0 0 11 0 1 0

TTP 19 1 0 0 12 0 0 0

Urinary tract infection 20 0 0 0 11 1 0 0


EVENT

10 8 1 1 7 3 2 0


S1612/II-III

S1612 Phase II-III


A Randomized Phase II/III Trial of “Novel Therapeutics” Versus Azacitidine

in Newly Diagnosed Patients with Acute Myeloid Leukemia (AML) or High-

Risk Myelodysplastic Syndrome (MDS), Age 60 or Older LEAP: LEss-

Intense AML Platform Trial

Participants:

SWOG, CTSU (Supported by CCTG and ECOG-

ACRIN)

Study Chairs:

L Michaelis, R Walter, S Assouline (CCTG), A Im

(ECOG-ACRIN)

Statisticians:

M Othus, A Moseley

Data Coordinator:

T Maher

SCHEMA

Objectives Phase II Component: To select, based on overall

survival, any or all of the "Novel Therapeutic"

regimens for further testing against azacitidine in

patients age 60 and older with newly diagnosed acute

myeloid leukemia (AML) or myelodysplastic

syndrome with excessive blasts-2 (MDS-EB-2).

Phase III Component: To compare overall survival of

the "Novel Therapeutic" regimens selected in the

R

E

G

I

S

T

R

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm A (control):

Azacitidine

Arm B:

Azacitidine + Nivolumab

Arm C:

Azacitidine + Midostaurin

Arm D:

Decitabine/Cytarabine

*NOTE: Arm D will open to accrual when Arms B and C have met Phase II accrual and

are temporarily closed for Phase II analysis

FLT3 Testing


S1612/II-III

Phase II portion of the trial to azacitidine in these

patient populations.


of the regimens in these patient populations.

To estimate response rates, event-free survival, and

relapse-free survival for these regimens in these

patient populations.

Patient Population Patients must have morphologically confirmed,

previously untreated AML or MDS-EB-2. Patients

with acute promyelocytic leukemia, biphenotypic

leukemia, blastic transformation of chronic

myelogenous leukemia are not eligible. Patients must

have disease present in the blood or bone marrow;

patients with only extramedullary disease are not

eligible. Patients must not be known to have AML in

the CNS. Patients must be deemed, in the judgment

of the treating physician, to be ineligible for intensive

induction therapy or must have refused intensive

induction therapy.

Patients who have received prior therapy with

midostaurin, any anti-PD-1 or anti-PD-L1 therapy,

any DNA-methyltransferase inhibitor, or prior 7+3

therapy for MDS are not eligible. Patients who are

transfusion-dependent and patients receiving growth

factor support are eligible; patients must discontinue

growth factor support prior to initiation of protocol

therapy. Prior malignancy is allowed providing

concurrent therapy is not required; active hormonal

therapy is allowed.

Patients must be at least 60 years old and must be

able to swallow oral medications. Clinical evaluation

at baseline including hematologic, hepatic, renal,

cardiac, and coagulation parameters must be

completed per protocol. Women and men must be

willing to use contraception as outlined in the

protocol. Patients must not have active infection

(systemic bacterial, fungal, or viral infection) that is

not controlled. Patients must be eligible for at least

one of the currently enrolling investigational

treatment arms. Refer to the protocol for arm-specific

eligibility criteria.

Patients must have specimens submitted for FLT3

testing as outlined in the protocol for randomization

stratification. Pretreatment cytogenetics must be

performed on all patients as outlined in the protocol.

Stratification/Descriptive Factors Patient randomization will be stratified by the

following factors: (1) Zubrod performance status: 0-1

vs 2-4; (2) FLT3-ITD status based on central

laboratory results: wild type FLT3 vs mutated FLT3-

ITD vs non-evaluable; and (3) baseline blast

percentage: MDS-EB-2 (< 20%) vs AML (20% or

higher).

Accrual Goals Up to 100 eligible patients will be enrolled to each

arm for Phase II analysis. Up to 200 additional

eligible patients will be enrolled to each arm for

Phase III analysis. If all three experimental arms

complete full Phase III accrual, this study will enroll

approximately 1500 eligible patients.

The Phase II interim analysis to evaluate for stopping

for futility will be performed when 52 events have

been observed. For arms carried forward for Phase III

testing, two additional interim analyses will be

performed when 50% and 75% of the expected

events have been observed (207 and 311 events,

respectively).

A041202 November 2016

Template Version Date: September 24, 2013

Alliance Study A041202 – A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (>/= 65 Years of Age) with

Chronic Lymphocytic Leukemia (CLL)

Committee: Leukemia Study Statisticians: Sumithra Mandrekar, Ph.D. Study Chair: Jennifer Woyach, MD Amy S. Ruppert, M.A.S.

1.0 OBJECTIVES Primary

To determine whether progression free survival (PFS) is superior after therapy with bendamustine in combination with rituximab, ibrutinib alone, or ibrutinib in combination with rituximab in patients age 65 or older with previously untreated CLL

Secondary 1. To determine 2-year PFS in each of the three treatment arms 2. To determine which treatment arm produces superior overall survival (OS) 3. To determine the complete response (CR) rate, complete and nodular partial response

(CR/nPR) rate, and overall response (PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms

4. To determine the impact of MRD-negative disease at time of CR documentation and at 2 years on PFS and OS in each of the treatment arms

5. To determine duration of response after each of the three treatments and compare these treatment arms

6. To determine toxicity and tolerability of the three treatment regimens 7. To determine response and PFS of patients initially on the bendamustine in

combination with rituximab arm who cross over to ibrutinib 8. To determine whether baseline cytogenetic markers, Zap-70 methylation, IgVH

mutational status, or select DNA mutations predict outcomes or time to response in these three arms

9. To determine whether local FISH results for del(11q22.3) and del(17p13.1) are consistent with central analysis.

10. To determine whether baseline microRNA and gene expression markers are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2 years versus not), as well as to explore changes in microRNA expression from baseline to post-treatment time points, with a focus on those with persistent lymphocytosis and relapse

11. To determine whether eradication of MRD predicts longer duration of response with standard therapy and ibrutinib-based regimens

12. To describe the baseline functional status, comorbid medical conditions, and number of medications of older CLL patients who meet criteria for therapy

13. To determine how functional status changes with therapy using baseline to 3-month evaluation and end-of-study/2-year evaluation; to determine whether this change is different among the treatment groups

14. To determine whether geriatric assessment variables known to be associated with chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity in the CLL population

15. To assess whether the FCGR3A polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and progression-free survival (PFS)

16. To assess whether C1QA polymorphism (rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS



2.0 CURRENT SCHEMA

3.0 ELIGIBILITY CRITERIA

• Diagnosis with CLL in accordance with IWCLL 2008 Criteria • Intermediate or high risk Rai Stage CLL • Criteria met for treatment as defined by IWCLL 2008 guidelines • No prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of

CLL with steroids or rituximab) • Age ≥ 65 • ECOG performance status 0-2 • No active hepatitis B • No active systemic anticoagulation with heparin or warfarin • No active intercurrent disease (see Section 4.8) • No history of Richter’s transformation or prolymphocytic leukemia • No prednisone over 20 mg daily or equivalent corticosteroid • No uncontrolled active system infection requiring intravenous antibiotics • No strong CYP3A4/5 inhibitors or inducers • No allergy to mannitol • No significant hypersensitivity to rituximab • No major surgery within 10 days or minor surgery within 7 days • ANC ≥ 1000/µL (unless due to bone marrow involvement) • AST and ALT ≤ 2.5 x ULN (except due to disease infiltration of the liver) • Total bilirubin ≤ 1.5 x ULN (unless due to liver involvement, hemolysis or Gilbert’s disease) • Creatinine Clearance ≥ 40 mL/min (calculated by Cockcroft-Gault formula) • Platelets ≥ 30,000/µL



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 For this phase III clinical trial, patients will be randomized using dynamic allocation procedures to three arms in a 1:1:1 manner: Arm 1: bendamustine + rituximab (BR) vs. Arm 2: ibrutinib (I) vs. Arm 3: ibrutinib + rituximab (IR). Randomization will be stratified on Rai stage (intermediate vs. high) and presence of high-risk FISH abnormalities (del(11q22.3) or del(17p13.1) vs. not). In addition, we will also stratify on ZAP-70 methylation status (methylated vs. not, using a 20% methylation cut point), which is hypothesized to be strongly associated with clinical outcomes in CLL.

5.2 Primary Endpoint

The primary endpoint of PFS will be compared in each of the 3 planned pairwise comparisons: Arm 1 vs Arm 2, Arm 2 vs Arm 3 and Arm 1 vs Arm 3. Each of these efficacy analyses will utilize an intent-to-treat approach, where patients will be analyzed in the arm to which they were randomized. Log-rank statistics will be used to compare the PFS distributions of the different treatment arms. The methods of Kaplan and Meier will be used to estimate PFS for the treatment arms. For each of the planned comparisons, we will assess the corresponding hazard ratios, 2-year PFS estimates, and PFS medians along with their 95% confidence intervals.

The overall Type I error rate for this trial will be constrained at 0.05 and with 90% power for each of the one-sided tests of the ibrutinib-based regimens versus bendamustine plus rituximab and for the one-sided comparison of the ibrutinib alone versus ibrutinib plus rituximab arms. Based on all of these considerations and constraints, this proposed study requires a total of 498 evaluable patients. This translates to 166 patients required for each treatment arm. We will plan to over-accrue by about 5% for a total accrual goal of 523 patients.

5.3 Target Accrual

The target accrual for this study is 523 patients using a 1:1:1 randomization. The target accrual rate is 15 patients per month.

6.0 CURRENT ACCRUAL

Study Activation Date 12/09/2013 Closure Date 5/16/2016 Target Accrual (n) 523 Final Accrual (n) 547



7.0 CURRENT STUDY STATUS

This study opened on December 9, 2013. Registration for this trial closed on May 16, 2016. As of September 6, 2016, 547 patients have been randomized; 432 patients (79%) are alive and remain on active treatment. Twelve (12) patients have crossed over from Arm 1 (B+R) to Arm 2 (Ibrutinib alone).

8.0 PATIENT CHARACTERISTICS

All randomized participant are included in the table.

Table 8a. Demographics

Arm 1

(N=183) Arm 2

(N=182) Arm 3

(N=182) Total

(N=547) Age N 183 182 182 547 Mean (SD) 71.6 (5.1) 71.7 (5.0) 71.9 (4.6) 71.7 (4.9) Median 70.0 71.0 71.0 71.0 Q1, Q3 67.0, 76.0 68.0, 75.0 68.0, 75.0 68.0, 75.0 Range (65.0-86.0) (65.0-89.0) (65.0-86.0) (65.0-89.0)

0 313 12

1514

2022

1825

2919

1912

22

3120

2124

4626

17

36

3222

280 0 10

Expected Accrual 523 Patients



Arm 1

(N=183) Arm 2

(N=182) Arm 3

(N=182) Total

(N=547) Race White 167 (91.3%) 169 (92.9%) 173 (95.1%) 509 (93.1%) Black or African American 9 (4.9%) 7 (3.8%) 7 (3.8%) 23 (4.2%) Asian 4 (2.2%) 2 (1.1%) 0 (0.0%) 6 (1.1%) American Indian or Alaska Native 1 (0.5%) 0 (0.0%) 1 (0.5%) 2 (0.4%) Not reported 1 (0.5%) 3 (1.6%) 1 (0.5%) 5 (0.9%) Unknown 1 (0.5%) 1 (0.5%) 0 (0.0%) 2 (0.4%) Gender Female 64 (35.0%) 59 (32.4%) 57 (31.3%) 180 (32.9%) Male 119 (65.0%) 123 (67.6%) 125 (68.7%) 367 (67.1%)

Table 8b. Stratification Factors

Arm 1

(N=183) Arm 2

(N=182) Arm 3

(N=182) Total

(N=547) Rai stage classification category Intermediate (Stage I/II) 84 (45.9%) 83 (45.6%) 84 (46.2%) 251 (45.9%) High (Stage III/IV) 99 (54.1%) 99 (54.4%) 98 (53.8%) 296 (54.1%) Presense of del(11q22) or del(17p13) Yes 51 (27.9%) 50 (27.5%) 50 (27.5%) 151 (27.6%) No 132 (72.1%) 132 (72.5%) 132 (72.5%) 396 (72.4%) Zap70 methlyation status of CpG3 Missing 1 0 0 1 <20% 95 (52.2%) 96 (52.7%) 96 (52.7%) 287 (52.6%) >= 20% 87 (47.8%) 86 (47.3%) 86 (47.3%) 259 (47.4%) (report generated on 06SEP2016)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary 525 (96%) patients are evaluable for adverse event (AE) analyses (Arm 1: 172, Arm 2: 175 and Arm 3: 178). Grade 3+ AE occurring in > 10% of patients include: Anemia (12% Arm 1, 10% Arm 2, 4% Arm 3), Leukocytosis (6% Arm 1, 10% Arm 2, 9% Arm 3), Lymphocyte count decreased (20% Arm 1, 2% Arm 2, 2% Arm 3), Lymphocyte count increased (7% Arm 1, 18% Arm 2, 13% Arm 3), Neutrophil count decreased (40% Arm 1, 12% Arm 2, 19% Arm 3), Platelet count decreased (16% Arm 1, 4% Arm 2, 3% Arm 3), White blood cell decreased (15% Arm 1, 2% Arm 2, 3% Arm 3), and hypertension (12% Arm 1, 20% Arm 2, 22% Arm 3). There have been 11 deaths reported on treatment:

• Sudden death NOS (unlikely) • Sudden death NOS (unlikely) • Neoplasms benign, malignant and unspecified: progressive disease (not related) • Heart failure (unlikely) • Death NOS (possible)



• Death NOS (unlikely) • Respiratory failure, (not related) • Cardiac arrest (not related). • Leukoencephalopathy (definite) • Sudden death NOS (unlikely) • Hematoma (probable)

11 (92%) patients from Arm 1 who crossed over to Arm 2 are evaluable for AEs. The most common hematologic grade 3+ AEs reported in these patients after crossover were Neutrophil count decreased (Gr 3: 0 pts; Gr 4: 3 pts), Anemia (Gr 3: 4 pts, Gr 4: 0 pts), and lymphocyte count increased (Gr 3: 4 pts, Gr 4: 0 pts).One death on crossover treatment has been reported: Neoplasms benign, malignant and unspecified: brain metastases unknown primary (not related).

Initial Treatment Summary of Grade 3+ Adverse Events

Regardless of Attribution Number of Evaluable Patients:

Arm 1=172 Arm 2=175 Arm 3=178

Patients with a maximum: Arm n (%)

Total

Grade 3 Event 1 71 (41.3%)

2 85 (48.6%)

3 86 (48.3%)

Grade 4 Event 1 58 (33.7%)

2 15 (8.6%)

3 22 (12.4%)

Grade 5 Event 1 1 (0.6%)

2 4 (2.3%)

3 6 (3.4%)

Hematologic Adverse Events

Grade 3 Event 1 57 (33.1%)

2 53 (30.3%)

3 50 (28.1%)

Grade 4 Event 1 45 (26.2%)

2 9 (5.1%)

3 15 (8.4%)


2 0 (0.0%)

3 0 (0.0%)

Non-Hematologic Adverse Events

Grade 3 Event 1 70 (40.7%)

2 73 (41.7%)



Initial Treatment Summary of Grade 3+ Adverse Events


Arm 1=172 Arm 2=175 Arm 3=178


3 74 (41.6%)


2 6 (3.4%)

3 9 (5.1%)


2 4 (2.3%)

3 6 (3.4%)

Note: Summaries are based on available patient data

Initial Treatment Listing of Grade 3+ Adverse Events

Max Grade Per Patient Per Event Regardless of Attribution

Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178

Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal

n (%) n (%) n (%) Hematologic Adverse Events Blood/Bone Marrow

Anemia 1 20 ( 12%) 0 ( 0%) 0 ( 0%) 2 15 ( 9%) 1 ( 1%) 0 ( 0%) 3 8 ( 4%) 0 ( 0%) 0 ( 0%) Blood and lymphat sys disord - Oth spec

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

2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Bone marrow hypocellular 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Leukocytosis 1 10 ( 6%) 0 ( 0%) 0 ( 0%) 2 18 ( 10%) 0 ( 0%) 0 ( 0%) 3 16 ( 9%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased 1 21 ( 12%) 13 ( 8%) 0 ( 0%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 2 ( 1%) 1 ( 1%) 0 ( 0%)







n (%) n (%) n (%) Lymphocyte count increased 1 12 ( 7%) 0 ( 0%) 0 ( 0%) 2 31 ( 18%) 0 ( 0%) 0 ( 0%) 3 24 ( 13%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased 1 38 ( 22%) 31 ( 18%) 0 ( 0%) 2 12 ( 7%) 8 ( 5%) 0 ( 0%) 3 20 ( 11%) 15 ( 8%) 0 ( 0%) Platelet count decreased 1 18 ( 10%) 10 ( 6%) 0 ( 0%) 2 6 ( 3%) 1 ( 1%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) White blood cell decreased 1 20 ( 12%) 5 ( 3%) 0 ( 0%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 5 ( 3%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events Blood and lymphatic sys disord

Febrile neutropenia 1 11 ( 6%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Thrombotic thrombocytopenic purpura

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

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

Cardiac disorders Aortic valve disease 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Atrial fibrillation 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 9 ( 5%) 1 ( 1%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Atrial flutter 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Atrioventricular block complete 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Cardiac arrest 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Cardiac disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Chest pain - cardiac 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Heart failure 1 0 ( 0%) 2 ( 1%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 1 ( 1%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Myocardial infarction 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Pericardial effusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Sick sinus syndrome 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Ventricular tachycardia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Ear and labyrinth disorders Ear and labyrinth disorders - Oth spec

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

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hearing impaired 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Eye disorders Conjunctivitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Retinopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%)

Gastrointestinal disorders Abdominal pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Ascites 1 3 ( 2%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Colitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Constipation 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Diarrhea 1 3 ( 2%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) Dysphagia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal disorders - Oth spec

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

2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis oral 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Nausea 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Pancreatitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Small intestinal obstruction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Vomiting 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)

Gen disord and admin site cond Death NOS 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 1 ( 1%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Edema face 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Edema limbs 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Fatigue 1 6 ( 3%) 0 ( 0%) 0 ( 0%) 2 6 ( 3%) 0 ( 0%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) Fever 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Infusion related reaction 1 11 ( 6%) 3 ( 2%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Multi-organ failure 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Non-cardiac chest pain 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Sudden death NOS 1 0 ( 0%) 0 ( 0%) 1 ( 1%) 2 0 ( 0%) 0 ( 0%) 1 ( 1%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%)

Hepatobiliary disorders Cholecystitis 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Immune system disorders Allergic reaction 1 3 ( 2%) 3 ( 2%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Anaphylaxis 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Immune system disorders - Other, specify

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

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

Infections and infestations Abdominal infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Appendicitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Bladder infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Bone infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Gallbladder infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec

1 4 ( 2%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 1 ( 1%) 0 ( 0%) Joint infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 5 ( 3%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Meningitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Otitis media 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Papulopustular rash 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Scrotal infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Sepsis 1 0 ( 0%) 5 ( 3%) 0 ( 0%) 2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 2 ( 1%) 0 ( 0%) Skin infection 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%) 3 5 ( 3%) 0 ( 0%) 0 ( 0%) Upper respiratory infection 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Urinary tract infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Wound infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Inj, pois and proced complic Ankle fracture 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Fall 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Hip fracture 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Seroma 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Investigations Alanine aminotransferase increased

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

2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Aspartate aminotransferase increased

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

2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Blood bilirubin increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Cardiac troponin I increased 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Creatinine increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Ejection fraction decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Investigations - Other, specify 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Metabol and nutrition disord Anorexia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Dehydration 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Glucose intolerance 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypercalcemia 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperglycemia 1 4 ( 2%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) Hyperkalemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Hypernatremia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hyperuricemia 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Hypoalbuminemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hypocalcemia 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypokalemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypomagnesemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hyponatremia 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 3 ( 2%) 1 ( 1%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Hypophosphatemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Tumor lysis syndrome 1 3 ( 2%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Musculosk and conn tiss disord Arthralgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Back pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Bone pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Generalized muscle weakness 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) Joint effusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Muscle weakness right-sided 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Musculoskeletal, conn tissue - Oth spec

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

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Myalgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Pain in extremity 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)

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

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

2 3 ( 2%) 0 ( 0%) 1 ( 1%) 3 4 ( 2%) 1 ( 1%) 0 ( 0%) Treatment related secondary malignancy

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

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

Nervous system disorders Dizziness 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Encephalopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Headache 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hydrocephalus 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Intracranial hemorrhage 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Leukoencephalopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Neuralgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Stroke 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Syncope 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Tremor 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Psychiatric disorders Anxiety 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Confusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Depression 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Renal and urinary disorders Acute kidney injury 1 1 ( 1%) 0 ( 0%) 0 ( 0%)







n (%) n (%) n (%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Chronic kidney disease 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hematuria 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Renal and urinary disorders - Oth spec

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

2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal calculi 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary retention 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)

Respirat, thor, mediast disord Adult respiratory distress syndrome

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

2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Aspiration 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Chylothorax 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Cough 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Dyspnea 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 3 ( 2%) 1 ( 1%) 0 ( 0%)







n (%) n (%) n (%) 3 4 ( 2%) 1 ( 1%) 0 ( 0%) Epistaxis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hypoxia 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Pleural effusion 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Pneumonitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Pulmonary edema 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Respiratory failure 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Sore throat 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Skin and subcutan tiss disord Pruritus 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Rash maculo-papular 1 11 ( 6%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 7 ( 4%) 0 ( 0%) 0 ( 0%) Skin and subcut tissue disord - Oth spec

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

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

Surgical and medical proced







n (%) n (%) n (%) Surgical and medical proced - Oth spec

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

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

Vascular disorders Flushing 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hematoma 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Hypertension 1 19 ( 11%) 1 ( 1%) 0 ( 0%) 2 35 ( 20%) 0 ( 0%) 0 ( 0%) 3 38 ( 21%) 1 ( 1%) 0 ( 0%) Hypotension 1 9 ( 5%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)

Crossover Patients

Summary of Grade 3+ Adverse Events Regardless of Attribution

Number of Evaluable Patients: Arm 2 (Cross Over) =11


Total

Grade 3 Event 2 (CO) 4 (36.4%)



Hematologic Adverse Events




Crossover Patients Summary of Grade 3+ Adverse Events


Arm 2 (Cross Over) =11




Non-Hematologic Adverse Events




Note: Summaries are based on available patient data

Crossover Patients Listing of Grade 3+ Adverse Events


Number of Evaluable Patients: Arm 2 (Cross over) =11


n (%) n (%) n (%) Hematologic Adverse Events Blood/Bone Marrow

Anemia 2 (CO) 4 ( 36%) 0 ( 0%) 0 ( 0%) Leukocytosis 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Lymphocyte count increased 2 (CO) 4 ( 36%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased 2 (CO) 0 ( 0%) 3 ( 27%) 0 ( 0%) Platelet count decreased 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events Blood and lymphatic sys disord

Febrile neutropenia 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Cardiac disorders

Atrial fibrillation 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Metabol and nutrition disord

Hypophosphatemia 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Neoplsm benign, mal and unspec

Neoplasms benign, mal, unspec - Oth spec

2 (CO) 0 ( 0%) 0 ( 0%) 1 ( 9%)



Crossover Patients Listing of Grade 3+ Adverse Events


Number of Evaluable Patients: Arm 2 (Cross over) =11


n (%) n (%) n (%) Respirat, thor, mediast disord

Pleural effusion 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) 10.0 IMBEDDED CORRELATIVES

A041202-LC1: Leukemia Correlative Studies in Alliance A041202 Participation to embedded correlative A041202-LC1 was mandatory for all patient registered to this study. As of September 6, 2016, there are 547 patients who consented. Bone marrow, peripheral blood and buccal cell samples are being collected. Within this correlative, ZAP 70 methylation testing is preformed centrally at pre-registration for stratification. In addition, samples are being banked for future analysis.

A041202-PP1: Evaluation of Candidate Pharmacogenetic Determinants of Ibrutinib or Ibrutinib/Rituximab Response

Participation to embedded correlative A041202-PP1 is optional for all patients registered to this study. As of September 6, 2016, there are 450 patients who consented and were randomized. Baseline peripheral blood samples are being banked for future analysis.

A041202-EL1: Geriatric Assessment in Alliance A041202

Participation to embedded correlative A041202-EL1 was optional for all patient registered to this study. As of September 6, 2016, there are 410 patients who consented and were randomized. Questionnaires are being completed by patients and health care professionals for future analysis.

CALGB 9665: The CALGB Leukemia Tissue Bank

Participation to stand alone correlative CALGB 9665 was optional for all patient registered to this study. This correlative study was closed to accrual as of March 1, 2014; 7 patients were randomized to A041202 and consented. For those who consented, samples are collected at baseline, remission and progression and are being banked for future analysis.

ECOG-ACRIN Cancer Research Group E1910

Study Progress and Safety Report Spring 2017

Page 1

E1910 A PHASE III RANDOMIZED TRIAL OF BLINATUMOMAB FOR NEWLY

DIAGNOSED BCR-ABL NEGATIVE B ACUTE LYMPHOBLASTIC LEUKEMIA IN

ADULTS

Sponsor(s)

Coordinating Group ECOG-ACRIN

Chairperson(s) Dr. Mark Litzow

Statistician Dr. Zhuoxin Sun

Imaging Statistician Dr. Fenghai Duan

Data Specialist Henry Baptista

Phase of Study III

Type of Study Therapeutic

Committee Leukemia

Accrual Objective 360 Patients

Participating Groups ECOG-ACRIN, CTSU

DCP Treatment Credit 1.0

NSC# 740, 3590, 10023, 14575, 26271, 34521, 63878,

67574, 141540, 624239, 697732, 765986

Clinicaltrials.gov Study ID NCT02003222

Study Status Open to Accrual

Date Proposed June 26, 2012

Date Activated December 17, 2013

Schema



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Schema Continued



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Schema Continued

Purpose of Study

1) To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to

chemotherapy alone in patients with BCR-ABL-negative B cell precursor ALL who are MRD positive after

induction and intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of

residual blasts. 2) If superiority of blinatumomab in the MRD positive group is shown, to compare the OS of

blinatumomab in conjunction with chemotherapy to chemotherapy alone in patients with

BCR-ABL-negative B cell precursor ALL who are MRD negative after induction and intensification

chemotherapy, based on MFC assessment of residual blasts. 3) If superiority of blinatumomab in the MRD

positive group is not shown, to compare the OS of blinatumomab in conjunction with chemotherapy to

chemotherapy alone in the overall population of patients with BCR-ABL-negative B cell precursor ALL. 4)

To determine if blinatumomab can convert patients who are MRD positive by MFC assessment of residual

blasts after induction and intensification chemotherapy to MRD negativity. 5) To assess the toxicities of

blinatumomab in this patient population. 6) To assess the toxicities of the modified E2993 chemotherapy

regimen in this patient population. 7) To describe the outcome of patients who proceed to allogeneic blood

or marrow transplant after treatment with or without blinatumomab. 8) To determine differences in MRD

kinetics among patients with the BCR/ABL1-like B-lineage ALL, and assess the efficacy of blinatumomab

in each molecular subgroup. 9) To evaluate the incidence of anti-blinatumomab antibody formation.

Study Population

Newly diagnosed, previously untreated BCR-ABL negative B cell precursor acute lymphoblastic leukemia

patients aged 30-70.



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Summary of Study Design

The primary objectives of this phase III study are to compare the OS in patients who received blinatumomab

in conjunction with chemotherapy to that of patients who received chemotherapy alone in MRD+ subset,

MRD- subset, and the overall population. OS is defined as the time between randomization and death from

any cause. Patients last known to be alive at the time of an analysis will be censored. To control the overall

one-sided type I error at 0.025, the OS comparison in the MRD+ subset will be tested first at one-sided type

I error of 0.02. If it is significant, the OS comparison in MRD- subset will be tested at one-sided type I error

of 0.025. Otherwise, the OS comparison in overall population will be tested at one-sided type I error of

0.005. Based on the previous phase III ALL study E2993, we assume 88% of patients enrolled can achieve

CR after induction chemotherapy and 10% of patients will drop out between achievement of CR and

randomization to blinatumomab. Therefore, 285 patients will be randomized to receive either

blinatumomab or no blinatumomab. We assume that about 1/3 of randomized patients will be MRD+. We

assume the survival function of this ALL patient population can be described by a cure rate model. For

MRD+ patients, we assume a 20% long-term cure rate and 7.5-month median OS in the non-cured group in

the control arm. Adjusted for sequential monitoring, with 95 MRD+ patients, the study will have 80%

power to detect 54% reduction in hazard rate in the blinatumomab arm relative to the no blinatumomab arm,

using one-sided log rank test at the significance level of 0.02 and assuming 2 years of follow-up, which is

equivalent to detecting an improvement in the 3-year OS rate from 23% to 51%. The number of events

needed is 61. If the MRD+ subgroup is significant, the MRD- subgroup will be tested at one-sided type I

error of 0.025. For MRD- patients, we assume a 35% long-term cure rate and 13-month median OS in the

non-cured group in the control arm. Adjusted for sequential monitoring, with 190 MRD- patients (2/3 of all

patients), the study will have 80% power to detect 45% reduction in hazard rate in the blinatumomab arm

relative to the no blinatumomab arm, using one-sided log rank test at the significance level of 0.025 and

assuming 2 years of follow-up, which is equivalent to detecting an improvement in the 3-year OS rate from

45% to 64%. The number of events needed is 94. If the MRD+ subgroup is not significant, the overall

population will be tested at one-sided type I error of 0.005. For all patients, we assume a 30% long-term

cure rate and 11-month median OS in the non-cured group in the control arm. Adjusted for sequential

monitoring, with 285 patients, the study will have 80% power to detect 43% reduction in hazard rate in the

blinatumomab arm relative to the no blinatumomab arm, using one-sided log rank test at the significance

level of 0.005 and assuming 2 years of follow-up, which is equivalent to detecting an improvement in the

3-year OS rate from 37% to 57%. The number of events needed is 160. The projected accrual rate is 72

patients per year.

Progress to Date

This study was activated on December 17, 2013. As of March 2, 2017, 189 patients have been accrued.

Accrual status and accrual by group are summarized in Tables 1a, 1b and 1c. Expected and actual

cumulative accrual are shown in Figure 1. Patient status as of March 2, 2017 is summarized in Table 2.

Demographic data are shown in Tables 3a, 3b, 3c and 3d. Record status is shown in Table 4. The

distribution of the reasons for discontinuation of protocol treatment is given in Table 5 by step.

Treatment-related toxicity data are available on 145 patients and are summarized in Table 6 by step,

treatment arm and cycle. Table 7 summarizes lethal adverse events (regardless of treatment relation). Table

8 summarizes incidences of second primary cancer.

Outcome data are not included in this report, but will be presented to the Data Safety Monitoring Committee

when appropriate.



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Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 0 Step 1 Step 2 Step 3 Step 4

Beth Israel Deaconess Medical Center 1 1 1 1 0

Cancer Research Consortium of West Michigan NCORP 1 1 1 1 0 Dayton NCORP 1 1 1 0 0

Froedtert and the Medical College of Wisconsin 13 12 9 7 3

Geisinger Cancer Institute NCORP 1 0 0 0 0 Georgia NCORP 7 5 0 0 0

Gulf South MU NCORP 1 1 0 0 0

Heartland Cancer Research NCORP 1 1 0 0 0 Johns Hopkins Univ/Sidney Kimmel Cancer Center 26 21 15 13 3

Loyola University Medical Center 2 1 1 1 0

Mayo Clinic 8 6 2 1 0 NorthShore Univ HealthSystem-Evanston Hospital 2 2 1 1 0

Northwestern University 9 6 3 2 0

Ochsner NCORP 4 1 1 1 1 Pacific Cancer Research Consortium NCORP 0 0 0 0 1

Penn State Milton S Hershey Medical Center 3 1 0 0 0

Rutgers Cancer Institute of New Jersey 3 1 0 0 0 Stanford Cancer Institute 1 1 0 0 0

University of Alabama at Birmingham Cancer Center 1 1 1 1 0

University of Pennsylvania/Abramson Cancer Center 18 13 7 5 2 University of Wisconsin Hospital and Clinics 3 3 1 1 0

VCU Massey Cancer Center MU NCORP 12 5 4 1 0

Washington University School of Medicine 5 3 0 0 0 Wichita NCORP 5 3 2 2 0

Total 128 90 50 38 10

Table 1b. Accrual by Group

Step 1 Step 2 Step 3 Step 4

ECOG-ACRIN 90 50 38 10

SWOG 50 31 25 14

ALLIANCE 46 26 19 5

NRG 3 3 2 1

Total 189 110 84 30

Table 1c. Projected Accrual


Accrual goal 360

Planned accrual rate 72/yr

Accrual to date 189 110 84 30

Annual accrual rate

Overall 59/yr 34/yr 26/yr 9/yr

Last 6 months 108/yr 50/yr 34/yr 18/yr

Projected date of closure September 2018



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Table 2. Patient Status as of March 2, 2017


Cases Entered 189 110 84 30

Ineligible 5 6 4 0

Never Started Assigned Therapy 3 0 2 0

Reason for ineligibility Step 1:

Patient was BCR/ABL+ (19004, 19063, 19193, 19259). Bone Marrow pathology report was not done

(19155).

Reason for not starting assigned therapy Step 1:

Patient withdrawal/refusal (19066); patient ineligible (19155, 19193).


CR/CRi not confirmed (19037, 19053, 19139, 19194, 19218); ECOG performance status as 3 and

neurological complications (19185).


Baseline labs (bilirubin, creatinine, anc, blasts, platelets) not done before randomization (19040);

Serum Creatinine and Bilirubin were not obtained within 48 of step 3 registration in order to confirm

eligibility (19051, 19053); Overall Response reported as SD in Step 2 (19011).


Patient withdrawal/refusal (19093); Disease progression (19044).



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Table 3a. Demographics - Step 1

Variable Level

Arm A

(n=189)

Sex Male 98 (51.9)

Female 91 (48.1)

Race White 153 (91.1)

African-American 9 (5.4)

Asian 4 (2.4)

Native Hawaiian 1 (0.6)

Multirace 1 (0.6)

Unknown/Unreported 21

Ethnicity Hispanic 27 (15.3)

Non-Hispanic 149 (84.7)

Unknown/Missing 13

Age Median 52

Minimum 30

Maximum 69

Table 3b. Demographics - Step 2

Variable Level

Arm B

(n=110)

Sex Male 51 (46.4)

Female 59 (53.6)



Asian 2 (2.1)

Multirace 1 (1.0)




Unknown/Missing 7

Age Median 53

Minimum 30

Maximum 69



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Table 3c. Demographics - Step 3

Variable Level

Arm C

(n=44)

Arm D

(n=40)

Total

(n=84)

Sex Male 20 (45.5) 18 (45.0) 38 (45.2)

Female 24 (54.5) 22 (55.0) 46 (54.8)

Race White 37 (92.5) 32 (97.0) 69 (94.5)

African-American 3 (7.5) 1 (3.0) 4 (5.5)

Unknown/Unreported 4 7 11

Ethnicity Hispanic 6 (14.0) 7 (20.0) 13 (16.7)

Non-Hispanic 37 (86.0) 28 (80.0) 65 (83.3)

Unknown/Missing 1 5 6

Age Median 53 51 52

Minimum 31 30 30

Maximum 68 69 69

Table 3d. Demographics - Step 4

Variable Level

Arm E

(n=30)

Sex Male 13 (43.3)

Female 17 (56.7)






Unknown/Missing 2

Age Median 54

Minimum 33

Maximum 68



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Table 4. Record Status

Form Name

Forms

Due

Forms

Received %

Demography 181 181 100.0

Patient Characteristics 377 369 97.9

Treatment Agent: 6 Mercaptopurine 234 216 92.3

Treatment Agent: Blinatumomab 95 93 97.9

Treatment Agent: Cyclophosphamide (1d) 32 28 87.5

Treatment Agent: Cyclophosphamide (2d) 127 127 100.0

Treatment Agent: Cytarabine (16d) 127 127 100.0




Treatment Agent: Daunorubicin (4d) 196 187 95.4

Treatment Agent: Dexamethasone 196 186 94.9

Treatment Agent: Etoposide (5d) 113 111 98.2

Treatment Agent: Leucovorin 96 92 95.8

Treatment Agent: Methotrexate (13d) 75 61 81.3




Treatment Agent: Methotrexate IT (13d) 3 1 33.3

Treatment Agent: Pegaspargase 433 418 96.5

Treatment Agent: Prednisone 76 66 86.8

Treatment Agent: Vincristine (1d) 79 73 92.4

Treatment Agent: Vincristine (4d) 196 187 95.4

Adverse Event Form 711 646 90.9

Follow-Up Hematology/Chemistry 5972 5927 99.2

Late Adverse Event Form 3 3 100.0

Other Adverse Event Form 293 293 100.0

Disease Follow-up Status 855 823 96.3

Off Treatment 24 21 87.5

Off-Treatment with Intent to Reg Next Step 272 269 98.9

Table 5a. Reasons Off Treatment - Step 1

For Patients Not Registered To Subsequent Steps

(Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N %

Adverse event/side effects/complications 2 4.7

Alternative therapy 3 7.0

Death on study 5 11.6

Disease progression- relapse during active treatment 8 18.6

Other 12 27.9

Patient withdrawal/refusal after beginning protocol therapy 6 14.0

Treatment completed per protocol criteria 7 16.3

Total off treatment 43 100.0



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Table 5b. Reasons Off Treatment - Step 2




Reasons N %


Other 2 12.5




Table 5c. Reasons Off Treatment - Step 3




Reasons N %





Other 1 3.0




Table 5d. Reasons Off Treatment - Step 4



Reasons N %



Other 2 28.6





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Table 6a. Toxicity Incidence- Step 1 (Arm A)

Toxicity Type

Treatment

Arm

A (n=145)

Grade

3 4 5

(n) (n) (n)

Anemia 66 14 -

Disseminated intravascular coagulation 1 - -

Febrile neutropenia 29 1 -

Chest pain - cardiac 1 - -

Sinus bradycardia 1 - -

Sinus tachycardia 1 - -

Fatigue 4 - -

General disorders and administration site conditions - Other, specify 1 - -

Pain 1 - -

Rash maculo-papular 1 - -

Abdominal pain 3 - -

Constipation 2 - -

Diarrhea 1 1 -

Gastrointestinal disorders - Other, specify 2 - -

Mucositis oral 1 - -

Nausea 10 - -

Pancreatitis 4 - -

Small intestinal obstruction - 1 -

Vomiting 9 - -

Hepatic failure - 1 -

Allergic reaction 1 - -

Anaphylaxis 1 - -

Catheter related infection 3 - -

Eye infection 1 - -

Infections and infestations - Other, specify 2 - -

Sepsis - 4 -

Sinusitis 1 - -

Skin infection 2 - -

Urinary tract infection 1 - -

Abdominal infection 1 - -

Bone infection 1 - -

Lung infection 1 - -

Alanine aminotransferase increased 12 2 -

Alkaline phosphatase increased 6 - -

Aspartate aminotransferase increased 9 1 -

Blood bilirubin increased 9 3 -



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Toxicity Type

Treatment

Arm

A (n=145)

Grade

3 4 5

(n) (n) (n)

Cholesterol high - 1 -

Fibrinogen decreased 2 - -

Lymphocyte count decreased 6 18 -

Neutrophil count decreased 4 111 -

Platelet count decreased 7 99 -

White blood cell decreased - 52 -

GGT increased 1 - -

Anorexia 2 - -

Dehydration 5 - -

Hyperglycemia 11 - -

Hyperkalemia 1 - -

Hypertriglyceridemia - 7 -

Hypoalbuminemia 2 - -

Hypocalcemia 1 - -

Hyponatremia 8 - -

Tumor lysis syndrome 12 - -

Glucose intolerance 3 - -

Arthralgia 1 - -

Back pain 1 - -

Generalized muscle weakness 1 - -

Cerebrospinal fluid leakage 1 - -

Cognitive disturbance 1 - -

Dizziness 2 - -

Encephalopathy 1 - -

Headache 7 - -

Syncope 3 - -

Vasovagal reaction 1 - -

Confusion 2 - -

Delirium 1 - -

Insomnia 1 - -

Personality change 1 - -

Dyspnea 2 - -

Epistaxis 1 - -

Pneumonitis 1 - -

Wheezing 1 - -

Acute kidney injury 1 - -



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Toxicity Type

Treatment

Arm

A (n=145)

Grade

3 4 5

(n) (n) (n)

Hypertension 6 - -

Hypotension 3 1 -

Thromboembolic event 3 2 -

WORST DEGREE (NON-HEMATOLOGIC) 61 23 -

Table 6b. Toxicity Incidence - Step 2 (Arm B)

Toxicity Type

Treatment

Arm

B (n=79)

Grade

3 4 5

(n) (n) (n)

Anemia 17 1 -

Febrile neutropenia 1 - -

Fatigue 1 - -

Hyperhidrosis 1 - -

Diarrhea 2 - -

Nausea 2 - -

Catheter related infection 2 - -

Sepsis - 1 -

Alanine aminotransferase increased 7 - -

Alkaline phosphatase increased 2 - -

Aspartate aminotransferase increased 6 - -

Blood bilirubin increased 2 1 -

Investigations - Other, specify 1 - -

Lipase increased - 1 -

Lymphocyte count decreased 6 4 -



White blood cell decreased 3 2 -

Alkalosis 1 - -

Dehydration 1 - -

Hyperglycemia 3 - -



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Toxicity Type

Treatment

Arm

B (n=79)

Grade

3 4 5

(n) (n) (n)

Hypertriglyceridemia - 1 -

Hypokalemia 1 - -

Hyponatremia 1 - -

Hypophosphatemia 1 - -

Tumor lysis syndrome 1 - -

Generalized muscle weakness 1 - -

Headache 1 - -

Hypertension 2 - -

Hypotension 1 - -




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Table 6c. Toxicity Incidence – Step3 (Arm C)

Toxicity Type

Treatment Arm

C (n=32)

Blinitumomab Consolidation

Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6

Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Anemia 2 - - - - - 2 - - 3 - - 7 - - 4 - - - - - 1 - - - - - 7 - -

Blood and lymphatic system disorders - Other,

specify - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - -

Febrile neutropenia - - - - - - - - - 2 1 - 1 - - 2 - - 1 - - 1 - - - - - 6 1 -

Chest pain - cardiac - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -

Fever - - - - - - - - - - - - - - - - - - - - - 1 - - - - - 1 - -

General disorders and administration site

conditions - Other, specify - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -

Cytokine release syndrome 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - -

Appendicitis perforated - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - -

Catheter related infection 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Infections and infestations - Other, specify 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Sepsis - - - - - - - - - - 2 - - - - - - - - - - - - - - - - - 2 -

Urinary tract infection - - - 1 - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - -

Alanine aminotransferase increased - 1 - - - - - 1 - 1 - - 1 - - - - - - - - - - - - - - 1 - -

Aspartate aminotransferase increased - 1 - - - - - 1 - - - - 1 - - - - - - - - - - - - - - 1 - -

Lymphocyte count decreased - 2 - - - - - 2 - - - - - - - - - - - - - - - - - - - - - -

Neutrophil count decreased 3 2 - 1 - - 4 2 - - 13 - 1 9 - 1 10 - 2 1 - - 10 - 2 - - 1 15 -

Platelet count decreased - 2 - - - - - 2 - 3 6 - 1 7 - - 10 - 1 - - - 6 - - - - 2 14 -

White blood cell decreased - 1 - - - - - 1 - 2 2 - - - - - 1 - - - - - 1 - - - - 2 4 -

Dehydration 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -



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Toxicity Type

Treatment Arm

C (n=32)

Blinitumomab Consolidation

Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6

Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Hyperglycemia 1 - - - - - 1 - - - - - 1 - - 1 - - - - - - - - - - - 1 - -

Hyponatremia 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Hypophosphatemia - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -

Cognitive disturbance 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Depressed level of consciousness 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Dysarthria - - - 1 - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Dysphasia 1 - - 1 - - 2 - - - - - - - - - - - - - - - - - - - - - - -

Encephalopathy 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - -

Headache - - - - - - - - - 1 - - 1 - - - - - - - - - - - - - - 2 - -

Intracranial hemorrhage - - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - -

Seizure 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - -

Tremor 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Epistaxis - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -

Capillary leak syndrome 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -

Hypertension - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - -

WORST DEGREE (NON-HEMATOLOGIC) 5 1 1 1 - - 6 1 1 4 2 - 4 - - 5 - - 1 - - 2 - - - - - 11 2 -



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Table 6d.Toxicity Incidence – Step 4 (Arm D)

Toxicity Type

Treatment Arm

D (n=29)

Cycle 1 Cycle 2 Cycle 3 Cycle 4

Cycles

1-4

Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Anemia 3 1 - 4 1 - 4 1 - 1 - - 9 2 -

Febrile neutropenia 3 - - 2 - - 1 - - - - - 5 - - Fatigue 1 - - - - - - - - - - - 1 - -

General disorders and administration site conditions -

Other, specify 1 - - - - - - - - - - - 1 - -

Vomiting 2 - - - - - - - - - - - 2 - -

Allergic reaction 1 - - - - - - - - - - - 1 - -

Catheter related infection 1 1 - - 1 - 1 - - - - - 2 1 -

Infections and infestations - Other, specify 1 - - - - - - - - - - - 1 - -

Sepsis - 2 - - 1 - - 1 - - - - - 3 -

Alanine aminotransferase increased 1 - - - - - - - - - - - 1 - -

Lymphocyte count decreased 2 - - - 1 - 1 2 - 2 - - 2 3 -

Neutrophil count decreased 4 16 - - 10 - 1 6 - 1 2 - 2 19 -

Platelet count decreased 5 9 - 1 5 - 2 3 - - 1 - 5 11 -

White blood cell decreased 1 6 - 2 1 - 2 2 - 1 2 - 1 7 -

Hyperglycemia - - - - - - 2 1 - - - - 2 1 -

Hypertriglyceridemia - 1 - - - - - - - - - - - 1 -

Hyponatremia 1 - - - - - - - - - - - 1 - -

Hypophosphatemia 1 - - - - - - - - - - - 1 - -

Headache 1 - - 2 - - 1 - - - - - 3 - -

Depression 1 - - - - - - - - - - - 1 - -

Hypertension 1 - - - - - - - - - - - 1 - -

WORST DEGREE (NON-HEMATOLOGIC) 7 3 - 3 1 - 2 2 - - - - 9 5 -

Table 6e. Toxicity Incidence – Step 3 Transplant

Toxicity Type

Treatment Arm

C (n=5) D (n=7)

Grade Grade

3 4 5 3 4 5

(n) (n) (n) (n) (n) (n)

Anemia 2 - - 2 - -

Febrile neutropenia 2 - - 2 - -



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Toxicity Type

Treatment Arm

C (n=5) D (n=7)

Grade Grade

3 4 5 3 4 5

(n) (n) (n) (n) (n) (n)

Atrial fibrillation 1 - - - - -

Anal mucositis - - - 1 - -

Colitis 1 - - - - -

Diarrhea 2 - - - - -

Mucositis oral - - - 1 - -

Nausea - - - 1 - -

Infections and infestations - Other, specify 1 - - - - -

Lung infection - - - 1 - -

Lymphocyte count decreased - - - - 2 -

Neutrophil count decreased - 3 - - 4 -

Platelet count decreased - 3 - - 3 -

White blood cell decreased - 2 - - 2 -

Anorexia - - - 1 - -

Dyspnea - - - 1 - -

Pulmonary edema - - - 1 - -

Respiratory failure - 1 - - - -

Acute kidney injury - 1 - - - -

WORST DEGREE (NON-HEMATOLOGIC) 2 1 - 2 - -

Table 6f. Toxicity Incidence – Step 4 Maintenance

Toxicity Type

Treatment Arm

C (n=12) D (n=10)

Grade Grade

3 4 5 3 4 5

(n) (n) (n) (n) (n) (n)

Anemia - - - 1 - -

Mucositis oral 2 - - - - - Nausea 1 - - - - -

Vomiting 1 - - - - -

Infections and infestations - Other, specify 1 - - - - -

Alanine aminotransferase increased 1 - - 2 - -

Aspartate aminotransferase increased 1 - - 2 - -

Blood bilirubin increased 1 - - 1 1 -

Lymphocyte count decreased - - - 2 - -

Neutrophil count decreased - 5 - 1 2 -

Platelet count decreased - 1 - - 1 -

White blood cell decreased 1 - - - 2 -

Dehydration 1 - - - - -



Page 19

Toxicity Type

Treatment Arm

C (n=12) D (n=10)

Grade Grade

3 4 5 3 4 5

(n) (n) (n) (n) (n) (n)

Hyperglycemia - - - 1 - -

Headache - - - 1 - -

Treatment related secondary malignancy - - 1 - - -

WORST DEGREE (NON-HEMATOLOGIC) 3 - 1 4 1 -

Table 7. Lethal Adverse Events

Case Arm Description of Event 19001 A Death NOS

19126 A Intracranial hemorrhage

19215 A Sudden death NOS

19220 A Febrile neutropenia

19243 A Sepsis

19119 C Intracranial hemorrhage

19088 D Cardiac arrest

Table 8. Second Primary Cancers

(By arm during which event was reported)

Site Arm A Arm E

Leukemia, Type Not Specified - 1

Non-Small Cell Lung 1 -



Page 1

E1912 E1912: A RANDOMIZED PHASE III STUDY OF IBRUTINIB (PCI-32765)-BASED

THERAPY VS STANDARD FLUDARABINE, CYCLOPHOSPHAMIDE, AND

RITUXIMAB (FCR) CHEMOIMMUNOTHERAPY IN UNTREATED YOUNGER

PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Sponsor(s)


Chairperson(s) Dr. Tait Shanafelt

Statistician Dr. Xin Victoria Wang

Data Specialist Elene Assefa

Phase of Study III


Committee Leukemia


Participating Groups ECOG-ACRIN, SWOG, CTSU, ALLIANCE, NRG


DCP Cancer Control Credit 0.4

NSC# 26271, 312887, 687451, 748645


Study Status Closed to Accrual

Date Proposed April 3, 2012

Date Activated January 31, 2014

Date Terminated June 9, 2016

Final Accrual 529 Patients

Schema



Page 2

Purpose of Study

Primary Objective: To evaluate the ability of Ibrutinib-based induction therapy to prolong progression

free survival (PFS) compared to standard FCR chemoimmunotherapy for younger patients with CLL.

Secondary Objectives: (1) To evaluate overall survival (OS) of patients based on treatment arm. (2) To

monitor and assess toxicity of treatment with Ibrutinib-based induction relative to standard FCR

chemotherapy. (3) To monitor and assess quality of life (QOL) in CLL patients receiving Ibrutinib-based

induction therapy relative to standard FCR chemoimmunotherapy. (4) To determine the effect of

pretreatment clinical and biological characteristics (e.g. disease stage, IGHV mutation status, FISH) on

clinical outcomes (e.g. complete response, PFS) of the different arms. (5) To determine if the minimal

residual disease (MRD) status as assessed by flow cytometry at different time points during and after

treatment is an effective surrogate marker for prolonged PFS and overall survival. (6) To conduct

confirmatory validation genotyping of single nucleotide polymorphisms (SNPs) associated with the

efficacy and toxicity of fludarabine-based therapy as in a prior ECOG GWAS analysis in the E2997 trial.

(7) To explore the effects of FCR and Ibrutinib-based therapy on T-cell immune function. (8) To evaluate

the ability of prognostic model that incorporates clinical and biologic characters to predict response to

therapy and clinical outcome (PFS, OS). (9) To collect relapse samples to study mechanisms of resistance

to both FCR and Ibrutinib-based therapy.

Study Population

Patients </= 70 years old with untreated chronic lymphocytic leukemia (CLL). Age >/= 18 years and </=

70 years.


Five hundred and nineteen (519) patients will be randomized 2:1 to the Ibrutinib-Rituximab arm (A) and

the FCR control arm (B). The primary objective is to definitively evaluate whether patients who receive

Ibrutinib have significantly longer PFS than those receiving FCR. With the planned sample size, we will

have 80% power to detect a true hazard ratio of 1.5 (FCR vs. Ibrutinib regimen; median PFS of 52 months

vs. 78 months) while controlling the one-sided type I error at 2.5%. Overall survival will be used as a

secondary endpoint. We expect the annual accrual rate to be approximately 180 patients per year. It will

take approximately 35 months to accrue the 519 patients for the study. Assuming median PFS for the

Ibrutinib and FCR arms to be 78 and 52 months, respectively, the study requires approximately 32 months

of follow-up to reach full information of 203 events.

Progress to Date

This study was activated on January 31, 2014 and terminated on June 9, 2016 with 529 patients accrued.

Accruals by ECOG-ACRIN institutions and by group are shown in Table 1a and 1b. Table 2 summarizes

patient status. Table 3 shows patient demographic information by treatment arm. Record status by form is

presented in Table 4. Table 5 summarizes off-treatment reasons. As of March 2, 2017, 14 patients have

refused to start protocol treatment. Treatment-related toxicity data are available for 358 patients and are

summarized in Table 6, with lethal toxicities briefly described 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.



Page 3


Institution Name Step 1

Aurora NCORP 15

Baystate Medical Center 2 Cancer Research Consortium of West Michigan NCORP 6

Cancer Research for the Ozarks NCORP 3

Carle Cancer Center NCORP 1 Case Western Reserve University 4

Catholic Health Initiatives NCORP 1

Colorado Cancer Research Program NCORP 5 Columbus NCORP 8

Dayton NCORP 3

Delaware/Christiana Care NCORP 5 Emory University/Winship Cancer Institute 7

Essentia Health NCORP 2

Fox Chase Cancer Center 1 Froedtert and the Medical College of Wisconsin 3

Geisinger Cancer Institute NCORP 5

Georgia NCORP 2 Heartland Cancer Research NCORP 10

Iowa-Wide Oncology Research Coalition NCORP 6

Main Line Health NCORP 5 Mayo Clinic 37

Metro Minnesota Community Oncology Res Consortium 17

Michigan Ca Res Consortium NCORP 12 Missouri Valley Cancer Consortium 1

Montana Cancer Consortium NCORP 1

Nevada Cancer Research Foundation NCORP 1 New Mexico MU NCORP 2

New York Oncology Hematology PC -Albany Med Center 4

NorthShore Univ HealthSystem-Evanston Hospital 6 Northwest NCORP 1

Northwestern University 8 Ochsner NCORP 4

Oncology Hematology West 1

Pacific Cancer Research Consortium NCORP 3 Penn State Milton S Hershey Medical Center 4

Sanford NCORP of the North Central Plains 5

Stanford Cancer Institute 6 Thomas Jefferson University Hospital 3

Toledo Community Hospital Oncology Program CCOP 1

Tufts Medical Center 1 UT Southwestern/Simmons Cancer Center-Dallas 1

University of Alabama at Birmingham Cancer Center 2

University of Massachusetts Medical School 5 University of Pennsylvania/Abramson Cancer Center 21

University of Pittsburgh Cancer Institute (UPCI) 10

University of Wisconsin Hospital and Clinics 10 VCU Massey Cancer Center MU NCORP 8

Washington University School of Medicine 6

Wichita NCORP 1 Wisconsin NCORP 10

Total 286



Page 4


ECOG-ACRIN 286

SWOG 130

ALLIANCE 76

NRG 37

Total 529


Cases Entered 529

Ineligible 10

Never Started Assigned Therapy 19

Reason for ineligibility:

Violation of section 3.1.9 GFR, SGOT and total Billirubin test date is greater than 14 days prior to

registration: 19025, 19114 and 19146.

Violation of section 3.1.1 t(11;14) or negative stains for cyclin D1 was not performed prior to registration:

19034, 19135, 19139, 19163, 19246

Deletion 17p: 19414, 19510.

Reason for not starting assigned therapy:

Ineligible: 19205, 19414

Patient refusal: 19010, 19021, 19045, 19060, 19075, 19127, 19197, 19289, 19322, 19357, 19420, 19423,

19434, 19454

Not covered by insurance: 19052, 19487

Medical decision: 19088.



Page 5

Table 3. Demographics

Variable Level

Arm A

(n=354)

Arm B

(n=175)

Total

(n=529)

Sex Male 236 (66.7) 120 (68.6) 356 (67.3)

Female 118 (33.3) 55 (31.4) 173 (32.7)

Race White 318 (91.9) 160 (93.6) 478 (92.5)


Asian 5 (1.4) 3 (1.8) 8 (1.5)

Native American 0 (0.0) 1 (0.6) 1 (0.2)

Multirace 0 (0.0) 1 (0.6) 1 (0.2)



Non-Hispanic 333 (97.9) 167 (98.2) 500 (98.0)


Age Median 58 57 58

Minimum 31 28 28

Maximum 70 70 70


Form Name Forms Due Forms Received %

Demography 529 529 100.0

Patient Characteristics 529 528 99.8

Treatment Form 4673 4531 97.0

Adverse Event Form 5691 4703 82.6

Disease Follow-up Status 5742 4498 78.3

Off Treatment 225 219 97.3

Table 5. Reasons Off Treatment



Reasons N %





Other 10 5.0

Patient off-treatment for other complicating disease 4 2.0






Page 6

Table 6. Toxicity Incidence

Toxicity Type

Treatment Arm

A (n=352) B (n=156)

Grade Grade

3 4 5 3 4 5

(%) (%) (%) (%) (%) (%)

Ear pain <1 - - - - -

Anemia 1 - - 8 3 -

Blood and lymphatic system disorders - Other, specify - - - 1 - -

Febrile neutropenia 2 - - 12 3 -

Hemolysis - - - 2 - -

Leukocytosis 9 <1 - 1 - -

Atrial fibrillation 2 - - - - -

Atrial flutter 1 - - - - -

Chest pain - cardiac <1 - - - - -

Heart failure <1 - - - - -

Sinus bradycardia <1 - - - - -

Supraventricular tachycardia <1 - - - - -

Ventricular tachycardia <1 - - - - -

Chills <1 - - 1 - -

Fatigue 2 - - 3 - -

Fever <1 - - 1 - -

Pain <1 - - - - -

Infusion related reaction - <1 - 1 - -

Rash maculo-papular 2 - - 2 - -

Skin and subcutaneous tissue disorders - Other, specify <1 - - - - -

Colitis <1 - - - - -

Diarrhea 2 - - - - -

Mucositis oral <1 - - - - -

Nausea - - - 1 - -

Vomiting <1 - - - - -

Allergic reaction <1 - - - - -

Infections and infestations - Other, specify 1 - - 1 - -

Sepsis - <1 - - 3 1

Sinusitis - - - 1 - -

Skin infection - - - 1 - -

Upper respiratory infection <1 - - 2 - -

Urinary tract infection <1 - - - - -

Enterocolitis infectious - - - 1 - -

Lung infection 2 - - 3 - -

Scrotal infection <1 - - - - -

Soft tissue infection 1 <1 - - - -

Arterial injury <1 - - - - -

Alanine aminotransferase increased 1 - - - - -

Alkaline phosphatase increased <1 - - - - -

Aspartate aminotransferase increased 1 - - 1 - -

Blood bilirubin increased <1 - - - - -

Creatinine increased <1 - - - - -

Investigations - Other, specify <1 - - - - -



Page 7

Toxicity Type

Treatment Arm

A (n=352) B (n=156)

Grade Grade

3 4 5 3 4 5

(%) (%) (%) (%) (%) (%)

Lymphocyte count decreased 1 - - 26 16 -

Lymphocyte count increased 11 - - 1 - -

Neutrophil count decreased 9 11 - 22 19 -

Platelet count decreased 2 1 - 10 4 -

White blood cell decreased 1 <1 - 21 14 -


Dehydration <1 - - - - -

Hypercalcemia - 1 - - - -

Hyperglycemia - - - 1 - -

Hyperkalemia 1 - - 1 - -

Hyperuricemia - <1 - - - -

Hypoalbuminemia - - - 1 - -

Hyponatremia <1 - - - - -

Tumor lysis syndrome 1 - - 1 - -

Arthralgia 4 - - 1 - -

Bone pain <1 - - - - -

Flank pain - - - 1 - -

Myalgia 1 - - - - -

Pain in extremity 1 - - - - -

Cognitive disturbance <1 - - - - -

Dizziness 1 - - - - -

Headache 1 - - 1 - -

Peripheral sensory neuropathy <1 - - 1 - -

Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other,

specify <1 - - - - -

Treatment related secondary malignancy 1 - - - - -

Insomnia - - - 1 - -

Dyspnea <1 - - 1 - -

Hiccups <1 - - - - -

Pleural effusion <1 - - - - -

Pneumonitis <1 - - - - -

Respiratory failure - - - - 1 -

Renal hemorrhage <1 - - - - -

Surgical and medical procedures - Other, specify <1 - - - - -

Hematoma 1 - - 1 - -

Hypertension 3 - - 2 - -

Hypotension - - - 1 - -

Thromboembolic event - - - - 1 -

WORST DEGREE 38 12 - 34 35 1



Page 8

Table 7. Lethal Adverse Events

Case Arm Description of Event

19196 B Sepsis

19333 A Died at home unexpectedly after showing improvements from grade 2 and 3 events.

19229 A Respiratory failure

19306 A Respiratory failure


Site Arm A Arm B

Basal Cell Carcinoma 3 1

Brain Tumor 1 -

Breast 2 -

Colon - 2

Gastric 1 -

Lung Cancer 1 -

Melanoma 3 1

Non-Small Cell Lung - 1

Other 1 1

Prostate - 1

Skin Cancer Not Melanoma 2 2

Table 9. QOL Table

QOL Timepoint

Patients

Reaching

Timepoint

% Forms

Completed

Baseline 510 99.4

Cycle 3 510 86.5

Cycle 6 502 81.5

At response evaluation 356 27.2

6 months post response evaluation 249 26.5



24 months post response evaluation 0



Page 1

E2905 RANDOMIZED PHASE III TRIAL COMPARING THE FREQUENCY OF MAJOR

ERYTHROID RESPONSE (MER) TO TREATMENT WITH LENALIDOMIDE

(REVLIMID) ALONE AND IN COMBINATION WITH EPOETIN ALFA (PROCRIT) IN

SUBJECTS WITH LOW- OR INTERMEDIATE-1 RISK MDS AND SYMPTOMATIC

ANEMIA

Sponsor(s)


Chairperson(s) Dr. Alan List

Statistician Dr. Zhuoxin Sun

Data Specialist Henry Baptista

Phase of Study III


Committee Leukemia


Participating Groups ECOG-ACRIN, RTOG, NCCTG, CALGB, SWOG,

NSABP, CTSU, ALLIANCE, NRG


NSC# 628281, 703813


Study Status Closed to Accrual

Date Activated January 29, 2009

Date Suspended September 23, 2010

Date Reactivated February 4, 2011

Date Suspended December 31, 2012

Date Reactivated June 6, 2013

Date Terminated May 13, 2016

Final Accrual 248 Patients

Schema



Page 2

Purpose of Study

(1)To compare the rate of major erythroid response (MER) between lenalidomide monotherapy and

combined treatment of lenalidomide and epoetin alfa in erythropoietin non-responsive Low/Int-1 risk MDS

patients or erythropoietin-treatment naive patients with low probability of erythropoietin benefit. (2)To

compare the time to MER by treatment assignment. (3)To evaluate the duration of MER by treatment

assignment. (4)To estimate the frequency of MER to salvage combination therapy in patients who fail to

experience a MER with lenalidomide monotherapy. (5)To evaluate and compare the frequency of minor

erythroid response by treatment assignment. (6)To investigate the mechanism and target of lenalidomide

action in patients with chromosome 5q31.1 deletion. (7)To evaluate the frequency of cytogenetic response

and progression, and the relation between cytogenetic pattern and erythroid response. (8)To evaluate the

frequency of bone marrow response (CR+PR). (9) To evaluate the relationship between erythroid response

and laboratory correlates outlined below: (a) Pretreatment and onstudy endogenous erythropoietin level

(Arm A); (b)To evaluate the effect of CD45 isoform profile on lenalidomide enhancement of

erythropoietin-induced STAT5 phosphorylation in CD71Hi erythroid precursors and the relationship to

erythroid response. (c)To characterize molecular targets relevant to lenalidomide cytotoxicity in del5q cells.

(d) To evaluate the frequency of cryptic chromosome 5q31 deletions in patients with non-del5q MDS by

array-based genomic scan, and to determine the relationship to hematologic response.

Study Population

Low-or intermediate-1 risk MDS and symptomatic anemia.


This study requires 212 patients without 5q31.1 deletion for the primary endpoint comparison. Assuming

that 10% of patients in the MDS population as defined in this study have the 5q31.1 deletion, a total of 252

patients will be entered. The primary endpoint in this phase III study is major erythroid response (MER),

defined as sustained transfusion independence in transfusion-dependent patients or a rise in hemoglobin > 2

g/dL in transfusion-independent patients with anemia for a minimum of eight consecutive weeks. The

objective MER will be assessed 16 weeks after start of study treatment. We hypothesize that the MER rate

in Arm A (lenalidomide) will be 30% and anticipate that the MER rate in Arm B(lenalidomide + epoetin

alfa) will be at least 50%. Thus the study is designed to detect an improvement of 20% in the MER rate from

30% to 50%, comparing Arm A to Arm B. Using the statistical package EaSt (Cytel Software Corporation,

1993) to account for multiple interim looks in a sequential design for binomial distribution with continuity

correction, a sample size of 212 eligible cases will provide approximately 80% power to detect

improvement in MER rate with an overall one-sided type I error rate of 0.025.

Progress to Date

This study was activated on January 29, 2009. Due to an interruption in drug supply, the study was

suspended on September 23, 2010 and was reopened on February 4, 2011. The study was suspended again

on December 31, 2012 due to changes in the supply of Epoetin Alfa, and reopened on June 6, 2013, after an

amendment was approved to allow patients to receive Erythropoietin, recombinant human (Epoetin alfa,

Procrit-Ortho-Biotech) commercially. On May 13, 2016, the study was closed to accrual after

ECOG-ACRIN Data Safety Monitoring Committee reviewed the fifth planned interim analysis of major

erythroid response (MER) and the study met the protocol criteria for stopping for efficacy. 248 patients

have been accrued to the study. Accrual by ECOG-ACRIN institution and accrual by group are summarized

in Tables 1a and 1b. Patient status as of March 7, 2017 is summarized in Table 2. Demographic data are

shown in Tables 3a and 3b. Record status is shown in Table 4. The distribution of



Page 3

the reasons for discontinuation of protocol treatment is given in Tables 5a and 5b by step.

Treatment-related toxicity data are available for 240 patients and are summarized in Tables 6a and 6b. Table

7 summarizes lethal adverse events (regardless of treatment relation). Table 8 summarizes incidences of

second primary cancer.


Institution Name Step 1 Step 2

Aurora NCORP 1 0

Beaumont NCORP 1 0

Case Western Reserve University 1 0 Catholic Health Initiatives NCORP 2 0

Colorado Cancer Research Program NCORP 1 1

Delaware/Christiana Care NCORP 3 1 Essentia Health NCORP 1 1

Fox Chase Cancer Center 2 0

Froedtert and the Medical College of Wisconsin 3 1 Heartland Cancer Research NCORP 3 0

Indiana Univ/Melvin and Bren Simon Cancer Center 2 1 Iowa-Wide Oncology Research Coalition NCORP 3 2

Johns Hopkins Univ/Sidney Kimmel Cancer Center 5 1

Laura and Issac Perlmutter Ca Ctr at NYU Langone 5 2 Mayo Clinic 9 3

Memorial Hospital of South Bend 1 0

Metro Minnesota Community Oncology Res Consortium 9 2 Michigan Ca Res Consortium NCORP 6 0

Montefiore MU NCORP 11 1

Nevada Cancer Research Foundation NCORP 1 0 NorthShore Univ HealthSystem-Evanston Hospital 6 0

Northwestern University 8 0

Pacific Cancer Research Consortium NCORP 1 0 Penn State Milton S Hershey Medical Center 8 3

Rutgers Cancer Institute of New Jersey 1 0

Sanford NCORP of the North Central Plains 2 0

Toledo Community Hospital Oncology Program CCOP 1 0

University of Alabama at Birmingham Cancer Center 2 0

University of Miami Miller Schl Med-SylvesterCaCtr 1 1 University of Pennsylvania/Abramson Cancer Center 11 3

University of Pittsburgh Cancer Institute (UPCI) 2 0

University of Wisconsin Hospital and Clinics 11 2 Wichita NCORP 3 0

Wisconsin NCORP 7 2

Total 134 27


Step 1 Step 2

ECOG-ACRIN 134 27

RTOG 2 0

NCCTG 1 0

CALGB 12 1

SWOG 79 20

NSABP 3 0

ACOSOG 1 1

CTSU 1 0

ALLIANCE 8 2

NRG 7 0

Total 248 51



Page 4


Step 1 Step 2

Not Del 5q31.1 Del 5q31.1

Cases Entered 209 39 51

Ineligible 5 4 0

Never Started Assigned Therapy 0 2 0


Baseline bone marrow was not done within 56 days (29003);

Baseline blood lab test was not done within the 21 days prior to randomization (29007, 29019, 29025);

History of thromboembolic events within 3 years prior to study randomization (29103).

No prior bone marrow documenting MDS lasting for more than 3 months (29055, 29090);

Serum erythropoietin level not documented before randomization and <= 56 days before day1 of study

treatment (29011, 29119).


Patient refused treatment (29096); Medical decision (29142).

Table 3a. Demographics - Step 1

Variable Level

Arm A

(n=142)

Arm B

(n=106)

Total

(n=248)

Sex Male 82 (57.7) 78 (73.6) 160 (64.5)

Female 60 (42.3) 28 (26.4) 88 (35.5)

Race White 133 (97.8) 96 (94.1) 229 (96.2)


Asian 2 (1.5) 3 (2.9) 5 (2.1)



Non-Hispanic 131 (97.0) 97 (99.0) 228 (97.9)


Age Median 74 73 74

Minimum 49 47 47

Maximum 89 92 92

Table 3b Demographics - Step 2

Variable Level

Arm B

(n=51)

Sex Male 35 (68.6)

Female 16 (31.4)



Asian 2 (3.9)

Ethnicity Non-Hispanic 49 (100.0)

Unknown/Missing 2

Age Median 73

Minimum 49

Maximum 90



Page 5


Form Type

Forms

Due

Forms

Received %

Baseline Step 1 Forms 489 465 95.1

Baseline Step 2 Forms 47 44 93.6

Treatment Forms 3126 2499 79.9

Disease Evaluation Forms 3366 2740 81.4

Adverse Event Forms 3211 2558 79.7

Hematology/Chemistry Forms 3890 3217 82.7

Off Treatment Forms 273 269 98.5

Follow-Up Forms 371 351 94.6

Table 5a. Reasons Off Treatment - Step 1




Reasons N %


Disease progression, relapse during active treatment 29 16.9

Adverse events/side effects/complications 41 23.8




Patient off treatment for other complicating disease 7 4.1

Other 8 4.7


Table 5b. Reasons Off Treatment - Step 2



Reasons N %


Disease progression, relapse during active treatment 7 14.9

Adverse events/side effects/complications 4 8.5




Other 6 12.8

Unknown reason 1 2.1




Page 6

Table 6a. Toxicity Incidence - Step 1

Toxicity Type

Treatment Arm

A (n=138) B (n=102)

Grade Grade

3 4 5 3 4 5

(%) (%) (%) (%) (%) (%)

Anemia 55 1 - 57 3 -

Febrile neutropenia 4 - - 3 1 -

Blood and lymphatic disorders - Other - 1 - - - -

Acute coronary syndrome - - - - 1 -

Atrial fibrillation 1 1 - - 1 -

Chest pain - cardiac - - - 1 - -

Heart failure 1 - - 1 - -

Left ventricular systolic dysfunction - - - 1 - -

Myocardial infarction - - - 1 - -

Cardiac disorders - Other, specify - - - 1 - -

Edema limbs 1 - - 1 - -

Fatigue 3 - - 8 - -

Fever - - - 1 1 -

Non-cardiac chest pain 1 - - - - -

Pruritus 1 - - - - -

Rash maculo-papular 5 - - 3 - -

Skin ulceration 1 - - - - -

Abdominal pain 1 - - 1 - -

Colitis 1 - - 1 - -

Colonic obstruction 1 - - - - -

Constipation - - - 1 - -

Diarrhea 2 - - 3 - -

Nausea - - - 1 - -

Vomiting 1 - - 1 - -

Anaphylaxis - - - 1 - -

Immune system disorders - Other, specify - - - 1 - -

Bronchial infection 1 - - - - -

Lung infection 1 - 1 1 1 -

Sepsis - 1 - - 1 -

Soft tissue infection 1 - - - - 1

Urinary tract infection - - - 1 - -

Blood bilirubin increased 1 - - 1 - -

Creatinine increased 1 1 - 3 1 -

Hemoglobin increased 1 - - - - -

Lymphocyte count decreased 3 - - 4 - -

Neutrophil count decreased 36 30 - 28 33 -

Platelet count decreased 17 14 - 17 9 -

Weight gain - - - 1 - -

White blood cell decreased 33 2 - 25 7 -


Dehydration 1 - - 1 - -

Hypocalcemia 1 - - - - -



Page 7

Toxicity Type

Treatment Arm

A (n=138) B (n=102)

Grade Grade

3 4 5 3 4 5

(%) (%) (%) (%) (%) (%)

Hypophosphatemia 1 - - - - -

Iron overload - - - 1 - -

Arthritis 1 - - - - -

Chest wall pain 1 - - - - -

Myalgia 1 - - - - -

Musculoskeletal and connective - Other - - - 1 - -

Ataxia - - - 1 - -

Dizziness - - - 1 - -

Peripheral motor neuropathy 1 - - - - -

Peripheral sensory neuropathy 1 - - - - -

Syncope 1 - - - - -

Treatment related secondary malignancy - - 1 - - -

Neoplasms - Other - - - 1 - -

Optic nerve disorder - - - 1 - -

Cough - - - 1 - -

Dyspnea 1 - - 3 - -

Respiratory thoracic mediastinal - Other - - - 1 - -

Renal and urinary disorders - Other - - - 1 - -

Thromboembolic event 1 - - - - -

WORST DEGREE (NON-HEMATOLOGIC) 27 3 1 26 4 1

Table 6b. Toxicity Incidence - Step 2

Toxicity Type

Treatment Arm

B (n=48)

Grade

3 4 5

(%) (%) (%)

Anemia 56 - -

Edema limbs 2 - -

Fatigue 4 - -

Multi-organ failure 2 - -

Pruritus 2 - -

Rash maculo-papular 2 - -

Constipation 2 - -

Wound infection 2 - -

Creatinine increased 2 - -

Lymphocyte count decreased 2 - -



White blood cell decreased 46 - -

Investigations - Other, specify - 2 -

Hyperglycemia - 2 -

Peripheral sensory neuropathy 2 - -



Page 8

Toxicity Type

Treatment Arm

B (n=48)

Grade

3 4 5

(%) (%) (%)

Acute kidney injury 2 - -


Table 7. Lethal Adverse Events via AdEERS (Regardless of

treatment relation)

Case # Arm Adverse Event Type

29009 A Infection Gr0-2 neut, lung

29052 A Death NOS

29084 A Acute coronary syndrome

29097 A Nervous system disorders - Other

29117 A Cardiac arrest

29123 A Intracranial hemorrhage

29129 A Neoplasms - Other

29141 A Treatment related secondary malignancy

29003 B cardiac-other

29004 B Soft tissue infection

29043 B Death NOS

29056 B Neoplasms - Other

29058 B Death NOS

29103 B Cardiac disorders

29112 B Sepsis

29159 B Death NOS

29244 B Neoplasms - Other


(By arm during which event was reported)

Site Arm A Arm B

Acute Non-Lymphocytic Leukemia - ANLL, AML 1 4

Bladder, Urinary Tract - 1

Colon - 1

Endometrium, Uterine Corpus 1 -

Lung Cancer 1 1

Non-Hodgkins Lymphoma - 1

Squamous cell Carcinoma - 1

Skin Cancer Not Melanoma - 1

leukemia committee - swog 2017/leukemia.pdfoctober 11 - 14, 2017 swog leukemia 4 patient...

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