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:

1. HRD status (positive/negative)

2. 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:

1. 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).

2. High-grade serious or high-grade endometrioid histology.

3. 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.

4. 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.

5. Target group: Age 18+

6. Histological confirmed ovarian, fallopian tube or peritoneal cancers

7. Patients must give informed consent

8. Patients may have undergone primary or interval debulking surgery

9. Patients may have received bevacizumab though no other prior use of anti-angiogenic
therapy

10. Patients may have received a PARP inhibitor as first-line maintenance therapy.

11. Patients must have disease that is measurable according to RECIST or assessable
according to the GCIG criteria

12. The patient agrees to complete PROs (QoL questionnaire) during study treatment AND at
one additional time point 8 weeks following progression of disease

13. ECOG performance status 0-2

14. 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.

15. Able to take oral medications

16. Life expectancy of at least 12 weeks

17. Patients must fulfill all inclusions criteria and according to investigator fit to
receive niraparib and/or bevacizumab.

18. 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:

1. Ovarian sarcomas, small cell carcinoma with neuroendocrine differentiation,
non-epithelial cancers and cancer types not mentioned in the inclusion criteria

2. Concurrent cancer therapy

3. Concurrent treatment with an investigational agent or participation in another
clinical trial

4. 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

5. 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

6. 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

7. Gastrointestinal disorders or abnormalities that would interfere with absorption of
the study drug

8. 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

9. Known contraindications to PARP inhibitors or VEGF directed therapy

10. Known uncontrolled hypersensitivity to the investigational drugs

11. 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.

12. History of a cerebral vascular accident, transient ischemic attack or subarachnoid
hemorrhage within the past 3 months

13. History of clinically significant hemorrhage in the past 3 months

14. 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)

15. 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

16. 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.

17. Radiographic evidence of cavitation or necrotic tumors with invasion of adjacent
major blood vessels

18. Active or chronic hepatitis C and/or B infection

19. Persistence of clinically relevant therapy related toxicity from previous
chemotherapy

20. 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
21. Patients must not have any known history of MDS

22. Patients must not have known persistent (> 4 weeks) ≥ Grade 2 hematological toxicity
from prior cancer therapy

23. Patients must not have known ≥ Grade 3 thrombocytopenia or anemia with the last
chemotherapy regimen.