1. 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

2. MITO - 23 Recurrent ovarian, primary peritoneal or fallopian tube cancers of BRCA mutated or BRCAness phenotype patients 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 STUDY DESIGN Randomized phase III Trabectedin 1.3 mg/mq d1 q 21 in 3 hours (central line) Random 1.1 STRATIFICATION CRITERIA: Measurable Disease Platinum Sensitivity Number of Previous CHT Lines Mutational status

3. MITO - 23 STUDY OBJECTIVES Primary: The primary objective is to compare the treatment groups in terms of progression free survival (PFS) according to Recist v1.1 criteria. Secondary: Overall survival (OS) Radiological response rate (in patients with measurable disease) Duration of response CA-125 response rate per GCIG Toxicity profile Quality of life using the EORTC C30 and EORTC 0V28

4. MITO - 23 INCLUSION CRITERIA Female of age 18 years or older; Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer (Subjects with borderline ovarian cancer are excluded; subjects with ovarian carcinosarcoma are included); Platinum resistant or sensitive patients with: - BRCA mutated patients; - BRCAness phenotype patients: patients who have received at least two previous platinum based chemotherapy lines reporting CR or PR or SD lasting at least 6 months; - Platinum sensitive patients not able to receive or not willing to receive platinum treatments. Measurable and evaluable disease per RECIST 1.1; Subjects with isolated rising CA-125 without radiographically visible disease are excluded; ECOG performance status 0 or 1; Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit of normal; Life expectancy of at least 3 months ; Adequate organ functions: - Hematopoietic; Absolute neutrophil count ≥ 1,500/mm^3; Platelet count ≥ 100,000/mm^3; Hemoglobin ≥ 9 g/dl; - Hepatic; AST and ALT ≤ 1.5 times upper limit of normal (ULN)* ; Alkaline Phosphatase ≤ 2.5 times ULN* ; Bilirubin ≤ 1.5 times; - ULN NOTE: * ≤ 3 times ULN if liver metastases are present ; - Renal; Creatinine Clearance ≥ 45 ml/min or Serum Creatinine ≤1.5 x ULN; - Serum Albumin >2.5 g/dl; 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.

5. MITO - 23 EXCLUSION CRITERIA Prior exposure to trabectedin; Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone; Less than 2 previous responses to platinum (i.e. subsequent recurrences at least 6 months after the first and the second platinum based treatment), unless BRCA mutation is documented; Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy ; History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer ; Known clinically relevant CNS metastases, unless treated and asymptomatic; Other serious illnesses, such as: - Congestive heart failure or angina pectoris; myocardial infarction within 1 year before enrolment; uncontrolled arterial hypertension or arrhythmias. - Psychiatric disorder that prevents compliance with protocol; - Active viral hepatitis; or chronic liver disease; - Active infection; - Any other unstable medical conditions.

6. AssessmentScreeningCycleEnd of TreatmentFollow Up DayDay 1Day 8Day 15Day 16-21 Written Informed Consent Before study procedures Demographic Data- 28 to 0 Medical History- 28 to 0 Prior surgical and/or chemotherapy treatments - 14 to 0 Vital Signs (heart rate, blood pressure, temperature) - 14 to 0XX Complete Physical Examination (assessment of signs and symptoms of desease) - 14 to 0XXXX Performance Status (ECOG)- 14 to 0XXXX ECG- 28 to 0Repeat if clinically indicatedX Echocardiogram-28 to 0 Repeat every 3 cycle only in case of PLD and T treatments, in all other cases repeat only if clinically indicated Concomitant Disease and Medication - 14 to 0Throughout the study Adverse Events- 14 to 0Throughout the study Hematology-7 to 0XXa X Coagulation Test-7 to 0X Chemistry and Liver Panel-7 to 0XXa X QoL assessmentsXEvery 3 chemotherapy cyclesX Radiologic evaluations- 28 to 0Every 12 +/- 1 weekXXb CA 125-7 to 0XX

7. MITO - 23 STATISTICS PROTOCOL Phase 3 The primary endpoint is PFS Hazard Ratio: 0.71 Median PFS expected in the control arm: 17 weeks Median PFS hoped for the experimental arm : 24 weeks Type I one-side error α: 0.025 Statistical Power 80% 288 events are required Overall 344 patients will be enrolled in 3 years (10 patients/months) Interim futility analysis at 172 events

8. MITO - 23 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 (BROCA panel).

9. MITO - 23 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 Istituto Mario Negri, 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)

10. MITO - 23 ADMINISTRATIVE INFORMATION Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Planned study start: March 2015 Pharma-Mar support: Trabectedin supply, financial support for insurance, translational studies and data management. To participate please contact: domenica.lorusso@istitutotumori.mi.it elisa.grassi@istitutotumori.mi.it