gcig endometrial cancer committee

GCIG Endometrial Cancer Committee

Chair: Stefano Greggi

Co-chair: Carien Creutzberg

AGENDA

1. Welcome – COI - Introductions

2. Approval of minutes of October 2016 meeting

3. Closed trials

4. Ongoing trials

5. Activating trials

6. New trial proposals

7. Challenging Debate:

• First line chemotherapy vs. molecular genetics

based treatment for recurrent/metastatic EC• Gini Fleming vs Karen Lu

8. Discussion




GCIG Trial Presentation Guidelines (2017): 1. Closed trials (Site Committee Chair): o Lead group should prepare 1 slide using the attached template. o NEWLY closed trials since the last meeting – final accrual o PREVIOUSLY closed trials – presentation plan, publications and plans

2. Ongoing trials without substantial NEW information (Site Committee Chair):o Lead group should prepare 2 slides using the attached template

3. Ongoing trials with substantial NEW information: o Lead group to request a time slot of 5 minutes and prepare up to 5 slides. Trial slides

will be presented by lead group representativeo Trials presented at the last GCIG meeting as “NEW TRIALS” are considered as ongoing

4. New trial concepts: o Concept/trial design presentation – lead group to request a time slot of 5 minutes o Trial proposal (funded/recruiting member participation) – lead group to request a

time slot of up 15 minutes (10 for presentation and 5 for discussion/questions)




Closed trials

PORTEC-3 trial / EN7

Trial setting: High-risk endometrial cancer (stages IB-III)

Study Design: Randomised trial of RT alone vs RT plus chemotherapy

Sponsor(s): LUMC – Funding: Dutch Cancer Society; CRUK; NHMRC; IMA; CCTG

Final No. of patients: 686 (660 evaluable)

Timeline (first patient – trial closing): 2006-2013

Publications: Toxicity and QoL: de Boer et al, Lancet Oncology 2016

Side studies: Patient preferences: Blinman et al, BJC 2016;

QA ANZGOG: Jameson et al, J Med Imaging Radiat Oncol 2016

Planned publications: Final analysis; Pathology review

Planned further studies: TransPORTEC analyses

Closed Trial – status update

Endometrial cancer: Stage I/II Adjuvant

• 3/23/2009 – 2/4/2013: Completed

• Endorsed by RTOG

• 562 accrued, 9% CCOP

• Presented: SGO 2014

• Publication: in preparation

GOG 249

Endometrial cancer : Stage III/IV

• 6/29/2009 – 7/28/2014: Completed


• 813/804 accrued

• Presentation: ASCO 2017

GOG 258

International Rare Cancers Initiative - Gynaecological sarcoma: EORTC

4 Jun 2012 opened

38/216 accrued

9 Sep 2016 closed

Leiomyosarcoma:

Stage I

GOG 277

GOG-0275: A PHASE III RANDOMIZED TRIAL OF PULSE

ACTINOMYCIN-D VERSUS MULTI-DAY METHOTREXATE

FOR THE TREATMENT OF LOW-RISK GESTATIONAL

TROPHOBLASTIC NEOPLASIAStudy Chair: Julian Schink, MD

Arm Regimen 2:

IV methotrexate (0.4 mg/kg) daily for 5 days every 14 days. (25mg max dailydose)

OR

IM methotrexate(50mg) on Days 1, 3, 5, 7(4 doses per cycle) with Leucovorin (15mg) on Days 2, 4, 6, 8. Repeat every 14 days.

Arm Regimen 1: IV actinomycin-D (1.25mg/m2) every 14 days. (2mg max dose)

Eligible patients:

Low-risk GTN

FIGO Score 0-6

R

A

N

D

O

M

I

Z

E

Opened June ‘12. 57/381 recruited: closed Sep ‘16


Chicago, June 2017

Ongoing trials

TOTEM Study: Multicentric randomized controlled clinical trialbetween two follow up regimens with different tests intensity

in endometrial cancer treated patients / NCT 00916708

Trial setting: patients surgically treated for endometrial cancer, if in complete clinical remission confirmed by imaging, FIGO stage I-IV

Study Design: multicentric RCT between minimalist and intensive follow up (after first stratification of patients between low risk [IA G1-2] and high risk [≥ IA G3] of recurrence)Primary objective: compare the effect of the two follow-up regimens on 5-years overall survival.

Sponsor(s): Azienda Ospedaliera San Giovanni Battista (now: Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino)

Ongoing Trials – status update

TOTEM Study: Multicentric randomized controlled clinical trialbetween two follow up regimens with different tests intensity

in endometrial cancer treated patients / NCT 00916708


Planned No. of patients: 2300

Current accrual: 1651 patients enrolled on 10th May 2017

Other important information:

2 French Institutions shared the trial (total number of units sharing the trial: 41)

the interim analysis is ongoing: are we able to close the trial?

A randomised double-blind placebo-controlled phase II trial of first line combination chemo-

therapy with nintedanib/placebo for patients with advanced or recurrent endometrial cancer.

Stratification:• Stage of disease (stage 3C 2 vs. stage 4 vs. recurrent disease)

• Prior adjuvant chemotherapy (yes/no)

• Disease status (Measurable vs. non-measurable disease according to RECIST 1.1)

Sponsor: NSGOProject Manager: Mette Berensen

Statistitian: René DePont ChristensenPI: Mansoor Raza Mirza

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ENGOT-EN1/FANDANGO

Primary Objectives: To compare Progression Free Survival (PFS)

Inclusion criteria

Histological confirmed endometrial cancer.• Stage 3C 2

• Stage 4 A & B

• Relapsed after adjuvant therapy for stage 1-3 disease

Prior therapy2. Patients may have undergone primary surgery.

3. Patients may have received adjuvant chemotherapy for stage 1 – 3.

4. Patients may have received vaginal brachytherapy

5. Patients may have received external beam radiotherapy. Patients who are to be enrolled for stage 3C2 diseases are allowed to receive external beam radiotherapy prior to trial entry.

6. Patients may have received hormonal treatment

Disease status7. Patients must have measurable disease or non-measurable disease on CT scan according to RECIST 1.1 outside irradiated field. For stage 3C2 disease patients without measureable or non-measureable disease are accepted.

ENGOT-EN1/FANDANGO

ENGOT-EN1/FANDANGO

Randomized Patients

0

20

40

60

80

100

120

140

160

Nov 16 Dec 16 Jan 17 Feb 17 Mar 17 Apr 17 May 17 Jun 17 Jul 17 Aug 17 Sep 17 Okt 17 Nov 17 Dec 17 Jan 18 Feb 18 Mar 18 Apr 18 May 18

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Expected Randomized patients Randomized patients 148 Patients in total

Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer.

ENGOT-EN2-DGCG - NCT01244789

Supported by

N=240

Endometrioid:Stage I - G3; II

Non-endometrioid:Stage I-II

ChemotherapyCarboplatin-Paclitaxel x 6+ Brachytherapy

Observation+ Brachytherapy

1:1 randomization

Randomized till date = 165/240

Creasman et al., IJGO, 2007

ENGOT-EN2-DGCGStudy Population

5-yr survival

Cyclin-Dependent Kinase (CDK) Inhibitors

- Oncogenesis is dependent upon cell-cycle regulatory process

- Cyclins act as activators to cyclin-dependent kinases

- Proliferative CDKs 2, 4, 6 regulate the transition from G1 to S phase

- In ER+ cell lines, E2F transcription & cell-cycle progression can occur independent of estrogen. These cells

rely on CDK4 to activate E2F

- CDK4/6 inhibitors are active in ER+ cell-lines

- Letrozole & CDK4/6 inhibitor (Palbociclib) are synergistic

Weinberg; Science 2014

Roberts et al. JNCI 2012

Schwartz et al. JCO 2005

Miller et al. Cancer Discov 2011

A randomized phase II trial of Palbociclib in combination with letrozole versus letrozole for patients with oestrogen receptor positive recurrent endometrial cancer.

ENGOT-EN3-NSGO/PALEO

Endometrial Cancer

Primary stage 4 or relapsed incurable

disease

ER positive endometrioid

adenocarcinoma

Randomize

Randomization: 1:1

N=78

ARM A

Letrozole, 2.5mg d 1-28 every 28 daysPlacebo d 1-21 every 28 days

Until progression

ARM B

Letrozole, 2.5mg d 1-28 every 28 daysPalbociclib 125mg d 1-21 every 28 days

Until progression

Stratification:• Number of prior lines of therapy (primary advanced disease vs. 1st relapse vs. ≥2

relapses)• Measurable vs. evaluable disease• Prior use of MPA/Megace (prior MPA/Megace use capped to a maximum of 50%)

A randomized phase II trial of Palbociclib in combination with letrozole versus letrozole for patients with oestrogen receptor positive recurrent endometrial cancer.

ENGOT-EN3-NSGO/PALEO

Study Chair: Mirza MR

NCT02730429

STATEC/NCRI

FIGO Stage I endometrial cancer- FIGO grade 3 endometrioid or mucinous- High grade serous, clear cell, undifferentiated or de-differentiated

carcinoma or mixed cell adenocarcinoma or carcinosarcoma

Hysterectomy and BSO* plus lymphadenectomy

(pelvic/PA)

Hysterectomy and BSO*Sentinel node sub study

Lymph node negative ~ 80%

Lymph node positive ~ 20%

Lymph nodes unknown

Vaginal brachytherapy

Systemic adjuvant treatment:chemotherapy +/- pelvic radiotherapy

5-year follow up, including adverse events and quality of life

RANDOMISE (2000 patients)

*Option for patients to be randomised < 28 days after

hysterectomy and BSO

STATEC/NCRI

Sponsor: University College London (UK)

2 UK sites open (April 2017), 20-30 in setup

1 patient recruited at 12 May 2017

ANZGOG to open sites, DGOG in setup

NiCCCSGCTG - NSGO

Trial setting: tumour type/stage Progressive or recurrent ovarian and endometrial

CCC within 6 months of previous platinum

Study Design: Open Label Randomised Phase II Study

Sponsor: NHS Greater Glasgow & Clyde

Planned No. of patients: 90 Ovarian and up to 30 endometrial

Current accrual: 32

Other important information: Open Sites: UK: 16, France: 16

Additional Participating Countries: The Netherlands, Denmark, Spain, Portugal,

Italy, Belgium still to open

Trial Design

90 pts with progressive or

relapsed CCC of ovary within 6

months of previous platinum.

Plus up to 30 women with

endometrial CCC

RANDOMISE

Control Arm: Chemotherapy

Ovary:

•PLD (40mg/m2 day 1q28)

•Weekly Paclitaxel (80mg/m2 day 1, 8, 15 q28)

•Weekly Topotecan IV (4mg/m2 day 1, 8, 15 q28)

Endometrium:

•Carboplatin (AUC 5) /Paclitaxel 175 mg/m2 q21

•Doxorubicin 60mg/m2 q21

Experimental Arm: Nintedanib

Nintedanib 200mg bd until progression

Primary Endpoint: PFS

Secondary Endpoints: OS, Toxicity, RR, QoL, Q-Twist

PORTEC-4a

Trial setting: Stage I-II endometrial cancer - high-intermediate risk

Study Design: Randomised trial of molecular profile-based versus standard recommendations for adjuvant radiotherapy

Sponsor(s): LUMC; funding: Dutch Cancer Society

Planned No. of patients: 500

Current accrual: 44

Other important information: ANZGOG and NCRI UK preparing

participation


PORTEC-4a


Molecular integrated vs standard indications for adjuvant treatment:

Surgery and pathology diagnosis

FIGO 2009 – high intermediate risk Stage IA (with invasion), any age and grade 3 (with or without LVSI)Stage IB, grade 1-2 and age > 60Stage IB, grade 1-2 and LVSI+Stage IB, grade 3 without LVSIStage II (microscopic), grade 1

Randomisation

Endometrial carcinoma

PORTEC-4a


Individual treatment recommendation based on

molecular pathology analysis

2 1 Standard treatment recommendation based on clinicopathological factors

Vaginal brachytherapy

Vaginal brachytherapy (~40%)

Observation (~55%)

External beam radiation therapy (~5%)

Follow-up and Quality of Life

Randomisation

Favourable

Intermediate

Unfavourable

PORTEC-4a


Pilot phase (n=50) endpoints:

• Logistics of molecular analysis (< 2 wks)

• Patient acceptance

• Current: 46 / 50 pts

PORTEC-4a study endpoints (n=500):

• Vaginal control and RFS

• Pelvic and distant recurrence and OS

• Quality of life and freedom from symptoms

• Costs and use of health care resources

Satellite : Today, 2:30 h, State II Room

Pelvic Recurrence• 2/25/2008


• 115/154 accrued

GOG 238

E.C.Co.

Endometrial Cancer Conservative treatment

A multicentre archive

Data collection is made by appropriate eCRFs via the Clinical Trials Unit of National Cancer Institute of Naples (Study Data Center) website

[email protected];

[email protected]

PROJECT TYPE / DESIGN & TIME PERSPECTIVE

Observational / Patient archive, Prospective (a first phase of three years is planned, eventually followed by further three years)

INCLUSION CRITERIA

- Conservatively treated endometrial cancer

- Informed consent to personal data processing

- Existence of an IRB-approved local protocol that allows conservative treatment to be performed (or statement that such

treatment is considered as a standard)

INTERVENTIONS & OUTCOME MEASURES

Data collection - PRIMARY OUTCOME MEASURES: proportion of complete regression, duration of response, frequency and pattern

of relapse, frequency of metachronous ovarian cancer, tumor-related deaths; SECONDARY OUTCOME MEASURES: treatment

related morbidity, frequency of spontaneous pregnancies, frequency of pregnancies after ART, pattern of residual disease on

definitive surgical specimens

TREATMENT

SINCE THIS IS A ARCHIVE, TREATMENT IS NOT DICTATED BY A PROTOCOL, HOWEVER, TREATMENT HAS TO BE ADMINISTERED ACCORDING

TO A IRB-APPROVED LOCAL PROTOCOL (except for the countries where conservative treatment can be given outside a IRB-

approved study because considered as a standard procedure)

E.C.Co.



Participation (17/05/2017)

E.C.Co.



Center Code PI Registration date N° of patients registered

National Cancer Institute of Naples,

Naples. Italy640 Stefano Greggi March 2014 31

Catholic University of the Sacred

Heart, Rome. Italy145 Giovanni Scambia September 2015 13

Papa Giovanni XXIII Hospital,

Bergamo. Italy254 Chiara Malandrino December 2015 6

San Raffaele Hospital, Milan. Italy 321 Patrizia De Marzi October 2015 4

National Cancer Institute of Rome,

Rome. Italy741 - July 2016 -

University of Bari, Bari. Italy 111 Gennaro Cormio October 2015 -

The Royal Women’s Hospital,

Parkville. Australia668 - August 2015 -

The Obstetrics & Gynecology Hospital

of Fudan University, Shanghai. China676 - September 2015 -

Leiden Medical University, Leiden.

Netherlands704 - September 2015 -

Tot N 54

Gestational Trophoblastic

disease study updates

Professor Michael J Seckl

GCIG Chicago meeting Jun ‘17

Phase II trial of anti-endoglin antibody (TRC105)

without or with bevacizumab in relapsed high risk GTN

Inclusion criteria:

• High risk GTN

• Elevated hCG or

Measurable PSTT/ETT

• 1 prior multi agent regimen

• PS 1

Single agent

TRC105

TRC105 +

bevacizumab

Single agent

bevacizumab

TRC105Continued for 4 cycles

TRC105 +

bevacizumab

CR

PR

NR PR

30 patients

Opening Nov ‘16

Primary Endpoint:

- ORR toTRC105 Bevacizumab

Secondary Endpoints:

- PFS

- ORR to bev in patients refractory to TRC105

- evaluate formation of anti-TRC105 antibodies

- evaluate PK of TRC105 and bev

- assess toxicity

- assess angiogenic biomarkers

Phase II trial of anti-endoglin antibody (TRC105)

without or with bevacizumab in relapsed high risk GTN

4 patients recruited: 1 CR and 2 PD and 1 starting

gcig endometrial cancer committee

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