1. MITO 25 A randomized phase II trial of Carboplatin-Paclitaxel- Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab- Rucaparib vs Carboplatin-Paclitaxel-Rucaparib in advanced (stage III B-C-IV) ovarian, primary peritoneal and fallopian tube cancer

2. MITO 25 Study design FIGO stage IIIB-IV high grade serous or endometrioid ovarian cancer, primary peritoneal and / or fallopian- tube cancer, HRD positive R A N D O M I Z A T I O N 1:1:1 N= 357 ARM A: Carboplatin AUC 5+Paclitaxel 175 mg/mq q 21 for 6 cycles + Bevacizumab 15 mg/kg q 21 for 22 cycles ARM B: Carboplatin AUC 5+ Paclitaxel 175 mg/mq q 21 + Bevacizumab 15 mg/kg for 22 cycles + Rucaparib 600 mg bid q 28 until progression or unacceptable toxicity ARM C: Carboplatin AUC 5+ Paclitaxel 175 mg/mq q 21 + Rucaparib 600 bid q 28 mg until progression or unacceptable toxicity Stratification Factor: Residual tumor at primary surgery; Stage of disease; HRD status (BRCA mutated vs BRCA like)

3. MITO 25 Study design Dose modification: Due to the absence of phase I trial on Bevacizuamb -Rucaparib combination a rapid reporting, monitoring and analysis of all Significant Safety Events (SSEs) (defined below) will be performed during the first three treatment cycles of the first 20 patients randomized in the bevacizumab/rucaparib arm. Information regarding the occurrence of all SSEs will be reported by the Investigator to the Coordinator Centre and to the IDMC within 48 hours from the time the event becomes evident to the investigator. A SSE is defined as any of the following: Any form of Grade 3-4 Toxicity (NCI-CTC AE, v4.03) including hospitalization; A patient death (grade 5). The starting dose of Rucaparib in this study will be 600 mg bid.

4. MITO 25 Objectives Primary: Progression free survival (PFS) The trial will test the hypothesis that Carboplatin-Paclitaxel- Bevacizumab-Rucaparib and the Carboplatin-Paclitaxel–Rucaparib arms will improve the progression-free survival in comparison to standard Carboplatin-Paclitaxel-Bevacizumab arm.

5. MITO 25 Objectives Secondary: To compare the overall survival (OS) of patients receiving Carboplatin- Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib; To compare the post progression survival (PFS2) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab- Rucaparib vs Carboplatin-Paclitaxel-Rucaparib; To compare the response rate (Recist and/or GCIG criteria) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel- Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib; To assess the safety and tolerability of Carboplatin-Paclitaxel- Bevacizumab- Rucaparib in this population; To evaluate LOH signature and its correlation with efficacy end-points; To assess changes in Quality of Life parameters in patients treated with Carboplatin-Paclitaxel-Bevacizumab compared to those treated with Carboplatin-Paclitaxel- Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel- Rucaparib.

6. MITO 25 Inclusion Criteria Female aged  18 years at the time of study inclusion; Patients with newly diagnosed, histologically confirmed, FIGO stage IIIB-IV high grade (based on local histopathological findings) serous or endometrioid ovarian cancer, primary peritoneal and / or fallopian-tube cancer. Patients with mixed histology are eligible providing that high grade tumor represent more than 70% of the total histology. HRD positive patients Stage III patients should have had one attempt at optimal debulking surgery (upfront or interval debulking). Stage IV patients must have had either a biopsy and/or upfront or interval debulking surgery; Archivial tumor tissue available. At progression fresh biopsy is optional for patients willing to submit; ECOG Performance Status of 0–1; Measurable and not measurable disease; CA-125 be <ULN at the time of maintenance treatment initiation; Adequate renal and hepatic function; Adequate bone marrow function, defined as: Able to understand and give written informed consent; Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

7. MITO 25 Exclusion Criteria Women who are pregnant or lactating; Presence of brain or other central nervous system metastases, not adequately controlled; Prior Anticancer treatment; Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 4 weeks prior to randomization; Another primary malignancy except for: Curatively treated non-melanoma skin cancer; Breast cancer treated curatively >3 years ago, or other solid tumor treated curatively >5 years ago, without evidence of recurrence; Synchronous endometrioid endometrial cancer (except for Stage 1A G1/G2); Known active HIV, hepatitis B or C infection; Concurrent treatment with immunosuppressive or investigational agents. History or evidence of thrombotic or hemorrhagic disorders; Clinically significant (i.e. active) cardiovascular disease; Serious active infection requiring i.v. antibiotics at enrolment. Known hypersensitivity to any of the study drugs or excipients; Evidence of any other medical conditions, physical examination or laboratory findings that may interfere with the planned treatment,; Prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with absorption of study drug; Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose of Rucaparib or have on-going requirements for these medications.

8. MITO 25 Statistical consideration All patients receiving at least one dose of study drug will be considered evaluable for safety. The adverse event incidence rates as well as the frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) will be described for each arm of the trial. The final analysis of the primary endpoint will be performed using a stratified log- rank test to determine whether treatment with Carboplatin-Paclitaxel- Bevacizumab-Rucaparib or treatments with Carboplatin-Paclitaxel-Rucaparib will prolong PFS relative to patients treated with Carboplatin-Paclitaxel-Bevacizumab. All patients randomized will be included in the Intent-to-Treat analysis. Success is defined as the rejection of the Null Hypothesis of no difference when comparing Carboplatin-Paclitaxel-Bevacizumab-Rucaparib and Carboplatin-Paclitaxel- Rucaparib treatment groups with the Carboplatin-Paclitaxel-Bevacizumab control group in which a statistically significant result favoring treatment with Carboplatin- Paclitaxel-Bevacizumab-Rucaparib and Carboplatin-Paclitaxel-Rucaparib for PFS is demonstrated. The statistical test of the null hypothesis will be carried out using a one-sided level of significance for which the overall alpha type 1 error is ≤ 0.10.

9. MITO 25 Rationale for Number of Patients The study is dimensioned considering two parallel comparisons (Arm B vs Arm A and Arm C vs Arm A). For each comparison, considering a prolongation in term of PFS of 7 months expected with the experimental Arm (from 17 months to 24 months) corresponding to an HR of 0.71, 152 events are needed to perform the final analysis with an 80% power and a one-tailed alpha of 0.1. Overall, 357 patients will be randomized with a 1:1:1 ratio into one of the study arms.

10. MITO 25 Study Drug Study drug: Rucaparib 600 mg bid q 28 until progression or unacceptable toxicity; Bevacizumab 15 mg/kg q 21 for 22 months ; Carboplatin and Paclitaxel standard dose for 6 cycles. Reference Therapy: Carboplatin AUC 5 + Paclitaxel 175 mg/mq q 21 for 6 cycles + Bevacizumab 15 mg/kg q 21 for 22 cycles Dosage and Administration: Rucaparib 600 mg bid per os will be administered in a 28 days cycle until disease progression or unacceptable toxicity or patient refusal which ever occurs first up to 24 months

11. MITO 25 Administrative Information Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Planned study start: April 2016 HRD EVALUATION CENTRALIZED BY Clovis Assurance and Rucaparib provided To participate please contact: domenica.lorusso@istitutotumori.mi.it elisa.grassi@istitutotumori.mi.it