Phase 2, A Study of Niraparib Combined With Bevacizumab Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy
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This is a Phase 2, open-label, single arm study to evaluate progression free survival rate at 18 months as well as evaluating the safety and efficacy of niraparib in combination with bevacizumab as maintenance therapy in patients with advanced ovarian cancer patients who have received prior front-line therapy with platinum-based chemotherapy in combination with bevacizumab and who have had at least one prior attempt at debulking surgery. Niraparib is an orally active poly adenosine diphosphate-ribose (PARP) inhibitor. Niraparib will be administered by mouth once daily continuously during a 21-day cycle. Bevacizumab will be administered intravenously D1 of each 21-day cycle for up to 15 mos, including the duration of the front-line therapy. Health-related quality of life will be measured by Eastern Cooperative Oncology Group performance status (ECOG). Safety and tolerability will be assessed by clinical review of adverse events (AEs), physical examinations, electrocardiograms (ECGs), RECIST tumor assessments and safety laboratory values.
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
Actual Study Start Date :
January 9, 2018
Estimated Primary Completion Date :
December 30, 2020
Estimated Study Completion Date :
September 30, 2021
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Assessment of Efficacy [ Time Frame: 18 months after last patient enrolled (approximately 24 months) ]
to evaluate the efficacy of niraparib in combination with bevacizumab in patients with Stage IIIB to IV ovarian cancer who have Complete Response (CR), Partial Response (PR), or no evidence of disease (NED) following front-line, platinum-based chemotherapy with bevacizumab. The primary efficacy endpoint is the progression free survival (PFS) rate at 18 months (PFS18), which is defined as the proportion of patients who have not progressed or died within 18 months after niraparib combined with bevacizumab treatment initiation. Progression will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria per Investigator assessment.
Secondary Outcome Measures :
Clinical Benefit - Progression Free Survival (PFS) by RECIST v 1.1 [ Time Frame: Approximately 24 months ]
PFS is assessed as the time from niraparib combined with bevacizumab treatment initiation 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.
Clinical Benefit - Overall Survival (OS) by patient assessment [ Time Frame: Approximately 24 months ]
OS is defined as the date of initiation of niraparib treatment in combination with bevacizumab to the date of death by any cause.
Clinical Benefit - RECIST or CA-125 PFS by RECIST v .1.1 or CA-125 measurement using Gynecologic Cancer Intergroup (GCIG) criteria. [ Time Frame: Approximately 24 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. Progressive Disease (PD) will not be diagnosed in case of CA-125 progression in the absence of radiologic evidence of progressive disease.
Clinical Benefit - Patient Reported Outcome (PRO) - Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI) [ Time Frame: Approximately 24 months ]
The FOSI is a validated 8-item measure of symptom response to treatment for ovarian cancer.16 Patients respond 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). The average score is calculated as an average of the 8 items. The total symptom index is calculated as the total of the 8 symptoms.
PROs will be collected every 6 weeks (± 7 days) for 6 months, then every 12 weeks (± 7 days) thereafter while the patient is receiving study treatment. Once a patient discontinues treatment, PRO evaluations will be performed 4 weeks, 8 weeks, 12 weeks, and 24 weeks after treatment discontinuation, regardless of subsequent treatment.
Clinical Benefit - Time to First Subsequent Therapy (TFST) [ Time Frame: Approximately 24 months ]
TFST is 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.
Clinical Benefit - Time to Second Subsequent Therapy (TSST) [ Time Frame: Approximately 24 months ]
TSST is 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.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Approximately 24 months ]
The safety and tolerability of niraparib in combination with bevacizumab will be analyzed based on the incidence of treatment emergent adverse events (TEAEs) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03, serious adverse events (SAEs), changes in Eastern Cooperative Oncology Group (ECOG) performance status, changes in clinical laboratory results (hematology and chemistry), vital sign measurements, observations during physical examination, and use of concomitant medications.
Other Outcome Measures:
6 month PFS - RECIST v 1.1 [ Time Frame: 6 months after last patient enrolled (approximately 12 months) ]
Defined as the proportion of patients who have not progressed or died within 6 months after initiation of treatment of niraparib in combination with bevacizumab treatment, respectively. Progression will be assessed by RECIST v1.1 criteria based on Investigator assessment.
12 month PFS - RECIST v 1.1 [ Time Frame: 12 months after last patient enrolled (approximately 18 months) ]
Defined as the proportion of patients who have not progressed or died within 12 months after initiation of treatment of niraparib in combination with bevacizumab treatment, respectively. Progression will be assessed by RECIST v1.1 criteria based on Investigator assessment.
Retrospective biomarker (HRD) analysis [ Time Frame: Approximately 18 months ]
HRD will be evaluated retrospectively as a potential biomarker for response to niraparib combined with bevacizumab maintenance treatment using archival tumor sample. For patients who do not have archival tissue, tissue from a fresh biopsy must be obtained prior to study treatment initiation.
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Ages Eligible for Study:
18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:
Gender Based Eligibility:
Accepts Healthy Volunteers:
Patients must be female, be ≥ 18 years of age, be able to understand the study procedures, and agree to participate in the study by providing written informed consent.
Patients 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.
Patients must have high-grade serous or endometrioid or high-grade predominantly serous or endometrioid histology, regardless of HRD or germline breast cancer susceptibility gene (gBRCA) mutation status. Patients with non mucinous epithelial ovarian cancer and gBRCA mutation are eligible.
Patients 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 platinum-based regimen must have consisted of a minimum of 6 and a maximum of 9 treatment cycles. Patients 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.
IV, intraperitoneal, or neoadjuvant platinum-based chemotherapy is allowed; for weekly therapy, 3 weeks is considered 1 cycle. Interval debulking is allowed.
Patients must have received, prior to enrollment, a minimum of 3 cycles of bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy. Patients 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.
Patients must have had 1 attempt at optimal debulking surgery.
Patients 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).
Patients must have adequate organ function, defined as (Note: Complete Blood Count (CBC) test should be obtained without transfusion or receipt of stimulating factors within 2 weeks before obtaining screening blood sample):
Absolute neutrophil count (ANC) ≥ 1,500/µL
Platelet count ≥ 100,000/µL
Hemoglobin ≥ 9 g/dL
Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation
Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ 1 × ULN
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN unless liver metastases are present, in which case they must be ≤ 5 × ULN
Patients must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
Patients must have normal blood pressure or well-controlled hypertension.
Patient must agree to complete PROs (quality of life [QoL] questionnaire) throughout the study, including after study treatment discontinuation.
Patients must be able to take oral medication.
Patient must agree to undergo tumor HRD testing at screening. The tumor sample must be submitted for HRD testing during the Screening Period. Patients do not have to wait for the HRD test result to be enrolled. If archival tumor tissue is not available for testing, the patient must agree to undergo a fresh biopsy.
Patients 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.
Patients 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 through180 days after the last dose of study treatment.
Patients with ovarian tumors of non-epithelial origin (eg, germ cell tumor) or any low grade tumors.
Patients 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).
Patients 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.
Patient has proteinuria as demonstrated by urine protein:creatinine ratio ≥ 1.0 at screening or urine dipstick for proteinuria ≥ 2 (patients discovered to have ≥ 2 proteinuria on dipstick at baseline should undergo a 24-hour urine collection and must demonstrate < 2 g of protein in 24 hours to be eligible).
Patient has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML).
Patient has received treatment previously with a PARP inhibitor.
Other than ovarian cancer, the patient has been diagnosed or treated for invasive cancer less than 5 years prior to study enrollment. Patients with cervical carcinoma in situ, non melanomatous skin cancer, and ductal carcinoma in situ definitively treated are allowed.
Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease, or active, uncontrolled infection.
Patient has known contraindication to PARP inhibitors or vascular endothelial growth factor (VEGF) inhibitors.
Patient 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).
Patient is immunocompromised (patients with splenectomy are allowed).
Patient has known, active hepatic disease (ie, hepatitis B or C).
Patient has a QT interval prolongation > 480 ms at screening. If a patient has a prolonged QT interval and the prolongation is deemed to be due to a pacemaker upon Investigator evaluation (ie, the patient otherwise has no cardiac abnormalities), then the patient may be eligible to participate in the study following discussion with the Medical Monitor.
Patient is pregnant, breastfeeding, or expecting to conceive children while receiving study drug or for 180 days after the last dose of study drug.