Carboplatin-Paclitaxel-Bevacizumab vs Carbo-Pacli-Beva-Rucaparib vs Carbo-Pacli-Ruca, Selected According to HRD Status, in Patients With Advanced Ovarian, Primary Peritoneal and Fallopian Tube Cancer, Preceded by a Phase I Dose Escalation Study on Ruca-Beva Combination

Study Overview
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Brief Summary
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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.

Detailed Description
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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 with histological documented high grade Stage IIIB-IIIC-IV ovarian cancer (regardless of residual tumor) will be randomized 1:1:1 according to a molecular driven treatment. HRD positive patients: ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance ARM C: Carboplatin AUC 5+ Paclitaxel 175 mg/m2 q 21 + Bevacizumab 15 mg/kg for 6 cycles followed by Bevacizumab 15 mg/kg q 21 days for 16 cycles (Bevacizumab will start from Cycle 2) + Rucaparib 500 mg part BID q 28 for 24 cycles as maintenance HRD negative patients: ARM A: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 + Bevacizumab 15 mg/kg for 6 cycles followed by Bevacizumab 15 mg/kg q 21 for 16 cycles (Bevacizumab will start from Cycle 2) ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance Stratification factors are: Residual tumor at primary surgery (RT=0 vs RT> 0) Neoadiuvant chemotherapy (Yes or not)

Official Title
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A Randomized, Molecular Driven Phase II Trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib, Selected According to HRD Status, in Patients With Advanced (Stage III B-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer Preceded by a Phase I Dose Escalation Study on Rucaparib-Bevacizumab Combination

Conditions
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Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Bevacizumab
* Drug: Rucaparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged >=18 years at the time of study inclusion; 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; Archival 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; 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); 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; 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. Exclusion Criteria: Women who are pregnant or lactating; Presence of brain or other central nervous system metastases, not adequately controlled by treatment; Prior Anticancer treatment; Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 3 weeks prior to randomization; Another primary malignancy except for: Curatively treated non-melanoma skin cancer; Breast cancer treated curatively ≥5 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; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or subarachnoid haemorrhage within _6 months prior to the first study treatment); 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); Serious active infection requiring i.v. antibiotics at enrolment; Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products); 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; 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard treatment<br>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) | Drug: Carboplatin<br>* chemotherapy medication<br>Drug: Paclitaxel<br>* chemotherapy medication<br>Drug: Bevacizumab<br>* Angiogenesis inhibitor<br>|
| Experimental: Carboplatin + Paclitaxel + Bevacizumab + Rucaparib<br>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) | Drug: Carboplatin<br>* chemotherapy medication<br>Drug: Paclitaxel<br>* chemotherapy medication<br>Drug: Bevacizumab<br>* Angiogenesis inhibitor<br>Drug: Rucaparib<br>* PARP inhibitor<br>|
| Experimental: Carboplatin + Paclitaxel + Rucaparib<br>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). | Drug: Carboplatin<br>* chemotherapy medication<br>Drug: Paclitaxel<br>* chemotherapy medication<br>Drug: Rucaparib<br>* PARP inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I Primary Objective: MTD | To identify the Maximum Tolerated Dose (MTD) of the combination Rucaparib-Bevacizumab in stage IIIB-C-IV ovarian cancer patients | 4 months | 
| Phase II Primary Objective: PFS | To compare progression-free survival (PFS) of patients with advanced ovarian, primary peritoneal and Fallopian tube cancer when treated with Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs carboplatin-Paclitaxel-Rucaparib according to Homologous Recombination Deficient (HRD) status. | from the date of randomization to the date of documented progression disease, recurrence or death (whichever occurs first), assessed up to 64 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I Secondary Objectives: toxicity of the Rucaparib-Bevacizumab combination in terms of haematologic and non haematologic events | Toxicity will be evaluated according to U.S. NCI Common Toxicity Criteria version 4.03 | 4 months | 
| Phase I Secondary Objectives: maximum plasma concentration (Cmax at Steady State) of Rucaparib | The evaluation of the effect of bevacizumab on rucaparib Cmax at SS will be performed by comparing (in each individual patient) the Cmax during cycle 1, on days 1 and 21, with the Cmax obtained on day -7 in which only Rucaparib will be administered. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on days -7,1,21 | 
| Phase I Secondary Objectives: minimal plasma concentration (Cmin at Steady State) of Rucaparib | The evaluation of the effect of bevacizumab on rucaparib Cmin at SS will be performed by comparing (in each individual patient) the Cmin during cycle 1, on days 1 and 21, with the Cmax obtained on day -7 in which only Rucaparib will be administered. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on days -7,1,21 | 
| Phase I Secondary Objectives: Area Under Curve (AUC) | The evaluation of the effect of bevacizumab on rucaparib AUC will be performed by comparing (in each individual patient) during cycle 1, on days 1 and 21, rucaparib AUC with AUC obtained on day -7 in which only Rucaparib will be administered. For this parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on days -7,1,21 | 
| Phase I Secondary Objectives: Cmax | The evaluation of the effect of bevacizumab on rucaparib Cmax will be performed by measuring the maximum seric concentration of drug. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on day1 | 
| Phase I Secondary Objectives: Tmax | The evaluation of the effect of bevacizumab on rucaparib will be performed by measuring the amount of time that the drug is present at the maximum concentration in serum. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on day1 | 
| Phase I Secondary Objectives: AUC (0-24h) | The evaluation of the effect of bevacizumab on rucaparib will be performed by measuring the AUC during 24 h. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on day1 | 
| Phase II Secondary Objectives: OS | Overall survival | from the date of randomization to the date of death, assessed up to 64 months | 
| Phase II Secondary Objectives: PFS2 | Progression-free survival 2 | from randomisation to second objective disease progression or death, assessed up to 64 months | 
| Phase II Secondary Objectives: TFST | Time to first subsequent therapy | from randomisation to the initiation of first subsequent therapy or death of patients, assessed up to 64 months | 
| Phase II Secondary Objectives: TSST | Time to second subsequent therapy | from randomisation to the initiation of second subsequent therapy or death, assessed up to 64 months | 
| Phase II Secondary Objectives: ORR | Overall response rate | 64 months | 
| Phase II Secondary Objectives: Safety and tolerability | Safety and tolerability will be evaluated by U.S. National Cancer Institute Common Toxicity Criteria Adverse Event (NCI CTCAE) version 4.03 and the number of dose reductions | 64 months | 
| Phase II Secondary Objectives: PRO for PHYSICAL WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months | 
| Phase II Secondary Objectives: PRO for SOCIAL/FAMILY WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months | 
| Phase II Secondary Objectives: PRO for EMOTIONAL WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months | 
| Phase II Secondary Objectives: PRO for FUNCTIONAL WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months |