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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AGO Research GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Aug 2022 → ongoing

Decision date (initial)

2026-04-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

GlaxoSmithKline Research & Development Limited

External identifiers

EU CT number

2024-516066-11-00

EudraCT number

2021-001271-16

ClinicalTrials.gov

NCT05009082

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Others, Efficacy

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)

Secondary objectives 4

1. 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
2. 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)
3. To evaluate the safety and tolerability of carboplatin/paclitaxel/bevacizumab followed by bevacizumab and niraparib compared to carboplatin/paclitaxel followed by niraparib
4. 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

Conditions and MedDRA coding

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)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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 clinical trial requirements
2. Female patients ≥ 18 years with histologically confirmed primary advanced invasive high grade non- mucinous, non-clear cell 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
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 10^9 /L, Platelets (PLT) ≥ 100 x 10^9 /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
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 trial 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 clinical trial procedures, that include the completion of patient-reported outcomes questionnaires

Exclusion criteria 33

1. Non-epithelial tumor origin of the ovary
2. Ovarian tumors of low malignant potential (e.g. borderline tumors) and low grade tumors
3. Planned intraperitoneal cytotoxic chemotherapy
4. Malignancies other than ovarian cancer within 5 years prior to randomization, with the 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 the breast, or stage I p53 wild type endometrial cancer)
5. Prior systemic treatment for ovarian cancer
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 the 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 or patient who has not completely recovered from the effects of any major surgery. Core biopsy or other minor surgical procedure within 7 days prior to day 1, cycle 1 is permitted.
10. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to day 1, cycle 1) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to day 1, cycle 1) 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 (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to day 1, cycle 1.
13. History or evidence of major thrombotic (e.g. symptomatic pulmonary embolism) or hemorrhagic disorders within 3 months prior to day 1, cycle 1.
14. History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures.
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 day 1, cycle 1 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 day 1, cycle 1, New York Heart Association (NYHA, see Appendix 3) Grade 2 Congestive Heart Failure (CHF), 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 [ADL] 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 with a history of or current Nephrotic syndrome.
23. Persistent cancer-related bowel obstruction (including subocclusive disease). Patients 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 day 1, cycle 1.
25. Patients unable to swallow orally administered medication and patients 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 (MDS) or acute myeloid leukemia (AML).
28. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
29. Current or recent (within 10 days prior to day 1, cycle 1) 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. Patients 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. Patient has known active hepatitis B or hepatitis C.
32. Patient has a history of Posterior Reversible Encephalopathy Syndrome (PRES).
33. Patients with chronic inflammatory bowel disease and active treatment for disease control.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS will be 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).

Secondary endpoints 4

1. PFS in subgroups defined by tBRCA status (presence or absence of a deleterious/suspected deleterious mutation)
2. OS (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 or death, whichever occurs earlier)
3. Safety and tolerability evaluated by AEs / SAEs, physical examination, vital signs including BP, heart rate, and laboratory findings including clinical chemistry / hematology parameters.
4. 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)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AGO Research GmbH

Sponsor organisation

AGO Research GmbH

Address

Kaiser-Friedrich-Ring 71

City

Wiesbaden

Postcode

65185

Country

Germany

Scientific contact point

Organisation

AGO Research GmbH

Contact name

AGO Study Office

Public contact point

Organisation

AGO Research GmbH

Contact name

AGO Study Office

Third parties 7

Locations

4 EU/EEA countries · 88 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 35 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications