Patient case: 64-year-old female with ovarian cancer; genetic feature: BRCA1

Clinical trial: Trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib in Patients With Advanced (Stage III B-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer.

Summary: This trial is a randomized, open-label Phase II multi-center study designed to evaluate the effect of first line therapy 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.
  The randomized phase of the study will be preceded by a single arm Phase I study aiming at evaluating the MTD of the combination Rucaparib-Bevacizumab. Once the MTD has been reached the randomized study will start.

Detailed description: Phase I study design:
  This is a single-centre, Phase I, open-label, dose-escalation study to evaluate the safety and tolerability of bevacizumab-rucaparib combination and determine the MTD in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.
  The dose of bevacizumab is fixed in cohort 1, 2 and 3 of the study at 15mg/kg, q 3 weekly.
  The dose of rucaparib is evaluated in three cohorts (400 mg BID; 500 mg BID; 600 mg BID).
  This trial will enroll at least 3 patients in cohort 1 with dose escalation to rucaparib 500 mg from cohort 1 to 2. Cohort 2 will enroll at least 3 patients with dose escalation to rucaparib 600 mg from cohort 2 to 3.
  The standard 3+3 design will be used. Patients will be enrolled in cohort of 3 patients, if no DLT event will be reported among the first 3 patients, a second cohort will be enrolled at the upper dose level. If 1 DLT event is registered in the first cohort, other 3 patients will be enrolled at the same dose.
  Phase II study design:
  Eligible patients will be randomized 1:1:1 to receive Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel- Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib in the following treatment arms:
  -  ARM A: Carboplatin AUC 5 + Paclitaxel 175 mg/mq d 1 q 21 for 6 cycles + Bevacizumab 15 mg/kg d 1 q 21 days for 22 cycles (in combination and maintenance);
  -  ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/mq d1 q 21 days for 6 cycles + Bevacizumab 15 mg/kg d1 q 21 for 22 cycles (in combination and maintenance) + Rucaparib at the dose defined by the Phase I study continuously for 2 years (Rucaparib only in maintenance);
  -  ARM C: Carboplatin AUC 5 + Paclitaxel 175 mg/mq d1 q 21 days for 6 cycles + Rucaparib 600 mg BID continuously for 2 years (Rucaparib only as maintenance).
  Randomization to study treatment will be performed within 28 days following surgery.
  Study treatment must be initiated within 4 days of randomization so chemotherapy treatment will be initiated within 32 days from previous surgery.

Eligibility: 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, clear cell 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; other histotypes may be enrolled providing BRCA mutation is present.
  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.

Relevance to patient case: definitely relevant