Elderly Women Ovarian Cancer Multicenter, randomized trial of carboplatin +/- paclitaxel in vulnerable elderly patients with stage III-IV advanced ovarian cancer 1 Participating Groups GINECO, AGO, MITO, ANZGOG, Canada, JGOG, GOTIC, NSGO

 In the population of vulnerable patients : Which is the best treatment regimen based on their respective benefit/risk ratio ?  Population of interest : Vulnerable patients defined with GVS ≥ 3  Randomized phase II trial  Main endpoint : Treatment completion rate with an interim analysis on efficacy and safety profiles (Bryant and Day method) 2

3 *GVS = Geriatric Vunerability Score : - score ADL < 6 - score IADL < 25 - score HADS > 14 - albuminemia < 35g/L - Lymphopenia < 1G/L GVS =  factors with vulnerable score

4 Based upon :  Initial debulking surgery versus planned interval debulking surgery  No macroscopic residue versus macroscopic residue (including surgery not done)  Interval debulking intent  Cancer stage (stage III versus stage IV)  Country

5

6 To compare the rate of success to deliver 6 courses of chemotherapy without progression at 6 months or unacceptable toxicity* of 3 different regimens in vulnerable elderly patients Screening Chemotherapy 6 cycles 6 month visit GVS>3 * Unacceptable Toxicity = is defined as a major adverse event related to chemotherapy or treatment procedures leading either to early treatment stopping, to an unplanned hospital admission or to death. Imagery QOL Imagery QOL Follow-up every 3 mo. (up to 2 years) Follow-up every 3 mo. (up to 2 years) +/- Interval debulking (stratified)

7  Therapeutical Feasability  Overall Survival (OS)  Quality of life (QOL)  Safety and tolerability  Geriatric Covariates and patient outcome  Aging biomarkers and patient outcome

8  The first step will include 22 patients in each arm (total = 66 patients for the 3 arms);  An interim analysis will be conducted when 22 patients in each arm will have completed their 6 courses of chemotherapy: - if a chemotherapy regimen is associated with more than 8/22 treatment failure, the regimen will be considered as having insufficient activity (expected number of failure n= 3) and the regimen will be dropped for the second step of the study; - if a chemotherapy regimen is associated with more than 6/22 major adverse event leading either to early treatment stopping, or to hospitalization for toxicity or to death, the regimen will be considered as having too high toxicity (expected number of major adverse event n= 3) and the regimen will be dropped for the second step of the study;  The second step of the study will be run with the chemotherapy regimens considered as active enough and tolerable at the interim analysis. This step will include an additional 58 patients per arm with the following assumptions: - a risk of accepting a regimen having insufficient activity α1 = 0,05, - a risk of accepting a regimen with too high toxicity α2 = 0,05, - a risk of rejecting regimen active enough (1-β) = 0,1 - with an unacceptable rate of disease progression at 6 month of > 0,4 - and an unacceptable toxicity rate > 0,3.  The total number of patients per arm will be of 80 for a maximum total number of patients of 240 if all 3 regimens are selected for step 2.  After completion of the 6 chemotherapy cycles, conditions to reject the experimental arms are the following: number of patients with insufficient efficacy n> 26/80 and/or number of patients with unacceptable toxicity n> 18/80 (expected tumour progression or treatment failure: 9, major adverse events: 9).

9  Woman >70 years old  Histologically or cytologically proven FIGO stage III to IV epithelial ovarian cancer or peritoneal primary and fallopian tube. A cytological proof is accepted if associated with a ratio of CA125/CEA >25 and a radiological pelvic mass.  GVS (Geriatric Vulnerability Score)≥3. GVS is the sum of geriatric covariates scores found to predict poor survival : ADL score 14, albuminemia <35g/L and lymphopenia <1G/L.  Neutrophils ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L and hemoglobin ≥9 g/dL  No icterus.

10 EWOC-1 GINECO First Patient In 12/12/2013 GINECO First Patient In 12/12/2013

11  Arcagy – Gineco trial;  Sponsor: LES HOSPICES CIVILS DE LYON (HCL);  Italian coordinating center: NCI of Milan;  Planned Italian study start: January 2015;  NCI of Milan financial support for insurance  Conference call for site initiation visit

SitePrincipal Investigator Upadate IRCCS Istituto Nazionale Tumori – MilanoDomenica LorussoProtocol approved on 27/05/15 Istituto Nazionale Tumori Pascale - NapoliSandro Pignata Policlinico Universitario A. Gemelli - RomaGiovanni Scambia IRCCS Arcispedale Santa Maria NuovaAlessandra BolognaProtocol Discussed on June 2015 CRO IRCCS - AvianoRoberto Sorio AOU Federico IISabino De Placido IRE-Istituto Nazionale Tumori REGINA ELENA - RomaPatrizia Vici Fondazione del Piemonte per l'Oncologia - Istituto di CandioloGiorgio ValabregaProtocol Discussed on June 2015 U.O.Oncologia Medica - Ospedale Vito Fazzi - LecceGraziana Ronzino ULLS 13, Mirano - VeneziaGrazia ArtioliProtocol Approval suspended on May 2015 Casa Sollievo della Sofferenza - S.Giovanni RotondoFrancesco Petruzzelli Fondazione IRCCS Policlinico S.Matteo di PaviaStefano BoglioloProtocol Discussed on June 2015 Oncologia Medica Sora - FrosinoneTeresa Gamucci 12 To activate new sites please contact: