Niraparib Versus Niraparib-bevacizumab Combination in Women With Platinum-sensitive Epithelial Ovarian Cancer

Part 1: This is a single-centre, phase 1a, open-label, dose-escalation study to evaluate the safety and tolerability of bevacizumab-niraparib combination and determine the RP2D in patients with platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The standard 3+3 design will be used. Part 2: (n=94) This multicenter, prospective, open-label, randomized phase 2 study is evaluating the efficacy of niraparib against niraparib-bevacizumab combination in Women with platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Stratification: Patients are stratified according to:

• HRD status (positive/negative)
• Treatment-Free interval to prior therapy (6-12 months > 12 months) Randomization: 1:1 randomization

Study arms: Patients are randomized to one of the two treatment arms:

Arm 1: Niraparib monotherapy until progression. Arm 2: Niraparib-bevacizumab combination therapy until progression.

Inclusion criteria

A patient will be eligible for inclusion only if all of the following criteria are fulfilled:

• Recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer (platinum sensitivity defined as no recurrence within 6 months of last receipt of platinum/chemotherapy).
• High-grade serious or high-grade endometrioid histology.
• Patient consents to perform HRD test.

• Patients with known BRCA status: BRCA positive patients must submit the tissue for HRD test, though these patients need not to wait for HRD test results and can be randomized in HRD positive stratum.
• If tumor tissue is not sufficient to perform HRD test: these patients shall be randomized in HRD negative stratum as HRD unknown.
• Prior line of therapy: Patients must have received platinum-containing therapy for primary disease.

• No limits on number of platinum-based therapies. Population of patients who has previously received ≥ 3 lines of therapy for relapsed disease will be capped at 40%.
• Up to one non-platinum-based line of therapy in recurrent setting.
• Patients who are treated with bevacizumab just prior to entering in the trial must not have progressed under or within 3 months after bevacizumab.
• Patients may have participated in a PARP inhibitor trial as first-line maintenance therapy and have not progressed within 3 months after PARP/placebo. Patients who received PARP inhibitor after relapse (definitive or maintenance therapy) are not eligible.
• Target group: Age 18+
• Histological confirmed ovarian, fallopian tube or peritoneal cancers
• Patients must give informed consent
• Patients may have undergone primary or interval debulking surgery
• Patients may have received bevacizumab though no other prior use of anti-angiogenic therapy
• Patients may have received a PARP inhibitor as first-line maintenance therapy.
• Patients must have disease that is measurable according to RECIST or assessable according to the GCIG criteria
• The patient agrees to complete PROs (QoL questionnaire) during study treatment AND at one additional time point 8 weeks following progression of disease
• ECOG performance status 0-2
• Adequate organ function

• Absolute neutrophil count (ANC) ≥1,5 x 109/L
• Platelets >100 x 109/L
• Hemoglobin ≥ 9g/dl
• Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥50mL/min using Cockcroft-Gault formula
• Total bilirubin ≤1.5x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN.
• Able to take oral medications
• Life expectancy of at least 12 weeks
• Patients must fulfill all inclusions criteria and according to investigator fit to receive niraparib and/or bevacizumab.
• Women of childbearing potential must use adequate birth control for the duration of study participation

Exclusion criteria

A patient will not be eligible for inclusion if any of the following criteria are fulfilled:

• Ovarian sarcomas, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancers and cancer types not mentioned in the inclusion criteria
• Concurrent cancer therapy
• Concurrent treatment with an investigational agent or participation in another clinical trial
• Major injuries or surgery within the past 21 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period
• Previous malignant disease: patients are not eligible for the study if diagnosis, detection or treatment of invasive cancer (other than ovarian cancer; with the exception of basal or squamous cell carcinoma of the skin that was definitively treated) was detected within 2 years prior to randomization
• Active infections or other serious underlying significant medical illness, abnormal laboratory finding or psychiatric illness/social situation that would, in the Investigator's judgment, makes the patient inappropriate for this study
• Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
• History of bowel obstruction, including sub-occlusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction
• Known contraindications to PARP inhibitors or VEGF directed therapy
• Known uncontrolled hypersensitivity to the investigational drugs
• History of major thromboembolic event defined as:

• Uncontrolled pulmonary embolism (PE)
• Deep venous thrombosis (DVT)
• Other related conditions, though patients with stable therapeutic anticoagulation for more than three months prior randomization are eligible for this study. This also apply to PE & DVT.
• History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 3 months
• History of clinically significant hemorrhage in the past 3 months
• Uncontrolled and/or symptomatic CNS metastasis or leptomeningeal carcinomatosis (Dexamethasone/prednisone therapy will be allowed if administered as stable dose for at least one month prior randomization)
• Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomization, congestive heart failure > NYHA III, severe peripheral vascular disease, QT prolongation >470 msec ,clinically significant pericardial effusion
• Pregnancy or breastfeeding. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards.
• Radiographic evidence of cavitation or necrotic tumors with invasion of adjacent major blood vessels
• Active or chronic hepatitis C and/or B infection
• Persistence of clinically relevant therapy related toxicity from previous chemotherapy
• Proteinuria as demonstrated by: (a) urine protein: creatinine (UPC) ratio >/= 1.0 at screening OR (b) urine dipstick for proteinuria >/=2+ (patients discovered to have >/=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hr urine collection and must demonstrate </=1g of protein in24 hours to be eligible
• Patients must not have any known history of MDS
• Patients must not have known persistent (> 4 weeks) ≥ Grade 2 hematological toxicity from prior cancer therapy
• Patients must not have known ≥ Grade 3 thrombocytopenia or anemia with the last chemotherapy regimen.