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

Phase 2

Completed

Conditions: Ovarian Neoplasms

Interventions: Drug: Niraparib
Biological: Bevacizumab

Registration Number: NCT03326193

Lead Sponsor: Tesaro, Inc.

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 105

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Participants receiving niraparib+ bevacizumab	Bevacizumab	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.
Participants receiving niraparib+ bevacizumab	Niraparib	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.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) Rate	At 18 months	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.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) by RECIST v 1.1	Up to end of study (approximately 79 months)	PFS was defined as the time from treatment initiation with niraparib combined with bevacizumab to the earlier date of assessment of progression, as assessed by RECIST v1.1 criteria, based on Investigator assessment, or death by any cause in the absence of progression.
Overall Survival (OS)	Up to end of study (approximately 79 months)	OS was defined as the date of initiation of niraparib treatment in combination with bevacizumab to the date of death by any cause.
RECIST or Cancer Antigen (CA)-125 Progression Free Survival	Up to end of study (approximately 79 months)	RECIST or CA-125 progression-free survival is defined as the time from initiation of niraparib treatment in combination with bevacizumab to the earliest date of progression assessed by RECIST v1.1 or CA-125 progression or death by any cause. CA-125 progression is defined as participants with elevated CA-125 pretreatment and normalization of CA-125 that must show evidence of CA-125 ≥ 2 × upper limit of normal (ULN) on 2 occasions at least 1 week apart OR elevated CA-125 pretreatment that never normalizes and must show evidence of CA-125 ≥ 2 × the nadir value on 2 occasions at least 1 week apart OR elevated CA-125 in the normal range pretreatment that must show evidence of CA-125 ≥ 2 × ULN on 2 occasions at least 1 week apart.
Change From Baseline (CFB) in Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI)	Baseline (Day 1), Cycles 3, 5, 7, 9, 13, 17, 21, 25, 29 (Each Cycle was of 21 days) and end of treatment (70 months)	FOSI is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants responded to their symptom experience over the past 7 days using a 5-point Likert scale scored from "not at all" (0) to "very much" (4). FOSI score was calculated as sum of item scores multiplied by 8 divided by number of items answered. The FOSI score ranged from 0 (severely symptomatic) to 32 (asymptomatic). A higher score indicated a better quality of life (QoL). Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Time to First Subsequent Therapy (TFST)	Up to end of study (approximately 79 months)	TFST was defined as the date of initiation of niraparib treatment in combination with bevacizumab treatment in the current study to the start date of the first subsequent anticancer therapy.
Time to Second Subsequent Therapy (TSST)	Up to end of study (approximately 79 months)	TSST was defined as the date of initiation of treatment of niraparib in combination with bevacizumab treatment in the current study to the start date of the second subsequent anticancer therapy.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), Non-serious TEAEs and Treatment-emergent Serious Adverse Events (TESAEs)	Up to end of treatment (70 months)	Adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. TEAEs is any AE that occurred for the first time after at least 1 dose of study treatment administration and until treatment duration. TEAEs which were not serious were considered as non-serious TEAEs. TESAE is defined as any untoward medical occurrence that, at any dose may result in death or is life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity or is congenital anomaly/birth defect or any other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system. Percentages are rounded off to the nearest decimal point.
Number of Participants With TEAEs Leading to Niraparib Treatment Discontinuation	Up to end of treatment (70 months)	AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. TEAE is any AE that occurred for the first time after at least 1 dose of study treatment administration. AEs were coded using the MedDRA coding system.
Number of Participants With TEAEs Leading to Niraparib Dose Reductions	Up to end of treatment (70 months)	AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. TEAE is any AE that occurred for the first time after at least 1 dose of study treatment administration. AEs were coded using the MedDRA coding system.
Number of Participants With AEs of Special Interest (AESI)	Up to end of treatment (70 months)	AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. AESIs of scientific and medical concern related to the treatment were monitored, and rapidly communicated by investigator to sponsor. AEs were coded using the MedDRA coding system.
Change From Baseline (CFB) in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Baseline (Day 1) and end of treatment (70 months)	Blood pressures (DBP and SBP) were measured after resting for at least 5 minutes in a supine or semi-recumbent position. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Pulse Rate	Baseline (Day 1) and end of treatment (70 months)	Pulse Rate was measured after resting for at least 5 minutes in a supine or semi-recumbent position. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Temperature	Baseline (Day 1) and end of treatment (70 months)	Temperature was measured after resting for at least 5 minutes in a supine or semi-recumbent position. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Number of Participants Who Used Concomitant Medications	Up to end of treatment (70 months)	Any permitted concomitant medication(s), including non-prescription medication(s) and herbal product(s), taken during the study were recorded.
Change From Baseline (CFB) in Hematology Parameters: Basophils, Eosinophil, Leukocytes, Platelets, Lymphocytes, Monocytes and Neutrophils	Baseline (Day 1) and end of treatment (70 months)	Blood samples were collected for the assessment of change from Baseline in hematology parameters. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Hematology Parameter: Hemoglobin (Hb)	Baseline (Day 1) and end of treatment (70 months)	Blood samples were collected for the assessment of change from Baseline in hematology parameter. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Hematology Parameter: Erythrocyte Mean Corpuscular Volume (MCV)	Baseline (Day 1) and end of treatment (70 months)	Blood samples were collected for the assessment of change from Baseline in hematology parameter. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Clinical Chemistry Parameters: Urea Nitrogen, Glucose, Calcium, Chloride, Sodium, Magnesium and Potassium	Baseline (Day 1) and end of treatment (70 months)	Blood samples were collected for the assessment of change from Baseline in clinical chemistry parameters. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Clinical Chemistry Parameters: Bilirubin and Creatinine	Baseline (Day 1) and end of treatment (70 months)	Blood samples were collected for the assessment of change from Baseline in clinical chemistry parameters. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Clinical Chemistry Parameters: Albumin and Protein	Baseline (Day 1) and end of treatment (70 months)	Blood samples were collected for the assessment of change from baseline in clinical chemistry parameters. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).
Change From Baseline (CFB) in Clinical Chemistry Parameters: Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)	Baseline (Day 1) and end of treatment (70 months)	Blood samples were collected for the assessment of change from baseline in clinical chemistry parameters. Baseline (Day 1) is defined as the most recent measurement prior to the first administration of study drug (including Cycle 1 Day 1).