Phase III Randomized Study of Niraparib Monotherapy Versus Niraparib and Bevacizumab Combination in Advanced High-Grade Epithelial Ovarian Cancer
- Trial ID
- 2024-516066-11-00
- Protocol
- AGO-OVAR 28
- Sponsor
- AGO Research GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of a treatment regimen consisting of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab and niraparib, compared to a regimen of carboplatin and paclitaxel followed by niraparib, in terms of **progression-free survival (PFS)** in patients with newly diagnosed advanced ovarian cancer. This is clinically relevant as PFS is a critical endpoint in assessing the effectiveness of cancer therapies, providing insights into how long a patient lives without the disease worsening.
Secondary objectives include:
- Evaluating the efficacy of the treatment regimens in terms of overall survival (OS), time to first subsequent therapy (TFST), PFS2, and time to second subsequent therapy (TSST).
- Assessing the safety and tolerability of the treatment regimens.
- Determining the effects on quality of life (QoL) of the treatment regimens.
Participants
The clinical trial involves **female** participants aged **18 years and older** who have been newly diagnosed with histologically confirmed primary advanced invasive high-grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer, classified as FIGO stage III/IV, excluding FIGO IIIA2 without nodal involvement. The study population is exclusively female, with no male participants included. Participants are required to have undergone upfront primary debulking surgery or plan to undergo chemotherapy with interval debulking surgery. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have adequate liver, kidney, and bone marrow function, normal or controlled blood pressure, and an ECOG performance status of 0-1. They must also have an estimated life expectancy of more than three months and be able to commence systemic therapy within eight weeks of cytoreductive surgery. The trial population includes a vulnerable population, and participants must provide a signed written informed consent prior to any study-specific procedures. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **niraparib** alone compared to the combination of **niraparib** and **bevacizumab** in patients with newly diagnosed advanced ovarian cancer. This is a multicenter, randomized, double-blind, controlled phase III trial. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), time to first subsequent treatment (TFST), and safety and tolerability. The trial is expected to conclude by December 31, 2031, with recruitment having commenced on September 1, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate liver and kidney function, normal blood pressure, and availability of tumor samples for BRCA status determination. Following randomization, participants will receive either **carboplatin**/**paclitaxel**/**bevacizumab** followed by **bevacizumab** and **niraparib**, or **carboplatin**/**paclitaxel** followed by **niraparib**. The treatment period will vary depending on the regimen, with a maximum treatment period of 126 weeks for some participants.
Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment protocol, and any adverse events. These visits will include physical examinations, laboratory tests, and completion of patient-reported outcomes questionnaires. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination from the study. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent.
The expected length of participant involvement will depend on the treatment arm and individual response to therapy, with the possibility of early termination due to adverse events or other protocol-specified conditions. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and are aware of their rights and responsibilities throughout the study.
Treatment
The clinical trial involves the administration of **Zejula** (niraparib tosilate monohydrate), which is provided in the form of 100 mg hard capsules. This medication is administered orally with a maximum daily dose of 300 mg. The treatment period for Zejula is up to 36 months. The medication is manufactured by GlaxoSmithKline (Ireland) Limited and is classified under the ATC code L01XK02. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Avastin** (bevacizumab) is used as a comparator treatment in the trial. It is supplied as a 25 mg/ml concentrate for solution for infusion and is administered intravenously. The maximum daily dose is 15 mg/kg, with a total maximum dose of 330 mg/kg over a treatment period of 15 months. Avastin is produced by Roche Registration GmbH and is categorized under the ATC code L01FG01. The administration schedule and participant adherence will be closely monitored.
**Paclitaxel-GRY®** is another comparator treatment, provided as a 6 mg/ml concentrate for the preparation of an infusion solution. It is administered intravenously with a maximum daily dose of 175 mg/m² and a total maximum dose of 1050 mg/m² over a treatment period of 126 days. This medication is manufactured by TEVA GmbH and falls under the ATC code L01CD01. Compliance with the dosing regimen will be assessed throughout the study.
**Carboplatin Kabi** is also used as a comparator treatment, available as a 10 mg/ml concentrate for the preparation of an infusion solution. It is administered intravenously with a maximum daily dose of 400 mg/m² and a total maximum dose of 2400 mg over a treatment period of 126 days. The product is manufactured by Fresenius Kabi Deutschland GmbH and is classified under the ATC code L01XA02. Participant adherence to the dosing schedule will be monitored during the trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**, defined as the time from randomization to the first occurrence of progressive disease or death, whichever occurs earlier. Progressive disease will be evaluated based on the investigator's assessment using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Secondary endpoints include PFS in subgroups defined by tumor BRCA status, overall survival (OS), time to first subsequent treatment (TFST), time to second progression (PFS2), and time to second subsequent treatment (TSST). Safety and tolerability will be evaluated through adverse events (AEs) and serious adverse events (SAEs), along with physical examinations, vital signs, and laboratory findings. Quality of life (QoL) will be assessed using the EORTC QLQ-C30 and QLQ-OV-28 questionnaires, as well as the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- 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)
- All patients must have had either upfront primary debulking surgery OR plan to undergo chemotherapy with interval debulking surgery
- 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
- Patients must be able to commence systemic therapy within 8 weeks of cytoreductive surgery
- ECOG performance status (PS) 0-1
- Estimated life expectancy > 3 months
- 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)
- 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.
- 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
- 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
- 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
- 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
- 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
- Non-epithelial tumor origin of the ovary
- Ovarian tumors of low malignant potential (e.g. borderline tumors) and low grade tumors
- Planned intraperitoneal cytotoxic chemotherapy
- 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)
- Prior systemic treatment for ovarian cancer
- Prior treatment with PARP inhibitor
- 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)
- Prior randomization in AGO-OVAR 28
- 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.
- 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.
- Significant traumatic injury like a major surgery during 4 weeks preceding the potential first dose of bevacizumab.
- Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to day 1, cycle 1.
- History or evidence of major thrombotic (e.g. symptomatic pulmonary embolism) or hemorrhagic disorders within 3 months prior to day 1, cycle 1.
- History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures.
- Pregnant or lactating women.
- 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.
- 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.
- 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.
- 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.
- Pre-existing sensory or motor neuropathy ≥ Grade 2.
- (Intentionally left blank)
- Patients with a history of or current Nephrotic syndrome.
- 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.
- 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.
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of niraparib.
- 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.
- Any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
- Previous allogeneic bone marrow transplant or previous solid organ transplantation.
- 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.
- 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..
- Patient has known active hepatitis B or hepatitis C.
- Patient has a history of Posterior Reversible Encephalopathy Syndrome (PRES).
- Patients with chronic inflammatory bowel disease and active treatment for disease control.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 01 Sept 2022 | 23 |
 Czechia | Not Yet Recruiting | 01 Sept 2022 | 40 |
 Germany | Recruiting | 01 Sept 2022 | 970 |
 Italy | Not Yet Recruiting | 01 Sept 2022 | 70 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Carboplatin Kabi 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 400 | 126 | PRD669106 |
Zejula 100 mg hard capsules | Test | HARD CAPSULE | ORAL USE | 300 | 36 | PRD5625301 |
Paclitaxel-GRY® 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 175 | 126 | PRD718972 |
Avastin 25 mg/ml concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 15 | 15 | PRD2153901 |
Zejula 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 300 | 36 | PRD10964959 |