A Study of Niraparib Combined With Bevacizumab Maintenance Treatment in Participants With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy

Study Overview
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Brief Summary
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Niraparib is an oral inhibitor of poly adenosine diphosphate-ribose polymerase (PARP)-1 and PARP-2. This study will evaluate safety and efficacy of niraparib combined with bevacizumab as maintenance treatment in participants with advanced (stage IIIB-IV) ovarian cancer, fallopian tube cancer, or primary peritoneal cancer following front-line platinum-based chemotherapy with bevacizumab. Eligible participants who achieve complete response (CR), partial response (PR), or no evidence of disease (NED) following treatment with platinum-based chemotherapy in addition to bevacizumab will be enrolled in the study and will receive maintenance treatment with niraparib (for up to 3 years) combined with bevacizumab (for up to 10 months during the maintenance phase or up to a total of 15 months inclusive of the approximately 5 months of bevacizumab received with chemotherapy) or until disease progression, unacceptable toxicity, participant withdrawal, Investigator's decision, or death, whichever comes first. Participants who have not progressed after 3 years of niraparib maintenance treatment may continue with niraparib beyond 3 years if they are benefiting from treatment, upon consultation with Sponsor.

Official Title
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A Phase 2, Single-arm, Open-label Study to Evaluate the Safety and Efficacy of Niraparib Combined With Bevacizumab as Maintenance Treatment in Patients With Advanced Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Following Front-line Platinum-based Chemotherapy With Bevacizumab

Conditions
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Ovarian Neoplasms

Intervention / Treatment
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* Drug: Niraparib
* Biological: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be female, be greater than equal to (>=) 18 years of age, be able to understand the study procedures, and agree to participate in the study by providing written informed consent. Participants must have newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) Stage IIIB to IV epithelial ovarian, fallopian tube, or peritoneal cancer and have recovered from debulking surgery. Participants must have high-grade serous or endometrioid or high-grade predominantly serous or endometrioid histology, regardless of homologous recombination deficiency (HRD) or germline breast cancer susceptibility gene (gBRCA) mutation status. Participants with non mucinous epithelial ovarian cancer and gBRCA mutation are eligible. Participants must have completed front-line, platinum-based chemotherapy with CR, PR, or NED and have first study treatment dose within 12 weeks of the first day of the last cycle of chemotherapy: a. A platinum-based regimen must have consisted of a minimum of 6 and a maximum of 9 treatment cycles. Participants who discontinued platinum-based therapy early as a result of non hematologic toxicity specifically related to the platinum regimen (ie, neurotoxicity or hypersensitivity) are eligible if they have received a minimum of 4 cycles of the platinum regimen. b. IV, intraperitoneal, or neoadjuvant platinum-based chemotherapy is allowed; for weekly therapy, 3 weeks is considered 1 cycle. Interval debulking is allowed. Participants must have received, prior to enrollment, a minimum of 3 cycles of bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy. Participants who undergo interval debulking surgery are eligible if they have received only 2 cycles of bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy. Participant must have had 1 attempt at optimal debulking surgery. Participant must have either CA-125 in the normal range or CA-125 decrease by more than 90% during front-line therapy that is stable for at least 7 days (ie, no increase > 15% from nadir). Participant must have adequate organ function. Participant must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. Participant must have normal blood pressure or well-controlled hypertension. Participant must agree to complete patient-reported outcome (PROs) (Functional Assessment of Cancer Therapy-Ovarian Symptom Index [FOSI] questionnaire) throughout the study, including after study treatment discontinuation. Participant must be able to take oral medication. Participant must agree to undergo tumor HRD testing at screening. The tumor sample must be confirmed to be available during the screening period and submitted after the participant has been enrolled. Participants do not have to wait for the HRD test result to be enrolled. If archival tumor tissue is not available for testing, the participant must agree to undergo a fresh biopsy. Participant of childbearing potential must have a negative serum or urine pregnancy test (beta human chorionic gonadotropin) within 72 hours prior to receiving the first dose of study treatment. Participants must be postmenopausal, free from menses for > 1 year, surgically sterilized, or willing to use adequate contraception to prevent pregnancy or must agree to abstain from activities that could result in pregnancy throughout the study, starting with enrollment through 180 days after the last dose of study treatment. Exclusion Criteria: Participants with ovarian tumors of non-epithelial origin (eg, germ cell tumor) or any low grade tumors. Participants with clinically significant cardiovascular disease (eg, significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia or unstable angina < 6 months to enrollment, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade II or greater peripheral vascular disease, and history of cerebrovascular accident (CVA) within 6 months). Participants with gastrointestinal disorders or abnormalities that would interfere with absorption of study treatment. History of bowel obstruction, including sub-occlusive disease, related to the underlying disease or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesses. Evidence of rectosigmoid involvement by pelvic examination or bowel involvement on computed tomography (CT) scan or clinical symptoms of bowel obstruction. Participant has proteinuria as demonstrated by urine protein:creatinine ratio >= 1.0 at screening or urine dipstick for proteinuria ≥ 2 (participants discovered to have >=2 proteinuria on dipstick at baseline should undergo a 24-hour urine collection and must demonstrate < 2 gram (g) of protein in 24 hours to be eligible). Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Participant has received treatment previously with a PARP inhibitor. Other than ovarian cancer, the participant has been diagnosed or treated for invasive cancer less than 5 years prior to study enrollment. Participants with cervical carcinoma in situ, non melanomatous skin cancer, and ductal carcinoma in situ definitively treated are allowed. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease, or active, uncontrolled infection. Participant has known contraindication to PARP inhibitors or (VEGF inhibitors. Participant is at increased bleeding risk due to concurrent conditions (eg, major injuries or surgery within the past 28 days prior to start of study treatment, history of CVA, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months). Participant is immunocompromised (participants with splenectomy are allowed). Participant has known, active hepatic disease (ie, hepatitis B or C). Participant has a QT interval prolongation > 480 milliseconds (ms) at screening. If a participant has a prolonged QT interval and the prolongation is deemed to be due to a pacemaker upon Investigator evaluation (ie, the participant otherwise has no cardiac abnormalities), then the participant may be eligible to participate in the study following discussion with the Medical Monitor. Participant is pregnant, or expecting to conceive children while receiving study drug or for 180 days after the last dose of study drug ; additionally, female participant should not breastfeed during treatment with niraparib and for 30 days after receipt of the last dose due to the potential for serious adverse reactions from niraparib in breastfed infants

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving niraparib+ bevacizumab<br>Participants will be administered bevacizumab 15 milligram per kilogram (mg/kg) via a 30 minute (min) intravenous (IV) infusion on Day 1 of each 21-day cycle. Niraparib will be administered orally once a day continuously throughout each 21-day cycle (84-day cycle after amendment 2). On Day 1 of each cycle, niraparib will be administered upon completion of bevacizumab infusion. The starting dose of niraparib will be based on the participant's Baseline actual body weight or platelet count. | Drug: Niraparib<br>* Niraparib will be administered orally once a day continuously throughout each 21 day cycle (84-day cycle after amendment 2). The starting dose of niraparib will be based on the participant's Baseline actual body weight or platelet count. Participants with a Baseline actual body weight of greater than equal to (>=) 77 kg and Baseline platelet count of >=150,000/ microliter (μL) will take 300 mg/day (3X100mg) at each dose administration. Participants with a Baseline actual body weight of less than (<) 77 kg and/or Baseline platelet count of <150,000/μL will take 200 mg (2X100 mg) at each dose administration.<br>* Other names: ZEJULA;Biological: Bevacizumab<br>* Maintenance bevacizumab 15 mg/kg will be administered via a 30-minute IV infusion on Day 1 of every 21-day cycle in the absence of progressive disease (PD), unacceptable toxicity, participant withdrawal, Investigator's decision, or death. Bevacizumab will be administered for up to 10 months during the maintenance phase or up to a total of 15 months inclusive of approximately 5 months of bevacizumab received with chemotherapy.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Rate | PFS rate at 18 months is defined as the percentage of participants who have not progressed or died within 18 months after niraparib combined with bevacizumab treatment initiation. Progression was assessed by response evaluation criteria in solid tumors (RECIST) version (v) 1.1 criteria per Investigator assessment and defined as a 20 percent (%) increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions. Survival rate is the percentage of participants without progression assessed by RECIST v1.1 or death by the landmark timepoint. Confidence intervals was constructed using exact method. | At 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival by RECIST v 1.1 | Data is not reported as participants response is still ongoing at the time of primary analysis. | Up to 3 years | 
| Overall Survival (OS) | Data is not reported as participants response is still ongoing at the time of primary analysis. | Up to 3 years | 
| RECIST or Cancer Antigen (CA)-125 Progression Free Survival | Data is not reported as participants response is still ongoing at the time of primary analysis. | Up to 3 years | 
| Change From Baseline in Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) | Data is not reported as participants response is still ongoing at the time of primary analysis. | Baseline and up to 3 years | 
| Time to First Subsequent Therapy (TFST) | Data is not reported as participants response is still ongoing at the time of primary analysis. | Up to 3 years | 
| Time to Second Subsequent Therapy (TSST) | Data is not reported as participants response is still ongoing at the time of primary analysis. | Up to 3 years | 
| Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) | TEAE is defined as any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Number of participants with non-serious TEAEs with 5% threshold are reported. | Up to a maximum of 33.68 months | 
| Number of Participants With TEAEs Leading to Niraparib Treatment Discontinuation | TEAE is defined as any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Number of participants with TEAEs leading to Niraparib treatment discontinuation are reported. | Up to a maximum of 33.68 months | 
| Number of Participants With TEAEs Leading to Niraparib Dose Reductions | TEAE is defined as any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Number of participants with TEAES leading to Niraparib dose reductions are reported. | Up to a maximum of 33.68 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, Ovarian Cancer, Primary Peritoneal carcinoma, Fallopian Tube, Vascular endothelial growth factor (VEGF) inhibitor, Bevacizumab, Niraparib