AGENDA Welcome COI - Introductions 1. 2. Approval of minutes of - - PowerPoint PPT Presentation

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 Endometrial Cancer Committee

Chair: Stefano Greggi Co-chair: Carien Creutzberg GCIG Trial Presentation Guidelines (2017):

• 1. Closed trials (Site Committee Chair):
• Lead group should prepare 1 slide using the attached template.
• NEWLY closed trials since the last meeting – final accrual
• PREVIOUSLY closed trials – presentation plan, publications and plans
• 2. Ongoing trials without substantial NEW information (Site Committee Chair):
• Lead group should prepare 2 slides using the attached template
• 3. Ongoing trials with substantial NEW information:
• Lead group to request a time slot of 5 minutes and prepare up to 5 slides. Trial slides

will be presented by lead group representative

• Trials presented at the last GCIG meeting as “NEW TRIALS” are considered as ongoing
• 4. New trial concepts:
• Concept/trial design presentation – lead group to request a time slot of 5 minutes
• 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)

GCIG Endometrial Cancer Committee

Chair: Stefano Greggi Co-chair: Carien Creutzberg

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
• Endorsed by RTOG
• 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 NEOPLASIA

Study Chair: Julian Schink, MD

Arm Regimen 2: IV methotrexate (0.4 mg/kg) daily for 5 days every 14 days. (25mg max daily dose) OR IM methotrexate(50mg) on Days 1, 3, 5, 7 (4 doses per cycle) with Leucovorin (15mg)

• n 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

GCIG Endometrial Cancer Committee Chicago, June 2017

Ongoing trials

TOTEM Study: Multicentric randomized controlled clinical trial between 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 trial between two follow up regimens with different tests intensity in endometrial cancer treated patients / NCT 00916708

Ongoing Trials – status update 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: NSGO Project Manager: Mette Berensen Statistitian: René DePont Christensen PI: Mansoor Raza Mirza

Randomization 1:1 N = 148

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 therapy

• 2. 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 status

• 7. 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

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 Number of patients 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

Chemotherapy

Carboplatin-Paclitaxel x 6 + Brachytherapy

Observation

+ Brachytherapy 1:1 randomization Randomized till date = 165/240

Creasman et al., IJGO, 2007

ENGOT-EN2-DGCG

Study 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 days Placebo d 1-21 every 28 days

Until progression

ARM B

Letrozole, 2.5mg d 1-28 every 28 days Palbociclib 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

NiCCC SGCTG - 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

• vary within 6

months of previous platinum. Plus up to 30 women with endometrial CCC

R A N D O M I S E

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 Ongoing Trials – status update

PORTEC-4a

Ongoing Trials – status update

• 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 > 60 Stage IB, grade 1-2 and LVSI+ Stage IB, grade 3 without LVSI Stage II (microscopic), grade 1 Randomisation Endometrial carcinoma

PORTEC-4a

Ongoing Trials – status update

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

Ongoing Trials – status update

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
• Endorsed by RTOG
• 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

s.greggi@istitutotumori.na.it; ginecologia@istitutotumori.na.it

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

• f 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. Endometrial Cancer Conservative treatment A multicentre archive

Participation (17/05/2017)

E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive

Center Code PI Registration date N° of patients registered

National Cancer Institute of Naples,

• Naples. Italy

640 Stefano Greggi March 2014 31 Catholic University

• f

the Sacred Heart, Rome. Italy 145 Giovanni Scambia September 2015 13 Papa Giovanni XXIII Hospital,

• Bergamo. Italy

254 Chiara Malandrino December 2015 6 San Raffaele Hospital, Milan. Italy 321 Patrizia De Marzi October 2015 4 National Cancer Institute of Rome,

• Rome. Italy

741

• July 2016
• University of Bari, Bari. Italy

111 Gennaro Cormio October 2015

• The

Royal Women’s Hospital,

• Parkville. Australia

668

• August 2015
• The Obstetrics & Gynecology Hospital
• f Fudan University, Shanghai. China

676

• September 2015
• Leiden

Medical University, Leiden. Netherlands 704

• 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 TRC105

Continued 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