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Part 1 (Phase 1): safety and tolerability of bevacizumab-Niraparib combination Part 2 (Randomized Phase 2): to compare Progression-Free Survival (PFS)
PARP inhibitors are active as monotherapy to treat patients with recurrent ovarian cancer; the strongest activity being observed in the platinum sensitive, gBRCAmut subgroup as well as in gBRCAwt, HRD population but also in HRD negative disease.
In the same population there is level one evidence that bevacizumab is beneficial. And a phase two randomized study has indicated that combination of a PARP inhibitor with anti-angiogenic drug is superior to PARP inhibitor alone.
The question is:
Is niraparib combined with bevacizumab superior to niraparib? The comparison of tolerability and efficacy of niraparib-bevacizumab combination against niraparib.
Full description
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:
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.
Enrollment
Sex
Ages
Volunteers
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.
Prior line of therapy: Patients must have received platinum-containing therapy for primary disease.
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
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:
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.
Primary purpose
Allocation
Interventional model
Masking
108 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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