Niraparib with BeVAcizumab After Complete CytoreductioN in Patients with OvArian Cancer

Inclusion Criteria:

For inclusion in the study, patient should fulfill the following criteria:

1. Female patient ≥ 18 years of age.

2. Signed informed consent and ability to comply with treatment and follow-up.

3. Patient with newly diagnosed, a. Ovarian cancer, primary peritoneal cancer and/orfallopian-tube cancer, b. Histologically confirmed (based on local histopathologicalfindings):

• high grade serous or

• high grade endometrioid (grade 2 and 3) or

• other epithelial non mucinous and non-clear cell ovarian cancer in a patientwith germline BRCA 1 or 2 deleterious mutation, c. At an advanced stage: FIGOstage IIIA to IIIC of the 2018 FIGO classification.

4. Patient having undergone frontline, complete cytoreductive surgery (i.e. no visibleresidual disease): The patient will be considered eligible once the ESGO QualityAssurance in Ovarian Cancer Surgery will have been filled out and validated

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

6. Patient must have received one cycle of carboplatin AUC 5-6 + paclitaxel 175 mg/m²

7. Patient must have started cycle 1 chemotherapy no later than 6 weeks after surgery.

8. Patient must have a thorax-abdomen-pelvis CT scan between surgery and Cycle 1, withno evidence of disease.

9. Patient eligible for first line platinum-taxane chemotherapy:

10. Patient eligible for bevacizumab treatment in combination with chemotherapy and inmaintenance. It must be started at the second chemotherapy cycle and be administeredat a dose of 15mg/kg every 3 weeks up to a total of 15 months.

11. Patient must have normal organ and bone marrow function before first cycle ofchemotherapy:

• Hemoglobin ≥ 9.0 g/dL.

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.

• Platelet count ≥ 100 x 109/L.

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).

• Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT))and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x ULN.

• Serum creatinine ≤ 1. 5 x institutional ULN and GFR > 50 mL/min, by using anexact measure (ie. Iohexol clearance) or the most appropriate formula (Jeliffe,Cockroft Gault, MDRD, CKD-EPI) to the investigator's discretion.

• Patient not receiving anticoagulant medication who has an InternationalNormalized Ratio (INR) ≥1.5 and an Activated ProThrombin Time (aPTT) ≥1.5 xULN. The use of full-dose oral or parenteral anticoagulants is permitted as long as theINR or APTT is within therapeutic limits (according to site medical standard). Ifthe patient is on oral anticoagulants, dose has to be stable for at least two weeksat the time of randomization.

12. Urine dipstick for proteinuria < 2+. If urine dipstick is ≥2+, 24-hour proteinuriamust be <1 g.

13. Normal blood pressure or adequately treated and controlled hypertension (systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).

14. Formalin fixed paraffin embedded (FFPE) tumor sample from the primary cancer must beavailable for local BRCA testing and if possible HRD testing (optional).

15. For countries where this will apply to: a subject will be eligible for randomizationin this study only if either affiliated to, or a beneficiary of a social securitycategory.

Exclusion Criteria:

1. Patient with clear cell adenocarcinoma or carcinosarcoma, non-epithelial originof the ovarian tumor, the fallopian tube or the peritoneal tumor (i.e. germcell tumors).

2. Ovarian tumor of low malignant potential (e.g. borderline tumor), or mucinouscarcinoma.

3. Patient with a diagnosis, detection, or treatment of another type of cancer ≤ 3years prior to initiating protocol therapy (except basal or squamous cellcarcinoma of the skin and cervical cancer in situ that has been definitivelytreated and synchronous grade 1 stage 1 endometrial cancer) Patient withhistory of primary triple negative breast cancer may be eligible provided shecompleted her definitive anticancer treatment more than 3 years ago and sheremains breast cancer disease free prior to start of study treatment.

4. Patient with synchronous high grade serous or clear cell adenocarcinoma orcarcinosarcoma of the endometrium is not eligible.

5. Patient with myelodysplastic syndrome/acute myeloid leukemia history. 6.Patient receiving radiotherapy within 6 weeks prior to study treatment. 7.Previous allogenic bone marrow transplant. 8. Any previous treatment with PARPinhibitor. 9. Administration of other simultaneous chemotherapy drugs - exceptduring a HIPEC procedure with cisplatin at PDS, any other anticancer therapy oranti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trialtreatment period (hormonal replacement therapy is permitted as are steroidantiemetics).

6. Current or recent (within 10 days prior to randomization) chronic use ofaspirin > 325 mg/day.

7. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensiveencephalopathy.

8. Clinically significant (e.g. active) cardiovascular disease, including:

• Myocardial infarction or unstable angina within ≤ 6 months of randomization,

• New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF),

• Poorly controlled cardiac arrhythmia despite medication (patient with ratecontrolled atrial fibrillation are eligible), or any clinically significantabnormal finding on resting ECG.

• Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering withactivities of daily living [ADL] requiring repair or revision).

13. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA),Sub- Arachnoids Hemorrhage (SAH) or Posterior Reversible EncephalopathySyndrome (PRES).
14. History or evidence of hemorrhagic disorders. 15. Evidence of bleedingdiathesis or significant coagulopathy (in the absence of coagulation).
15. History or clinical suspicion of brain metastases or spinal cordcompression. CT/MRI of the brain is mandatory (within 4 weeks prior torandomization) in case of suspected brain metastases. Spinal MRI ismandatory (within 4 weeks prior to randomization) in case of suspectedspinal cord compression.
16. History or evidence upon neurological examination of central nervoussystem (CNS) disease, unless adequately treated with standard medicaltherapy (e.g. uncontrolled seizures).
17. Significant traumatic injury during 4 weeks prior to randomization. 19.Non-healing wound, active ulcer, or bone fracture. Patient withgranulating incisions healing by secondary intention with no evidence offacial dehiscence or infection is eligible but require 3 weekly woundexaminations.
18. History of VEGF therapy related abdominal fistula or gastrointestinalperforation or active gastrointestinal bleeding within 6 months prior tothe first study treatment.
19. Current, clinically relevant bowel obstruction, including sub-occlusivedisease, related to underlying disease.
20. Patient with evidence of abdominal free air not explained by paracentesisor recent surgical procedure.
21. Evidence of any other disease, metabolic dysfunction, physical examinationfinding or laboratory finding giving reasonable suspicion of a disease orcondition that contraindicates the use of an investigational drug or putsthe patient at high risk for treatment related complications.
22. Pregnant or lactating women. 25. Participation in another clinical studywith any intravenous or oral investigational product is not allowed.However, participation in a surgical clinical study including HyperthermicChemotherapy (HIPEC) during the surgical procedure is allowed.
23. Patient unable to swallow orally administered medication and patient withgastrointestinal disorders likely to interfere with absorption of thestudy medication.
24. Patient with a known contraindication or uncontrolled hypersensitivity tothe components of paclitaxel, carboplatin, niraparib, bevacizumab, ortheir excipients.
25. Immunocompromised patient, e.g., with known active hepatitis (i.e.Hepatitis B or C) due to risk of transmitting the infection through bloodor other body fluids or patient who is known to be serologically positivefor human immunodeficiency virus (HIV).
26. Participant has a serious, uncontrolled medical disorder, nonmalignantsystemic disease, or active, uncontrolled infection. Examples include, butare not limited to uncontrolled major seizure disorder, unstable spinalcord compression, superior vena cava syndrome, or any psychiatric disorderthat prohibits obtaining informed consent.