Summary
This trial is a randomized, open-label Phase I-2 multi-center study designed to evaluate the effect of Carboplatin-Paclitaxel-Bevacizumab (in combination and maintenance) vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib (Rucaparib only in maintenance) vs Carboplatin-Paclitaxel-Rucaparib (Rucaparib only in maintenance) on progression-free survival in patients with advanced high grade ovarian cancer treated according to HRD status . 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 in HRD negative (HR proficient) patients and that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib will improve PFS with respect to Carboplatin-Paclitaxel-Rucaparib in HRD positive patients. The randomized phase of the study will be preceded by a single arm Phase I study which will be conducted only in the National Cancer Institute of Milan, aiming at evaluating the MTD of the combination Rucaparib-Bevacizumab. Once the MTD has been reached, the randomized study will start.
Key Facts
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Inclusion Criteria: 1. Women aged \>=18 years at the time of study inclusion; 2. Patients with newly diagnosed, histologically confirmed, high grade serous, high grade endometrioid, FIGO stage IIIB-C-IV epithelial ovarian cancer, primary peritoneal cancer and / or Fallopian-tube cancer. Patients with mixed histology (carcinosarcoma) are eligible providing that high grade tumor represent more than 50% of the total histology. 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; 3. Archival tumor tissue available. At progression fresh biopsy is optional for patients willing to submit ; 4. ECOG Performance Status of 0-1; 5. Measurable and not measurable disease; 6. Adequate renal and hepatic function, defined as: * Total serum bilirubin ≤ 1.5 institutional ULN unless patient has Gilbert's syndrome in which case total serum bilirubin must be \<2 ULN for the institution AST and/or ALT ≤ 2.5 x ULN for the institution. (or ≤ 5 x ULN if liver metastases are present); * Alkaline phosphatase \< 1.5 x ULN for the institution (if \> 1.5 x ULN, then alkaline phosphatase liver fraction must be \< 1.5 ULN) * Serum creatinine ≤ 1.5 x ULN for the institution (or calculated creatinine clearance ≥ 45 mL/min/1.73 m2); 7. Adequate bone marrow function, defined as: * Total leukocytes 2.5 x 109/L; * ANC 1.5 x 109/L; * Platelet count 100 x 109/L; 8. Able to understand and give written informed consent; 9. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment. Exclusion Criteria: 1. Women who are pregnant or lactating; 2. Presence of brain or other central nervous system metastases, not adequately controlled by treatment; 3. Prior Anticancer treatment; 4. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 3 weeks prior to randomization; 5. Another primary malignancy except for: 1. Curatively treated non-melanoma skin cancer; 2. Breast cancer treated curatively ≥5 years ago, or other solid tumor treated curatively ≥5 years ago, without evidence of recurrence; 3. Synchronous endometrioid endometrial cancer (except for Stage 1A G1/G2); 6. Known active HIV, hepatitis B or C infection; 7. Concurrent treatment with immunosuppressive or investigational agents; 8. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or subarachnoid haemorrhage within \_6 months prior to the first study treatment); 9. Clinically significant (i.e. active) cardiovascular disease, including: * Myocardial infarction or unstable angina within \_6 months prior to the first study treatment; * New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF); * Serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia); * Peripheral vascular disease \> grade 3 (i.e.symptomatic and interfering with activities of daily living requiring repair or revision); 10. Serious active infection requiring i.v. antibiotics at enrolment; 11. Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products); 12. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications; 13. Prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with absorption of study drug; 14. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose of Rucaparib or have on-going requirements for these medications.