Evaluation of Niraparib alone compared to the combination of Niraparib and Bevacizumab in patients receiving chemotherapy for newly diagnosed advanced ovarian cancer

Phase 1

• Conditions: 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); MedDRA version: 20.0Level: PTClassification code 10033128Term: Ovarian cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10016180Term: Fallopian tube cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10052171Term: Peritoneal carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-001271-16-DE
• Lead Sponsor: AGO Research GmbH

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-10-06
• Last Update Posted: 2 September 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Female
• Target Recruitment: 970

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

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified