Randomized phase III trial on Trabectedin (ET 743) vs clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal or fallopian tube cancers of BRCA mutated or BRCAness phenotype patients MITO – 23

Randomized phase III STRATIFICATION CRITERIA: Measurable Disease Platinum Sensitivity Number of Previous CHT Lines Mutational status II line chemotherapy (physician choice): - PLD 40 mg/mq d1 q28; - Topotecan 4 mg/mq d1,8,15 q 28 - Weekly Paclitaxel 80 mg/mq d1,8,15 q28 Gemcitabine 1000 mg/mq gg1,8,15 q28 Carboplatin AUC 5 g 1 q 21 Random1.1 Recurrent ovarian, primary peritoneal or fallopian tube cancers of BRCA mutated or BRCAness phenotype patients Trabectedin 1.3 mg/mq d1 q 21 in 3 hours (central line) MITO - 23 2

STUDY OBJECTIVES Primary: The primary objective is to compare the treatment groups in terms of overall survival (OS) Secondary: Progression free survival (PFS) Radiological response rate (in patients with measurable disease) Duration of response CA-125 response rate per GCIG Toxicity profile Quality of life using the QLQ-C30 and QLQ-0V28 MITO - 23 3

INCLUSION CRITERIA Female of age 18 years or older Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer Platinum resistant or sensitive patients with either: BRCA mutated patients BRCAness phenotype patients: patients who have received and responded (subsequent PFI>6 months) to at least 2 previous platinum based chemotherapy lines Platinum sensitive patients who are not able to receive or not willing to receive other platinum treatments Measurable and evaluable disease per RECIST 1.1(Subjects with isolated rising CA-125 without radiologically visible disease are excluded) ECOG performance status 0 or 1 No limits in the number of previous chemotherapy lines, previous treatment with parp inhibitors is allowed Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal Life expectancy of at least 3 months Adequate organ functions No other invasive malignancy within the past 3 years except non-melanoma skin cancer or in situ cervical cancer (patients with previous cancers may be enrolled providing that no recurrences have be reported in the last 3 years) Written Informed Consent Adequately recovered from the acute toxicity of any prior treatment For agents in the standard arm, also refer to the local prescribing information with regards to warnings, precautions, and contraindications MITO - 23 4

STATISTICS PROTOCOL Phase III The primary endpoint is OS Hazard Ratio: 0.67 Median OS expected in the control arm: 10 months Median OS hoped for the experimental arm : 15 months Two-sided log-rank test at the error alfa= 0.05 Statistical Power 80% 198 events are required Overall 244 patients will be enrolled in 30 months (8 patients/months) Interim futility analysis at ~ 99 events MITO - 23 5

MITO-23: TRANSLATIONAL STUDIES Evaluating the impact of altered gene and microRNA (miRNA) expression on trabectedin efficacy with the aim of identify which genes are involved in the so called BRCAness phenotype; Analysis of cellular infiltrate present on tumor specimens of patients treated with trabectedin; DNA sequencing in order to evaluate mutation/genetic aberration profile in selected panels of genes associated to tumor sensibility to trabectedin (BRCA test). MITO - 23 6

TRANSLATIONAL STUDIES: Specimens Tumor histological blocks (FFPE material): samples will be collected at primary surgery and/or interval debulking surgery (or before trabectedin treatment by dedicated biopsies). Storage and analysis will be centralized at Fondazione Istituto Nazionale dei Tumori. Characterization of tumor infiltrate by IHC (2 slides per marker & 1 HE slide & 3 backup slides); Extraction of RNA from tissue sections for gene expression by DASL microarray analysis; Extraction of DNA from tissue sections for targeted sequencing of “Panel cancer related genes” (in collaboration with Istituto Mario Negri, Milan). Blood samples: Blood samples will be collected at baseline (registration), at third cycle of treatment and at progression. Storage and analyses will be centralized at Fondazione IRCCS Istituto Nazionale Tumori, Milan. 10 ml blood sample will be taken at each time point, centrifuged in EDTA, processed to obtain 5 ml plasma collected and stored at -20°C or at -80°C when possible. Analysis of miRNA profile by Agilen microarrays or evaluation of selected miRNA by RT-qPCR (in collaboration with Fondazione Istituto Nazionale dei Tumori) MITO - 23 7

8 Site Principal Investigator Ethical Committee approval Status (70/244 pts) IRCCS Istituto Nazionale Tumori – Milano COORDINATING CENTER Domenica Lorusso 22.01.2016 35 patient enrolled Fondazione Policlinico Universitario A. Gemelli - Roma Giovanni Scambia 15.09.2016 7 patient enrolled Istituto Nazionale Tumori Pascale - Napoli Carmen Pisano 17.12.2015 6 patient enrolled Ospedale San Raffaele – Milano Giorgia Mangili 05.05.2016 3 patient enrolled Fondazione del Piemonte per l'Oncologia - Istituto di Candiolo Giorgio Valabrega 03.11.2016 1 patient enrolled Ospedale Fatebenefratelli - Roma Enrico Breda 01.07.2016 ULLS 13 - Mirano Grazia Artioli 31.05.2016 2 patient enrolled IRST - Meldola Ugo De Giorgi 20.07.2016 A.O. di Perugia - Ospedale Santa Maria Misericordia - Perugia Anna Maria Mosconi Sapienza Università di Roma-Policlinico Umberto I - Roma Pierluigi Benedetti Panici 17.10.2016 Inactive CRO IRCCS - Aviano Roberto Sorio 01.03.2016 IRE-Istituto Nazionale Tumori REGINA ELENA - Roma Patrizia Vici 12.04.2016 AOU Federico II Sabino De Placido Fondazione IRCCS Policlinico S.Matteo di Pavia Stefano Bogliolo 19.04.2016 U.O.Oncologia Medica - Ospedale Vito Fazzi - Lecce Graziana Ronzino Waiting EC approval Ospedale degli Infermi - Faenza Stefano Tamberi Active AULSS 21 Regione Veneto - Legnago Filippo Greco 21.09.2016 Ospedale Civile SS. Trinità - Sora Teresa Gamucci 08.03.2016 A.O. S.Giuseppe Moscati - Avellino Cesare Gridelli Study withdrawal by PI - Ospedale Santa Croce - Fano Rodolfo Mattioli 13.10.2016 A.O. Carlo Poma - Mantova Maria Giovanna Cavazzini Not approved Ospedale S.Maria delle Croci - Ravenna Claudia Casanova A.O.U. Santa Maria della Misericordia - Udine Claudia Andreetta 20.09.2016 IRCCS AOU San Martino - IST - Genova Serafina Mammoliti Ospedale Civile G.Fornaroli - Magenta Silvia Elvira Negretti 22.04.2016 Istituto Europeo di Oncologia - Milano Nicoletta Colombo 27.07.2016 Arcispedale sant'anna - Cona, Ferrara Antonio Frassoldati 12.05.2016 Spedali Civili di Brescia - Brescia Germana Tognon AOU Maggiore della Carità - Novara Roberta Buosi New PI, Amendment 1 MITO - 23 8

ADMINISTRATIVE INFORMATION Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Study start: 11 April 2016 Pharma-Mar support: Trabectedin supply , financial support for insurance, translational studies and data management. MITO - 23 9

Amendment 1.0 _ 16.05.2017 New Investigators Brochure (Version 11); New Informed Consent; New Italian Sites: - Policlinico di Bari – Bari (PI Gennaro Cormio); - P.O. A.Perrino – Brindisi (PI Saverio Cinieri); - Centro Sociale Oncologico - ASUITS – Trieste (PI Rita Ceccherini); - ARNAS Garibaldi – PO Nesima – Catania (PI Daniela Sambataro); 15 Spanish sites (GEICO Collaboration_ Coordinating by IVO (PI Ignacio Romero); New version of Protocol and synopsis (V. 1.7_ 05.05.2017). MITO - 23 10