| Eligibility |
Inclusion Criteria:
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 or any histology with known
BRCA mutation.
3. Patient consents to perform BRCA test, and PD-L1 expression.
4. Prior line of therapy: Patients must have received platinum-containing therapy for
primary disease.
5. No limits on number of platinum-based therapies.
6. Up to one non-platinum-based line of therapy in recurrent setting is allowed.
7. Patients may have received bevacizumab (or other anti-VEGF therapy) prior to entering
in the trial.
8. Patients may have participated in a PARP inhibitor maintenance trial or have received
maintenance PARP inhibitor therapy are allowed, though it is necessary to unblind
patient in order to correctly stratify. Patients who received a PARP inhibitor as
definitive are not eligible. Patients may have participated in a trial containing
immune-checkpoint inhibitor.
9. Target group: Age 18+
10. Histological confirmed ovarian, fallopian tube or peritoneal cancers
11. Patients must give informed consent
12. Patients may have undergone primary or interval debulking surgery
13. Patients may have received bevacizumab or other anti-angiogenic therapy
14. Patients may have received a PARP inhibitor as first-line maintenance therapy.
15. Patients must have disease that is measurable according to RECIST or assessable
according to the GCIG criteria
16. The patient agrees to complete PROs (QoL questionnaire) during study treatment AND at
one additional time point 8 weeks following progression of disease
17. ECOG performance status 0-2
18. Adequate organ function
1. Absolute neutrophil count (ANC) =1,5 x 109/L
2. Platelets >100 x 109/L
3. Hemoglobin = 9g/dl
4. Serum creatinine =1.5x upper limit of normal (ULN) or calculated creatinine
clearance =50mL/min using Cockcroft-Gault formula
5. Total bilirubin =1.5x ULN
6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =2.5x ULN
unless liver metastases are present, in which case they must be =5x ULN.
19. Able to take oral medications
20. Life expectancy of at least 12 weeks
21. Patients must fulfill all inclusions criteria and according to investigator fit to
receive niraparib, bevacizumab and TSR042.
22. Women of childbearing potential must use adequate birth control for the duration of
study participation -
Exclusion Criteria:
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, VEGF directed therapy or
immune checkpoint inhibitors 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 </=1g of protein in24 hours to be eligible 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.
|
