GCIG reviews: Delineated Process

Consensus NCI US B Greer; NCI US T Trimble; AGO- review De P Harter; ANZGOG M Friedlander; elaboration by MRC-NCRI C Gourley; GICOM EM Gomez coordinator/co Garcia; MRC-NCRI A Clamp; MRC-NCRI I coordinators McNeish; ANZGOG D Rischin; MITO K N = 20 Lorusso; G Daniele; H Hal; Blagden, SP; NSGO E Avall-Lundqvist; GINECO I Ray- J.Brown, P.Pautier, M.Hensley, Coquard, SGCTG R Glasspool; ANZGOG F.Amant, M.Leitao, B.Rigaud, X.Cheng, C Lee; C Scott; JGOG D Aoki; JGOG N.Reed, P.Harter, D.Gershenson, Editing board Review by all group; SWOG M Bookman; NSGO G C.Gourley, N.Colombo, R.Glasspool, Liverpool members of Kristensen; EORTC N Ottevanger; JGOG A.Gonzalez, K.Fujiwara, E.Gomez, 10/2013 the RTWG N Susumu; G Keiichi A.Okamoto, K.Lorusso, Susumu for N = 20 N = 19 S.Sagae, A.Viswanathan, M.Seckl, and M.Friedlander,J Lederman, E Pujade- Lauraine, I Ray-Coquard, J Bryce

Group Représentatives: ACRIN S Lee , Review by chairs AGO Au C Marth, AGO De J Pfisterer >, and co chairs from ANZGOG A Brand , COGI J Berek , Review by all sub committees & DGOG C Creutzberg EORTC A Casado, national from some other GEICO A Poveda, GICOM D Gallardo, groups groups such as N = 20 GINECO AC Hardy , GOG T Thigpen , ISTDD or WSN GOTIC K Fujiwara , ICORG D Donnell , N = 19 JGOG D Aoki , KGOG JW Kim , MaNGO R Fossati , MITO S Pignata , MRC-NCRI J Ledermann , NCIC CTG M Fung-Kee- Editing Cervix: S Sagae & B Monk Fung , NSGO M Mirza , RTOG D Gaffney committee Endometrial : K Lorusso & S Greggi , SGCTG N Siddiqui , SGOG R Zang , N = 20 Ovarian : P Harter & A Gonzalez NOGGO J Sehouli , PMHC A Oza

J Bryce, M Friedlander, J Ledermann, A Oza, I Ray-Coquard GCIG consensus reviews update

leader Co GCIG consensus review Group Coordinator 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 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 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 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 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 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 GCIG RTWG meeting London Nov. 2013, first step

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 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) ALIENOR DESIGN : 60 patients

Standard Arm A R Paclitaxel alone of care A Standard PD or N Toxicity D 80mg/m², IV, at D1, D8 and D15 surveillance

O every 4 weeks Bevacizumab M 15mg/Kg every 3 weeks I S At the investigator discretion A T I Paclitaxel O 80mg/m², IV, D1, D8 and D15 N every 4 weeks Bevacizumab PD or Standard Arm B + Toxicity 15mg/Kg every 3 weeks of care Bevacizumab 10mg/kg, IV, D1 and D15

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

Population : Patients with an histologically Stratification confirmed diagnosis of Primary objective : Anterior chemotherapy lines : Clinical benefit rate 1 or 2 vs 3 and more ovarian sex-cord stromal Platinum Free Interval Interval (PFI) tumor in relapse after a (non-progression rate after <12 months vs >12 months platinum-based 6 months of treatment) chemotherapy.

7 ALIENOR - Satellite Meeting More details during the satellite meeting (13:30 to 14:00)

70

60

50

40 AGO 04/04/2014 Planned 30 Actual 20 20 GINECO First Patient In 28/02/2013 10

0

• 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 8 NiCCC Nintedanib in Clear Cell Carcinoma

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

SGCTG/NCRI/NSGO NiCCC Trial Design

Chemotherapy Ovary: R •PLDH (40mg/m2 day 1q28) 90 pts with A •Weekly Paclitaxel (80mg/m2 day 1, 8, 15 q28) progressive or N •Weekly Topotecan iv (4mg/m2 day 1, 8, 15 q28) relapsed CCC of ovary within 6 D Endometrium: months of O •Carboplatin (AUC 5) /Paclitaxel 175 mg/m2 q21 previous platinum. M •Doxorubicin 60mg/m2 q21 Plus up to 30 I women with S endometrial CCC Nintedanib 200mg bd until E progression

Primary Endpoint: PFS Secondary Endpoints: OS, Toxicity, RR, QoL, Q-Twist SOON OPEN FOR INCLUSION AUGUST 2014 Paragon trial: Phase II study of aromatase inhibitors in women with 11 potentially hormone responsive recurrent/metastatic gynaecological SCREENING Metastatic or recurrent ER+ve and/or PR+ve gynaecological cancer

Epithelial Endometrial Endometrial Granulosa 1. Rising CA125 after 1st line cancer stromal sarcomas cell/sex cord therapy (closed to further (closed to stromal tumours accrual) further accrual) and other 2. Recurrent low grade ovarian gynaecological Suitable for • cancersThere are currently 23 sites recruiting across Australiasarcomas & New Zealandendocrine therapy 3. Platinum(ANZGOG) resistant/refractory with a further 21 in the United Kingdom (CRUK) • Current accrual 255 from a target of 350 REGISTRATION PROCEDURES • Of the seven tumour subgroups,Signed theinformed Epithelial consent Ovarian cancer - Platinum Resistant / Refractory and Endometrial subgroups have completed accrual • All other tumour subgroups remainTREATMENT open to recruitment. Anastrozole (1 mg daily) • Accrual expectedStudy to visits close monthly Dec for2015 first 3 months then every 3 months Tumour markers at each visit (if initially elevated) & imaging every 3 months in patients with measurable disease

GCIGHyatt Meeting, Canberra Chicago, | 26–29 MayMarch 2014 2014 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

Assessments N = 250 patients Clinical: Primary endpoint: PFS LOGS Study Trial Schema • At screening day 1 of each Secondary endpoints: cycle • Adverse effects • Following disease • Objective response progression, pts will be • Overall survival followed every 12 wk • Molecular analyses CT Scans: • Quality of Life R Screening, then every 8 wk until disease progression

Arm B = Experimental Arm Arm A = Control Arm Trametinib 2 mg po daily Investigators Choice of following: continuous treatment • Letrozole 2.5 mg po qd continuously For each arm, 1 cycle = 28 days • Tamoxifen 20 mg po bid continuously • Paclitaxel 80 mg/m2 IV over 1 hr on day Competitive1 q. 7d, 3trials wks on, on 1 wk-going: off • Pegylated Liposomal Doxorubicin 40 or - MILO50 trial mg/m 2 IV over 1 hr on day 1 q. 28d • Topotecan 4.0 mg/m2 over 30 min on - Merckdays trial 1, 8 and(Mek 15 of inhibitor a 28 day cycle plus or less PI3k inh) For each arm, 1 cycle = 28 days 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 drugsProgression for a so small pop of patients

Crossover to Trametinib Off Study 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 RANDOMIZATION 1:1 REGISTRATION (54 patients) (78 patients expected) Late Phase II study Non-PD within 12 weeks after CT

Cabozantinib maintenance

Locally advanced: 60 mg QD continuously Investigator choice Newly diagnosed 2 year or withdrawal criterion HGUS with advanced disease (stage III or Doxorubicin based regimens stage IV) or residual disease after primary 4 to 6 cycles of doxorubicin alone or Protocol treatment surgery in combination with ifosfamide (for recommended regimens, appendix Metastatic: H) Investigator choice Placebo Diagnosed HGUS with (cabozantinib allowed) disease relapse after 2 year or withdrawal local treatment for Screening phase criterion primary tumor

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) 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

History and Purpose of MaGIC • 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.

Collaboration of Major Pediatric and Adult Clinical Trial Groups

• Pediatric Group • Gyn Oncology • COG • NRG • CCLG (UK) • ? • TATA Memorial (Mumbai) • Testis Cancer • Centro Infantil Boldrini • Alliance (Brazil) • SWOG • 57357 Children’s Cancer Hospital (Cairo) • ECOG • MRC (UK) • ANZUP (Australia/NZ)

Children’s Oncology Group AGCT1431

• 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 , all grades • Stratum 2: MGCT that contain at least one of the following: Yolk sac tumor, embyronal carcinoma or .

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) Other topics under discussion

• Poor risk “Germinational” Trial

• Will require cooperation of pediatric, and testes cancer groups • Potential regimens: - Dose dense (Accel-BEP every 2 weeks)

 People from - theNew RT agents group will (TIP be – verytaxol happy, ifosfamide to participate, platinum)  Some concerns - Combination about the administrative of both: GETUG13 limits induced or CBOP by NCI-BEP cooperative group  Contacts• Optimal will be organizedtherapy for • Optimal therapy for immature teratoma • Surgical guidelines for germ cell tumors

The most « sexy » proposal from GOG

Umbrella trial delineated during the London Brainstorming meeting

Patients can enroll Carcinosarcoma At Randomization Uterine and Ovarian 1 or 2 Molecular Randomization 1 Pathology, Staging At initial diagnosis Stage and Pathology n= 100s

SOC: Surgical SOC+ Carboplatin/paclitaxel staging +TC Anti-angiogenic plus Cedirinib

+/-RT +/-RT Possibility to add/remove experimental arms

Recurrence Experimental 1 AKT inhibitor

 Intergroup agreementRandomization 2 Experimental 2 PARP  AZ seems toAt be Recurrence interested - inhibitor  People fromStage the RT and group Bx will be very happy to participate  Consortium will be organized Clinician Chemotherapy N=100s choice?