| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with newly diagnosed, histologically confirmed, primary advanced invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer, FIGO stage III/IV (except FIGO IIIA2 without nodal involvement), with indication for a platin/paclitaxel chemotherapy, who have either undergone upfront primary surgery or plan to undergo chemotherapy with interval debulking surgery (IDS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with newly diagnosed advanced ovarian cancer with indication for a platin/paclitaxel chemotherapy, who had a surgery for primary tumor or where surgery is planned after start of chemotherapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052171 |
| E.1.2 | Term | Peritoneal carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To evaluate the efficacy of carboplatin/paclitaxel/bevacizumab followed by bevacizumab and niraparib compared to carboplatin/paclitaxel followed by niraparib in terms of progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of carboplatin/paclitaxel/bevacizumab followed by bevacizumab and niraparib compared to carboplatin/paclitaxel followed by niraparib in terms of progression-free survival (PFS) according to tBRCA status
- To evaluate the efficacy of carboplatin/paclitaxel/bevacizumab followed by bevacizumab and niraparib compared to carboplatin/paclitaxel followed by niraparib in terms of overall survival (OS), time to first subsequent therapy (TFST), PFS2, time to second subsequent therapy (TSST)
- To evaluate the safety and tolerability of carboplatin/paclitaxel/bevacizumab followed by bevacizumab and niraparib compared to carboplatin/paclitaxel followed by niraparib
- To determine the effects on Quality of life (QoL) of carboplatin/paclitaxel/bevacizumab followed by bevacizumab and niraparib compared to carboplatin/paclitaxel followed by Niraparib |
|
| 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 |
The study will include the ancillary study “Evaluation of the impact of single-nucleotide variants determined by a Genome-wide association study (GWAS) on survival and neurotoxicity” in Germany only.
Most of the studies undertake so far are of retrospective character, with mixed blood samples taken before onset of chemotherapy, leading to biased genotyping. Furthermore, other clinical factors have been gathered retrospectively, (e.g. evaluation of cumulative chemotherapy dosages, CIPN determination) leading to some varying degrees of bias. Within this protocol, prospectively determined analyses will take place to reduce bias as much as possible.
Specific purpose for the survival analyses is to conduct a GWAS on germline DNA containing known single nucleotide polymorphisms (SNPs) associated with survival, and inclusion of new SNPs, in combination with known clinical prognostic factors (e.g. FIGO-stage, residual disease, ECOG, BRCA/HRD). Specific purposes for the chemotherapy-induced peripheral sensory neuropathy (CIPN) analyses are to conduct a GWAS on germline DNA containing known SNPs associated with neurotoxicity, and inclusion of new SNPs, in combination with known clinical factors increasing the risk for CIPN (e.g. age, educational level, Charlson Comorbidity Index, BMI, diabetes and physical activity). Further details are specified in protocol section 20. |
|
| E.3 | Principal inclusion criteria |
1. Signed written informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient’s awareness and willingness to comply with the study requirements
2. Female patients ≥ 18 years with histologically confirmed primary advanced invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement) according to recent FIGO classification (= FIGO IIIB-IV according to FIGO 2009 classification)
3. All patients must have had either upfront primary debulking surgery OR plan to undergo chemotherapy with interval debulking surgery
4. Patients must have available tumor samples to be sent to central laboratory as formalin-fixed, paraffin-embedded (FFPE) sample for determination of BRCA status prior to randomization for stratification
5. Patients must be able to commence systemic therapy within 8 weeks of cytoreductive surgery
6. ECOG performance status (PS) 0-1 (Appendix 1)
7. Estimated life expectancy > 3 months
8. Adequate bone marrow function (within 28 days prior to day 1, cycle 1 and within 3 days prior to day 1, cycle 2)
- Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
- Platelets (PLT) ≥ 100 x 109/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 7 days prior to day 1, cycle 2)
- Patients not receiving anticoagulant medication who have an International Normalized Ratio
(INR) ≤ 1.5 and an Activated ProThrombin Time (aPTT) ≤ 1.5 x institutional upper limit of normal (ULN)
- The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and the patient has been on a stable dose of anticoagulants for at least one week at the time of randomization
10. Adequate liver and kidney function (within 28 days prior to day 1, cycle 1 and within 3 days prior to day 1, cycle 2)
- Total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in patients with known Gilbert’s syndrome) 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 liver metastases values must be ≤ 5 x ULN
- Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24 hour urine must 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 controlled BP, 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 medical professional within 4 weeks prior to day 1, cycle 1 and within 7 days prior to day 1, cycle 2.
12. Negative highly sensitive urine or serum pregnancy test within 7 days prior to day 1, cycle 1 in women of childbearing potential (WOCBP), confirmed prior to treatment on day 1
13. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 6 months after administration of the last dose of medication. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified 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 but are not limited to bilateral tubal ligation and/or occlusion, male sterilization, and intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, that include the completion of patient-reported outcomes questionnaires |
|
| E.4 | Principal exclusion criteria |
1. - 3. see protocol
4. Malignancies other than ovarian cancer within 5 years prior to randomization, with exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ of breast, or stage I p53 wild type endometrial cancer)
5. see protocol
6. Prior treatment with PARP inhibitor
7. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during trial treatment period (hormonal replacement therapy is permitted)
8. Prior randomization in AGO-OVAR 28
9. Major surgery within 7 days prior to day 1, cycle 1 (C1D1) or patient who has not completely recovered from effects of any major surgery. Core biopsy or other minor surgical procedure within 7 days prior to C1D1 is permitted.
10. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of brain is mandatory (within 4 weeks prior to C1D1) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to C1D1) in case of suspected spinal cord compression.
11. Significant traumatic injury like a major surgery during 4 weeks preceding the potential first dose of bevacizumab
12. Previous Cerebro-Vascular Accident, Transient Ischemic Attack or Sub-Arachnoids Hemorrhage within 6 months prior to C1D1
13. History or evidence of major thrombotic (e.g. symptomatic pulmonary embolism) or hemorrhagic disorders within 3 months prior to C1D1
14. History or evidence upon neurological examination of central nervous system disease, unless adequately treated with standard medical therapy
15. Pregnant or lactating women
16. Treatment with any other investigational agent, or participation in another clinical trial testing a drug within 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to C1D1 or concomitantly within this trial
17. Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanized antibodies. Known hypersensitivity to niraparib, paclitaxel and carboplatin and its components or excipients
18. Non-healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no severe evidence of facial dehiscence 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 C1D1
- New York Heart Association Grade 2 Congestive Heart Failure
- Poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible)
- Grade ≥ 3 peripheral vascular disease (i.e. symptomatic and interfering with activities of daily living requiring repair or revision)
- Significant vascular disease including aortic aneurysm requiring surgical repair
20. Pre-existing sensory or motor neuropathy ≥ Grade 2
21. (Intentionally left blank)
22. Patients (Pts) with a history of or current Nephrotic syndrome
23. Persistent cancer-related bowel obstruction (including subocclusive disease). Pts with a known history of ileus, who have been successfully treated and who are free of symptoms, may be eligible after consultation of sponsor.
24. History of abdominal fistula or tracheoesophageal fistula or gastrointestinal perforation or active gastrointestinal bleeding or anastomotic insufficiency or intraabdominal abscess within 6 months of C1D1
25. Pts unable to swallow orally administered medication and pts with gastrointestinal disorders likely to interfere with absorption of niraparib
26. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
27. Any known history or current diagnosis of myelodysplastic syndrome or acute myeloid leukemia
28. Previous allogeneic bone marrow transplant or previous solid organ transplantation
29. Current or recent (within 10 days prior to C1D1) chronic use of aspirin > 325 mg/day. Patients treated with other inhibitors of platelet aggregation such as clopidogrel, prasugrel, ticlopidine, tirofibane or dipyridamole should not be included into the trial
30. Pts considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. This includes also any psychiatric disorder that prohibits obtaining informed consent
31. Known active hepatitis B or hepatitis C
32. History of Posterior Reversible Encephalopathy Syndrome
33. Chronic inflammatory bowel disease and active treatment for disease control |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) defined as the time from randomization to first progressive disease (PD) or death, whichever occurs earlier. PD is based on investigators assessment using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis of the primary endpoint, i.e. confirmatory testing of the null hypothesis for PFS will be performed after observation of 586 PFS events or three years after inclusion of the last patient, whichever occurs earlier.
The analysis of PFS will be performed in the Intention-to-treat (ITT) population. The analysis will be repeated in the Per Protocol (PP) population as a sensitivity analysis. All details of primary efficacy analysis will be specified in the Statistical Analysis Plan (SAP). |
|
| E.5.2 | Secondary end point(s) |
- PFS in subgroups defined by tBRCA status (presence or absence of a deleterious/suspected deleterious mutation)
- OS defined as the time from randomization to death
- TFST (time from randomization to the first subsequent treatment or death, whichever occurs earlier)
- PFS2 (time from randomization to the second progression or death, whichever occurs earlier)
- TSST (time from randomization to the second subsequent treatment death, whichever occurs earlier)
- Safety and tolerability evaluated by AEs / SAEs, physical examination, vital signs including BP, heart rate, and laboratory findings including clinical chemistry / hematology parameters
- Effects on Quality of life (QoL) assessed by EORTC QLQ-C30 (functional and HRQoL scales), QLQ-OV-28 questionnaires (items 31 to 36 from the abdominal/GI symptoms subscale), Patient reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be analyzed using appropriate statistical methodology. All details of secondary analyses and subgroup analyses will be specified in the SAP.
The safety analyses will be based on the safety population. All safety parameters will be summarized and also listed by patient. Summary tables will be presented for incidence rates (number of patients with at least one occurrence) of AEs, SAEs, AEs that led to premature with-drawal of trial treatment and interruptions/dose modifications, as well as summaries of severity (CTCAE v5.0 grades) and causal relationship. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life, Translational Research, Evaluation of the impact of single-nucleotide variants determined by a Genome-wide association study (GWAS) on survival and neurotoxicity |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 2 |
| 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 | 80 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 185 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| Austria |
| Belgium |
| Czechia |
| Germany |
| Italy |
| Spain |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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