GCIG reviews: Delineated Process

Consensus review

elaboration by coordinator/co

coordinators N = 20

Review by all members of the RTWG

N = 19

Review by chairs and co chairs from sub committees & from some other groups such as ISTDD or WSN

N = 19

Editing committee

N = 20

Review by all national groups N = 20

Editing board Liverpool 10/2013 N = 20

Group Représentatives: ACRIN S Lee , AGO Au C Marth, AGO De J Pfisterer >, ANZGOG A Brand , COGI J Berek , DGOG C Creutzberg EORTC A Casado, GEICO A Poveda, GICOM D Gallardo, GINECO AC Hardy , GOG T Thigpen , GOTIC K Fujiwara , ICORG D Donnell , JGOG D Aoki , KGOG JW Kim , MaNGO R Fossati , MITO S Pignata , MRC-NCRI J Ledermann , NCIC CTG M Fung-Kee-Fung , NSGO M Mirza , RTOG D Gaffney , SGCTG N Siddiqui , SGOG R Zang , NOGGO J Sehouli , PMHC A Oza

J Bryce, M Friedlander, J Ledermann, A Oza, I Ray-Coquard

Cervix: S Sagae & B Monk Endometrial : K Lorusso & S Greggi Ovarian : P Harter & A Gonzalez

NCI US B Greer; NCI US T Trimble; AGO-De P Harter; ANZGOG M Friedlander; MRC-NCRI C Gourley; GICOM EM Gomez Garcia; MRC-NCRI A Clamp; MRC-NCRI I McNeish; ANZGOG D Rischin; MITO K Lorusso; G Daniele; H Hal; Blagden, SP; NSGO E Avall-Lundqvist; GINECO I Ray-Coquard, SGCTG R Glasspool; ANZGOG C Lee; C Scott; JGOG D Aoki; JGOG group; SWOG M Bookman; NSGO G Kristensen; EORTC N Ottevanger; JGOG N Susumu; G Keiichi

J.Brown, P.Pautier, M.Hensley, F.Amant, M.Leitao, B.Rigaud, X.Cheng, N.Reed, P.Harter, D.Gershenson, C.Gourley, N.Colombo, R.Glasspool, A.Gonzalez, K.Fujiwara, E.Gomez, A.Okamoto, K.Lorusso, Susumu for S.Sagae, A.Viswanathan, M.Seckl, and M.Friedlander,J Lederman, E Pujade- Lauraine, I Ray-Coquard, J Bryce

GCIG consensus reviews update

GCIG consensus review leader Group Coordinator

Co Coordinator step

Ov & Ut carcinosarcoma GINECO D Berton Rigaud Accepted with minor Changes low malignant potential tumors AGO P Harter Submitted low grade serous carcinoma GOG D Gershenson C Gourley Submitted Sex cord tumor GINECO I Ray Coquard N Colombo Submitted germ Cell Tumor GOG J Brown M Seckl Submitted squamous Ov carcinoma SGCTG R Glasspool Antonio Gonzales Submitted Small Cell carcinoma cervix GOTIC K Fujiwara N Reed Accepted with some comments

small cell carcinoma OV EORTC N Reed P Pautier Submitted

vulvar & vagina melanoma US NCI M Leitao Xi Cheng Accepted ovarian carcinoid tumor GICOM N Reed E Gomez Submitted Mucinuous carcinoma MRC/NCRI J Ledermann J Brown Submitted clear cell carcinoma Ovary JGOG A Okamoto R Glasspool Just submitted clear cell carcinoma Cervix & Ut GOTIC K Fujiwara & Dr Hasegawa Need to be submitted trophoblastic diseases MITO K Larusso M Seckl Submitted

low grade endometrial stromal sarcoma EORTC F Amant Submitted

HG uterine sarcoma GINECO P Pautier Submitted uterine serous carcinoma JGOG S Sagae A Viswanathan Need to be submitted

adenosarcoma ANZGOG M Friedlander Accepted with minor changes

Ut & Ov leiomyosarcoma US NCI M Hensley Submitted glandular carcinoma of cervix GOTIC K Fujiwara B Monk Submitted

Next steps for consensus reviews documents

Publications : Publications on website and in journal

One paper summarizing all documents (non answered questions) in progress 20 papers in a supplement (Int J Gyn Cancer) to be finalized

What place for rare tumors in the 5th OCCC, Japan 2015? A special team will be designed to help the Chairs

The most easy part of the job is made, the next will be really more difficult (updating, implementation …) Updating:

Every 3 years for paper version Every year for website version (addendum will be posted if needed) Current coordonator will be asked to be the sentinel for the next 3 years

Implementation within national group: Experiences will be reported next meeting

Objectives: To define current recommendations for rare gynecologic

tumors; To help to define control arm for present and future

clinical trials involving rare cancer; To identify national & international barriers for

trials dedicated to rare gynecologic cancers To summarize and prioritize key issues for

research and agree new set of trial concepts to address the key issues in several rare tumors

To prioritize and design 3 international initiatives in rare gynecologic cancer

GCIG RTWG meeting London Nov. 2013, first step

GCIG Rare Tumors project, the future Publications:

one paper to summarize London meeting (500 words per section) harmonization, statistical, biology and specific recommendations for very very rare, rare and not so rare disease (cut-off date Sept 2014)

More dedicated projects to rare gynecologic cancer

= Limited resources imply concerted actions

Combination of clinical trials and other projects (specific databases & tumor collections)

Next tasks to be delivered: Cervix proposals will be sent to Cervix subgroups for considerations Carcinosarcoma is on –going to be delineated with Phase II group New Proposals adapted to rare diseases/situations A specifc session is anticipated bringing pathologists & clinicians to delineate

recommendations for inclusion of patients in clinical trials with rare tumors (ESGO 2015)

7

ALIENOR DESIGN : 60 patients

Bevacizumab 15mg/Kg every 3 weeks

Paclitaxel alone

80mg/m², IV, at D1, D8 and D15

every 4 weeks

Paclitaxel 80mg/m², IV, D1, D8 and D15

every 4 weeks +

Bevacizumab 10mg/kg, IV, D1 and D15

RANDOMISATION

Maximum of 6 cycles Up to 1 year or until PD / intolerance

Arm A

Arm B

Standard

surveillance

Standard of care

PD or Toxicity

Bevacizumab 15mg/Kg every 3 weeks

Standard of care

PD or Toxicity

At the investigator discretion

Population : Patients with an histologically confirmed diagnosis of ovarian sex-cord stromal tumor in relapse after a platinum-based chemotherapy.

Primary objective : Clinical benefit rate (non-progression rate after 6 months of treatment)

Stratification Anterior chemotherapy lines : 1 or 2 vs 3 and more Platinum Free Interval Interval (PFI) <12 months vs >12 months

ALIENOR - Satellite Meeting

8

20

0

10

20

30

40

50

60

70

Planned

Actual

GINECO First Patient In 28/02/2013

AGO 04/04/2014

• Enrollment period : 36 months First Patient In : February 2013 • Treatment + maintenance : 18 months Last Patient Out of Maintenance : August 2017 • Follow-up : 36 months Last Patient Out : August 2020

ALIENOR - Satellite Meeting

More details during the satellite meeting (13:30 to 14:00)

A Randomised Phase II Study of BIBF 1120 versus Chemotherapy in Recurrent Clear Cell Carcinoma of the

Ovary or Endometrium

SGCTG/NCRI/NSGO

NiCCC Nintedanib in Clear Cell Carcinoma

NiCCC 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

Chemotherapy Ovary:

•PLDH (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

Nintedanib 200mg bd until progression

Primary Endpoint: PFS

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

SOON OPEN FOR INCLUSION AUGUST 2014

11

Hyatt Canberra | 26–29 March 2014

Paragon trial: Phase II study of aromatase inhibitors in women with potentially hormone responsive recurrent/metastatic gynaecological

neoplasms SCREENING

Metastatic or recurrent ER+ve and/or PR+ve gynaecological cancer

Epithelial ovarian cancer

1. Rising CA125 after 1st line therapy (closed to further accrual)

2. Recurrent low grade ovarian cancers

3. Platinum resistant/refractory

Endometrial cancer (closed to further accrual)

Endometrial stromal sarcomas

and other

gynaecological sarcomas

Granulosa cell/sex cord

stromal tumours

Suitable for endocrine therapy

REGISTRATION PROCEDURES Signed informed consent

TREATMENT Anastrozole (1 mg daily)

Study visits monthly for first 3 months then every 3 months Tumour markers at each visit (if initially elevated) & imaging every 3 months in

patients with measurable disease

GCIG Meeting, Chicago, May 2014

• There are currently 23 sites recruiting across Australia & New Zealand (ANZGOG) with a further 21 in the United Kingdom (CRUK)

• Current accrual 255 from a target of 350 • Of the seven tumour subgroups, the Epithelial Ovarian cancer - Platinum

Resistant / Refractory and Endometrial subgroups have completed accrual • All other tumour subgroups remain open to recruitment. • Accrual expected to close Dec 2015

GOG 0281/LOGS Trial

• Phase II/III • International trial: UK (NCRI) and US (NRG) • Target sample size = 250 pts • Activated in US 2-14 • Crossover design

R

LOGS Study Trial Schema

Arm A = Control Arm Investigators Choice of following:

• Letrozole 2.5 mg po qd continuously • Tamoxifen 20 mg po bid continuously • Paclitaxel 80 mg/m2 IV over 1 hr on day

1 q. 7d, 3 wks on, 1 wk off • Pegylated Liposomal Doxorubicin 40 or

50 mg/m2 IV over 1 hr on day 1 q. 28d • Topotecan 4.0 mg/m2 over 30 min on

days 1, 8 and 15 of a 28 day cycle For each arm, 1 cycle = 28 days

Arm B = Experimental Arm Trametinib 2 mg po daily

continuous treatment For each arm, 1 cycle = 28 days

Crossover to Trametinib

N = 250 patients Primary endpoint: PFS Secondary endpoints: • Adverse effects • Objective response • Overall survival • Molecular analyses • Quality of Life

Assessments

Clinical: • At screening day 1 of each

cycle • Following disease

progression, pts will be followed every 12 wk

CT Scans: Screening, then every 8 wk until disease progression

Progression

Off Study

Competitive trials on-going:

- MILO trial

- Merck trial (Mek inhibitor plus or less PI3k inh)

The RTWG highlighted how important and constructive could be to have

an academic steering committee across the 3 RCT to support and help

the development of these new drugs for a so small pop of patients

Late Phase II study

1° endpoint: PFS rate at 4 months from randomization 2° endpoints: PFS, OS, RR and duration of response (RECIST 1.1), QoL (QLQ-C30 + QLQ-EN24), Toxicity (CTCAE 4.0)

Locally advanced:

Newly diagnosed HGUS with advanced disease (stage III or stage IV) or residual

disease after primary surgery

Metastatic:

Diagnosed HGUS with disease relapse after local treatment for

primary tumor

Doxorubicin based regimens

4 to 6 cycles of doxorubicin alone or in combination with ifosfamide (for recommended regimens, appendix H)

Screening phase

Cabozantinib maintenance

60 mg QD continuously

2 year or withdrawal criterion

Placebo

2 year or withdrawal criterion

Protocol treatment

Investigator choice

Investigator choice (cabozantinib

allowed)

REGISTRATION

(78 patients expected)

RANDOMIZATION 1:1

(54 patients)

Non-PD within 12 weeks after CT

A randomized double-blind phase II study evaluating the role of maintenance therapy with Cabozantinib in High Grade Uterine Sarcoma (HGUS) after chemotherapy for

advanced or metastatic disease or in metastatic first line treatment

EORTC-CRUK-NCI study in uterine sarcoma

• International Rare Cancer Initiative (IRCI) launched in 2011 to perform clinical trials in different rare tumors. One working group will launch trials.

• Three (sub)studies in the domain of gynaecological sarcoma have been identified: • ESS: Advanced recurrent stage (EORTC lead) – 55112-62111 • HGUS (EORTC lead) – 62113-55115 • Adjuvant treatment of uterine LMS (NCI lead) – 55116-62114

• Question at the end, IRCI will be able to avoid the complexicity of NCI/US organization?

“MaGIC” Malignant Germ Cell

International Collaboration

David Gershenson A. Lindsay Frazier MD Anderson Dana-Farber Cancer Institute

• The IGCCC (International Germ Cell Consensus Collaboration) “revolutioned” testis cancer. • Universally-accepted risk

stratification allowed for international collaboration and comparison.

• Our goal: Duplicate for pediatric germ cell tumors.

• In 2010, COG signed a Memorandum of Understanding with CCLG in the UK and merged 25 years of clinical trial data resulting in data set of ~ 1000 patients.

History and Purpose of MaGIC

• Pediatric Group • COG • CCLG (UK) • TATA Memorial (Mumbai) • Centro Infantil Boldrini

(Brazil) • 57357 Children’s Cancer

Hospital (Cairo)

Collaboration of Major Pediatric and Adult Clinical Trial Groups

• Gyn Oncology • NRG • ? • Testis Cancer • Alliance • SWOG • ECOG • MRC (UK) • ANZUP (Australia/NZ)

• Goals and Specific Aims

1. Eliminate chemotherapy for all Stage I patients • All stage I ovarian germ cell tumors will be observed after surgery

• Stratum 1: Stage I pure immature teratoma, all grades • Stratum 2: MGCT that contain at least one of the following:

Yolk sac tumor, embyronal carcinoma or choriocarcinoma.

2. Evaluate carboplatin vs. cisplatin • Expect to accrue 588 patients over 6 years

• Have 88% power to detect carboplatin as inferior if the long term EFS for BEP is 84% and EFS for JEB is 76%

• (Relative hazard ratio of 1.6)

Children’s Oncology Group AGCT1431

• Poor risk “Germinational” Trial • Will require cooperation of pediatric, gynecologic oncology

and testes cancer groups • Potential regimens: - Dose dense (Accel-BEP every 2 weeks) - New agents (TIP –taxol, ifosfamide, platinum) - Combination of both: GETUG13 or CBOP-BEP

• Optimal therapy for dysgerminoma • Optimal therapy for immature teratoma • Surgical guidelines for germ cell tumors

Other topics under discussion

People from the RT group will be very happy to participate Some concerns about the administrative limits induced by NCI cooperative

group Contacts will be organized

The most « sexy » proposal from GOG

Carcinosarcoma Uterine and Ovarian

SOC: Surgical staging +TC

+/-RT

SOC+ Anti-angiogenic

+/-RT

Recurrence Experimental 1

Experimental 2

Chemotherapy

Molecular Pathology, Staging

Randomization 1 At initial diagnosis Stage and Pathology

Randomization 2 At Recurrence - Stage and Bx

Patients can enroll At Randomization 1 or 2

n= 100s

N=100s

AKT inhibitor

PARP inhibitor

Carboplatin/paclitaxel plus Cedirinib

Clinician choice?

Possibility to add/remove experimental arms

Intergroup agreement AZ seems to be interested People from the RT group will be very happy to participate Consortium will be organized

Umbrella trial delineated during the London Brainstorming meeting