Niraparib vs Niraparib Plus Bevacizumab in Patients With Platinum/Taxane-based Chemotherapy in Advanced Ovarian Cancer

Inclusion Criteria:

1. Signed written informed consent obtained prior to initiation of any study-specificprocedures and treatment as confirmation of the patient's awareness and willingnessto comply with the clinical trial requirements.

2. Female patients ≥ 18 years with histologically confirmed primary advanced invasivehigh grade non-mucinous, non-clear cell epithelial ovarian cancer, peritonealcancer, or fallopian tube cancer FIGO III/IV (except FIGO stage IIIA2 without nodalinvolvement) according to recent FIGO classification (= FIGO stage IIIB - IVaccording to FIGO 2009 classification).

3. All patients must have had either upfront primary debulking surgery OR plan toundergo chemotherapy with interval debulking surgery.

4. Patients must have available tumor samples to be sent to central laboratory asformalin-fixed, paraffin-embedded (FFPE) sample for determination of BRCA statusprior to randomization for stratification.

5. Patients must be able to commence systemic therapy within 8 weeks of cytoreductivesurgery.

6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

7. Estimated life expectancy > 3 months.

8. Adequate bone marrow function (within 28 days prior to day 1, cycle 1 and within 3days prior to day 1, cycle 2)

• Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L

• Platelets (PLT) ≥ 100 x 10^9/L

• Hemoglobin (Hb) ≥ 9 g/dL (can be post-transfusion)

9. Adequate coagulation parameters (within 28 days prior to day 1, cycle 1 and within 7days prior to day 1, cycle 2)

• Patients not receiving anticoagulant medication who have an InternationalNormalized Ratio (INR) ≤ 1.5 and an Activated ProThrombin Time (aPTT) ≤ 1.5 xinstitutional upper limit of normal (ULN).

• The use of full-dose oral or parenteral anticoagulants is permitted as long asthe INR or aPTT is within therapeutic limits (according to institution medicalstandard) and the patient has been on a stable dose of anticoagulants for atleast one week at the time of randomization.

10. Adequate liver and kidney function (within 28 days prior to day 1, cycle 1 andwithin 3 days prior to day 1, cycle 2)

• Total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in patients with known Gilbert'ssyndrome) OR direct bilirubin ≤ 1.0 x ULN.

• Aspartate aminotransferase / Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT) and Alanine aminotransferase / Serum Glutamic Pyruvate Transaminase (ALAT/SGPT) ≤ 2.5 x ULN, unless liver metastases are present, in case of livermetastases values must be ≤ 5 x ULN.

• Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24 hour urinemust demonstrate ≤ 1 g of protein in 24 hours.

• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 30 mL/min (see Appendix 2).

11. Patients must have normal blood pressure (BP) or adequately treated and controlledBP, with a systolic BP of ≤ 140 mmHg and diastolic BP of ≤ 90 mmHg for eligibility.Patients must have a BP of ≤ 140/90 mmHg taken in the clinic setting by a medicalprofessional within 4 weeks prior to day 1, cycle 1 and within 7 days prior to day 1, cycle 2.

12. Negative urine or serum pregnancy test within 7 days prior to day 1, cycle 1 inwomen of childbearing potential (WOCBP), confirmed prior to treatment on day 1.

13. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use a highly effective contraceptive method with afailure rate of < 1% per year during the treatment period and for at least 6 monthsafter administration of the last dose of medication. A woman is considered to be of childbearing potential if she is postmenarcheal, hasnot reached a postmenopausal state (≥ 12 continuous months of amenorrhea with noidentified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include butare not limited to bilateral tubal ligation and/or occlusion, male sterilization,and intrauterine devices. The reliability of sexual abstinence should be evaluatedin relation to the duration of the clinical trial and the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,symptothermal, or postovulation methods) and withdrawal are not acceptable methodsof contraception.

14. Willingness and ability to comply with scheduled visits, treatment plans, laboratorytests, and other clinical trial procedures, that include the completion ofpatient-reported outcomes questionnaires.

Exclusion Criteria:

1. Non-epithelial tumor origin of the ovary.

2. Ovarian tumors of low malignant potential (e.g. borderline tumors) and low gradetumors.

3. Planned intraperitoneal cytotoxic chemotherapy.

4. Malignancies other than ovarian cancer within 5 years prior to randomization, withthe exception of those with a negligible risk of metastasis or death (e.g., 5-yearOS rate > 90%) and treated with expected curative outcome (such as adequatelytreated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductalcarcinoma in situ of the breast, or stage I p53 wild type endometrial cancer).

5. Prior systemic treatment for ovarian cancer.

6. Prior treatment with Poly adenosine diphosphate ribose polymerase (PARP) inhibitor.

7. Administration of other simultaneous chemotherapy drugs, any other anticancertherapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during thetrial treatment period (hormonal replacement therapy is permitted).

8. Prior randomization in this trial.

9. Major surgery within 1 week of starting study treatment or patient who has notcompletely recovered from the effects of any major surgery. Core biopsy or otherminor surgical procedure within 7 days prior to day 1, cycle 1 is permitted.

10. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRIof the brain is mandatory (within 4 weeks prior to day 1, cycle 1) in case ofsuspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to day 1,cycle 1) in case of suspected spinal cord compression.

11. Significant traumatic injury during 4 weeks preceding the potential first dose ofbevacizumab.

12. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) orSub-Arachnoids Hemorrhage (SAH) within 6 months prior to day 1, cycle 1.

13. History or evidence of thrombotic or hemorrhagic disorders within 3 months prior today 1, cycle 1.

14. History or evidence upon neurological examination of central nervous system (CNS)disease, unless adequately treated with standard medical therapy e.g. uncontrolledseizures.

15. Pregnant or lactating women.

16. Treatment with any other investigational agent, or participation in another clinicaltrial testing a drug within 4 weeks or 5 times the half-life of the drug, whicheveris longer, prior to day 1, cycle 1 or concomitantly within this trial.

17. Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cellproducts or other recombinant human or humanized antibodies. Known hypersensitivityto niraparib, paclitaxel and carboplatin and its components or excipients.

18. Non-healing wound, active ulcer or bone fracture. Patients with granulatingincisions healing by secondary intention with no severe evidence of facialdehiscence or infection are eligible; regular wound examination will be performed.

19. Clinically significant cardiovascular disease, including

• Myocardial infarction or unstable angina within 6 months of day 1, cycle 1

• New York Heart Association (NYHA) Grade 2 Congestive Heart Failure (CHF),

• Poorly controlled cardiac arrhythmia despite medication (patients withrate-controlled atrial fibrillation are eligible)

• Grade ≥ 3 peripheral vascular disease (i.e. symptomatic and interfering withactivity of daily living (ADL) requiring repair or revision)

• Significant vascular disease including aortic aneurysm requiring surgicalrepair

20. Pre-existing sensory or motor neuropathy ≥ Grade 2.

21. (Intentionally left blank)

22. Patients with a history of or current Nephrotic syndrome.

23. Persistent cancer-related bowel obstruction (including subocclusive disease).Patients with a known history of ileus, who have been successfully treated and whoare free of symptoms, may be eligible after consultation of sponsor.

24. History of abdominal fistula or tracheoesophageal fistula or gastrointestinalperforation or active gastrointestinal bleeding or anastomotic insufficiency within 6 months of day 1, cycle 1.

25. Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of niraparib.

26. Evidence of any other disease, metabolic dysfunction, physical examination findingor laboratory finding giving reasonable suspicion of a disease or condition thatcontra-indicates the use of an investigational drug or puts the patient at high riskfor treatment-related complications.

27. Any known history or current diagnosis of myelodysplastic syndrome (MDS) or acutemyeloid leukemia (AML).

28. Previous allogeneic bone marrow transplant or previous solid organ transplantation.

29. Current or recent (within 10 days prior to day 1, cycle 1) chronic use of aspirin > 325 mg/day. Patients treated with other inhibitors of platelet aggregation such asclopidogrel, prasugrel, ticlopidine, tirofibane or dipyridamole should not beincluded into the trial.

30. Patients considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection. Thisincludes also any psychiatric disorder that prohibits obtaining informed consent.

31. Patient has known active hepatitis B or hepatitis C.

32. Patient has a history of Posterior Reversible Encephalopathy Syndrome (PRES).

33. Patients with chronic inflammatory bowel disease and active treatment for diseasecontrol.