E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Homologous Recombination Deficient (HRD) platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Homologous Recombination Deficient (HRD) platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective: Part 2 ( Phase 2): o compare Progression-Free Survival (PFS) |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives: Part 2 (Phase 2): o PFS in each group according to trial stratification factors o PFS comparison of sequential versus concomitant bevacizumab and niraparib o Objective response rate according to RECIST (ORR) o PFS2 in each group according to trial stratification factors o TFST (Time to First Subsequent Therapy) o TSST (Time to Second Subsequent Therapy) o Overall response according to GCIG criteria (CA125 response; best overall response in patients without initial measurable disease and who are evaluable by CA125; best overall response with measurable disease and who are also evaluable by CA125) o Disease control rate (DCR) (CR+PR+SD) o Patient Reported Outcomes (PROs) o Safety and tolerability o Overall survival (OS) in each group according to trial stratification factors (exploratory objective) |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Niraparib and niraparib-bevacizumab combination against bevacizumab alone in Women with Homologous Recombination Deficient (HRD) platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer. Part 1: AVANOVA1 - A phase I study to evaluate the safety and tolerability of bevacizumab-niraparib combination therapy and determine the Recommended Phase 2 Dose (RP2D) in Women with platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer.
Primary objective: Part 1( Phase 1): o safety and tolerability of bevacizumab-niraparib combination
Secondary objectives: Part 1 ( Phase 1): o determine the Recommended Phase 2 Dose (RP2D) of bevacizumab-niraparib combination o determine the pharmacokinetics (PK) and pharmacodynamics (PDn) of bevacizumab-niraparib combination o describe anti-tumor response in these patients |
|
E.3 | Principal inclusion criteria |
Study population 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. Other histological types are allowed if documented BRCA mutation. 3. Patient consents to perform HRD test. 4. HRD test positive. 5. Prior line of therapy: Patients must have received platinum-containing therapy for primary disease. o 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%. o Up to one non-platinum-based line of therapy in recurrent setting. o Patients who are treated with bevacizumab just prior to entering in the trial must not have progressed under or within 3 months after bevacizumab. Other inclusion criteria: 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 or other anti-angiogenic therapy 10. Patients must have disease that is measurable according to RECIST or assessable according to the GCIG CA-125 criteria 11. The patient agrees to complete PROs (QoL questionnaire) during study treatment AND at one additional time point 8 weeks following progression of disease 12. ECOG performance status 0-2 13. Adequate organ function o Absolute neutrophil count (ANC) ≥1,5 x 109/L o Platelets >100 x 109/L o Hemoglobin ≥ 9g/dl o Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥50mL/min using Cockcroft-Gault formula o Total bilirubin ≤1.5x ULN o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN. 14. Able to take oral medications 15. Life expectancy of at least 12 weeks 16. Patients must be fit to receive niraparib and/or bevacizumab 17. Women of childbearing potential must use adequate birth control for the duration of study participation |
|
E.4 | Principal exclusion criteria |
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. Prior treatment with PARP inhibitors 5. 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 6. 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 7. 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 8. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug 9. 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 10. Known contraindications to PARP inhibitors or VEGF directed therapy 11. Known uncontrolled hypersensitivity to the investigational drugs 12. 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 13. History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 3 months 14. History of clinically significant hemorrhage in the past 3 months 15. 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) 16. 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 17. 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. 18. Radiographic evidence of cavitation or necrotic tumors with invasion of adjacent major blood vessels 19. Active or chronic hepatitis C and/or B infection 20. Persistence of clinically relevant therapy related toxicity from previous chemotherapy 21. 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 22. Patients must not have any known history of MDS 23. Patients must not have known persistent (> 4 weeks) ≥ Grade 2 hematological toxicity from prior cancer therapy 24. Patients must not have known ≥ Grade 3 thrombocytopenia or anemia with the last chemotherapy regimen. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression-Free Survival (PFS) of patients treated with: A: Niraparib alone against bevacizumab alone B: Niraparib-bevacizumab combination against bevacizumab alone PFS is defined as the duration of time from date of randomization/enrolment to date of progression or death, whichever occurs first. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1 of each cycle (- 3 +1 days) Every 9 weeks (±7 days) During whole study period |
|
E.5.2 | Secondary end point(s) |
PFS in each group according to trial stratification factors PFS comparison of sequential versus concomitant bevacizumab and niraparib PFS2 (Progression Free Survival 2) TFST (Time to First Subsequent Therapy) TSST (Time to Second Subsequent Therapy) Objective Response Rate (ORR) Overall response according to GCIG criteria (CA125 response; best overall response in patients without initial measurable disease and who are evaluable by CA125; best overall response with measurable disease and who are also evaluable by CA125) Disease control rate (DCR) (CR+PR+SD) Patient Reported Outcomes (PROs) Safety and tolerability Overall survival in each group according to trial stratification factors (exploratory end point) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1 of each cycle (- 3 +1 days) Every 9 weeks (±7 days) During whole study period |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |