Randomized Evaluation of Paclitaxel-Carboplatin with Maintenance Niraparib versus Paclitaxel-Carboplatin-Bevacizumab with Maintenance Niraparib-Bevacizumab in Advanced Ovarian Cancer
- Trial ID
- 2023-504166-37-00
- Protocol
- GINECO-OV129b
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine whether **paclitaxel** and **carboplatin** followed by maintenance with **niraparib** improves the progression-free survival rate at 24 months compared to paclitaxel, carboplatin, and **bevacizumab** followed by maintenance with niraparib and bevacizumab in patients with advanced ovarian cancer, primary peritoneal cancer, and/or fallopian-tube cancer. This is clinically relevant as it aims to enhance treatment efficacy and prolong survival in these patient populations following front-line complete cytoreductive surgery.
Secondary objectives include:
- Evaluate **Progression-Free Survival** (PFS)
- Evaluate Progression-Free Survival 2 (PFS2)
- Evaluate **Safety** assessed based on CTCAE version 5
- Evaluate Time to First Subsequent Treatment (TFST)
- Evaluate Time to Second Subsequent Treatment (TSST)
- Evaluate Overall Survival (OS) at 5 years
- Confirm the predictive value (overall chemo-sensitivity) of the KELIM (CA-125 Elimination rate constant K)
Participants
The clinical trial involves a total of **74 participants** who are exclusively female, aged 18 years and older, diagnosed with **advanced ovarian, tubal, or peritoneal cancer**. The study population was selected based on specific inclusion criteria, including eligibility for bevacizumab treatment in combination with chemotherapy, normal organ and bone marrow function, and having undergone frontline complete cytoreductive surgery. Participants are required to have a histologically confirmed diagnosis of high-grade serous or endometrioid ovarian cancer, or other epithelial non-mucinous and non-clear cell ovarian cancer with a germline BRCA 1 or 2 deleterious mutation, at an advanced stage (FIGO stage IIIA to IIIC). The trial does not include male subjects or vulnerable populations. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and must have received one cycle of carboplatin and paclitaxel chemotherapy. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **niraparib** and **bevacizumab** in patients with advanced ovarian, tubal, or peritoneal cancer following front-line complete cytoreductive surgery. This is a randomized, double-blind, controlled trial with a primary objective to assess whether the combination of paclitaxel-carboplatin followed by maintenance with niraparib, compared to paclitaxel-carboplatin-bevacizumab followed by maintenance with niraparib and bevacizumab, improves progression-free survival at 24 months. The trial is expected to run until January 2031, with recruitment having started in January 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and previous treatment history. Following randomization, participants will receive treatment according to their assigned group, with regular follow-up visits to monitor safety and efficacy. These visits will include assessments of tumor progression, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 24 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards, ensuring that all procedures are conducted in accordance with regulatory requirements and best practices in clinical research.
Treatment
The clinical trial involves the administration of **Zejula 100 mg hard capsules**, which contain the active substance **niraparib**. Niraparib is a chemical compound used in the treatment of advanced ovarian cancer. The pharmaceutical form of this medication is a hard capsule, and it is administered orally. The maximum daily dose is 300 mg, with a total treatment period of up to 24 months. Participants will receive bottles containing 72 capsules as part of the investigational supply. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.
Additionally, the trial includes the use of **MVASI 25 mg/mL concentrate for solution for infusion**, which contains the active substance **bevacizumab**. Bevacizumab is a protein-based therapeutic agent administered intravenously. The maximum dose is 15 mg/kg, with a treatment period of up to 15 months. This medication is provided as a concentrate that must be prepared into a solution for infusion prior to administration. The administration of bevacizumab will be closely monitored to ensure proper dosing and participant safety.
In this study, participants will receive standard-of-care therapy with paclitaxel and carboplatin, followed by maintenance therapy with niraparib alone or in combination with bevacizumab. The trial aims to evaluate the progression-free survival rate at 24 months in patients with advanced ovarian cancer, primary peritoneal cancer, and/or fallopian-tube cancer following front-line complete cytoreductive surgery. Compliance with the treatment protocol will be assessed regularly to ensure the integrity of the study outcomes.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**, which is defined as the time from randomization until objective tumor progression or death, whichever occurs first. This endpoint is crucial in evaluating the effectiveness of the treatment regimens being compared in the study. Secondary endpoints include additional measures such as Progression-Free Survival 2 (PFS2), Overall Survival (OS) at 5 years, Time to First Subsequent Treatment (TFST), Time to Second Subsequent Treatment (TSST), and the safety profile assessed based on CTCAE version 5. The trial will also aim to confirm the predictive value of the KELIM (CA-125 Elimination rate constant K) for overall chemo-sensitivity.
The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial duration, with the primary endpoint being evaluated at 24 months. The trial is designed to determine whether the combination of paclitaxel, carboplatin, and bevacizumab followed by maintenance with niraparib and bevacizumab improves the progression-free survival rate in patients with advanced ovarian cancer, primary peritoneal cancer, and/or fallopian-tube cancer following a front-line complete cytoreductive surgery. The study will utilize validated scales and laboratory tests to ensure the accuracy and reliability of the efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Female patient ≥ 18 years of age.
- Signed informed consent and ability to comply with treatment and follow-up.
- Patient with newly diagnosed, a. Ovarian cancer, primary peritoneal cancer and/or GINECO-OV129b / ENGOT-OV63 / EUDRACT 2021-004278-76 – NIRVANA-1 – Protocol - Version 2.0 – 30/03/2022 (From FORM 113-02 : Protocol – Application date : 22/JUN/2020) Page 6 on 96 fallopian-tube cancer, b. Histologically confirmed (based on local histopathological findings): • high grade serous or • high grade endometrioid (grade 2 and 3) or • other epithelial non mucinous and non-clear cell ovarian cancer in a patient with germline BRCA 1 or 2 deleterious mutation, c. At an advanced stage: FIGO stage IIIA to IIIC of the 2018 FIGO classification.
- Patient having undergone frontline, complete cytoreductive surgery (i.e. no visible residual disease): The patient will be considered eligible once the ESGO Quality Assurance in Ovarian Cancer Surgery will have been filled out and validated
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Patient must have received one cycle of carboplatin AUC 5-6 + paclitaxel 175 mg/m²
- Patient must have started cycle 1 chemotherapy no later than 6 weeks after surgery.
- Patient must have a thorax-abdomen-pelvis CT scan or MRI between surgery and Cycle 1, with no evidence of disease.
- Patient eligible for first line platinum-taxane chemotherapy:
- Patient eligible for bevacizumab treatment in combination with chemotherapy and in maintenance. It must be started at the second chemotherapy cycle and be administered at a dose of 15mg/kg every 3 weeks up to a total of 15 months.
- Patient must have normal organ and bone marrow function before first cycle of chemotherapy: • Hemoglobin ≥ 9.0 g/dL. • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. • Platelet count ≥ 100 x 109/L. • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). • Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x ULN. • Serum creatinine ≤ 1. 5 x institutional ULN and GFR > 50 mL/min, by using an exact measure (ie. Iohexol clearance) or the most appropriate formula (Jeliffe, Cockroft Gault, MDRD, CKD-EPI) to the investigator’s discretion. GINECO-OV129b / ENGOT-OV63 / EUDRACT 2021-004278-76 – NIRVANA-1 – Protocol - Version 2.0 – 30/03/2022 (From FORM 113-02 : Protocol – Application date : 22/JUN/2020) Page 7 on 96 • Patient not receiving anticoagulant medication who has an International Normalized Ratio (INR) ≥1.5 and a Partial Thromboplastin Time (PTT) or an activated PTT (aPTT) ≥1.5 x ULN. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or the PTT or aPTT is within therapeutic limits (according to site medical standard). If the patient is on oral anticoagulants, dose has to be stable for at least two weeks at the time of randomization.
- Urine dipstick for proteinuria < 2+. If urine dipstick is ≥2+, 24-hour proteinuria must be <1 g.
- Normal blood pressure or adequately treated and controlled hypertension (systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).
- Formalin fixed paraffin embedded (FFPE) tumor sample from the primary cancer must be available for local BRCA testing and if possible HRD testing (optional).
- For countries where this will apply to: a subject will be eligible for randomization in this study only if either affiliated to, or a beneficiary of a social security category.
Exclusion Criteria
- Patient with clear cell adenocarcinoma or carcinosarcoma, non-epithelial origin of the ovarian tumor, the fallopian tube or the peritoneal tumor (i.e. germ cell tumors).
- Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.
- Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.
- Clinically significant (e.g. active) cardiovascular disease, including: • Myocardial infarction or unstable angina within ≤ 6 months of randomization, • New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF), • Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG. • Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision).
- Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA), Sub- Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.
- History or evidence of hemorrhagic disorders within 6 months prior to randomization.
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).
- History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression.
- History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
- Significant traumatic injury during 4 weeks prior to randomization.
- Non-healing wound, active ulcer, or bone fracture. Patient with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection is eligible but require 3 weekly wound examinations.
- Ovarian tumor of low malignant potential (e.g. borderline tumor), or mucinous carcinoma.
- History of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.
- Current, clinically relevant bowel obstruction, including sub- GINECO-OV129b / ENGOT-OV63 / EUDRACT 2021-004278-76 – NIRVANA-1 – Protocol - Version 2.0 – 30/03/2022 (From FORM 113-02 : Protocol – Application date : 22/JUN/2020) Page 9 on 96 occlusive disease, related to underlying disease.
- Patient with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
- Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications.
- Pregnant or lactating women.
- Participation in another clinical study with any intravenous or oral investigational product is not allowed. However, participation in a surgical clinical study including Hyperthermic Chemotherapy (HIPEC) during the surgical procedure is allowed.
- Patient unable to swallow orally administered medication and patient with gastrointestinal disorders likely to interfere with absorption of the study medication.
- Patient with a known contraindication or uncontrolled hypersensitivity to the components of paclitaxel, carboplatin, niraparib, bevacizumab, or their excipients.
- Immunocompromised patient.
- Patient with active viral infection (Hepatitis B or C and/or Human Immunodeficiency Virus).
- Patient with a diagnosis, detection, or treatment of another type of cancer ≤ 3 years prior to initiating protocol therapy (except basal or squamous cell carcinoma of the skin and cervical cancer in situ that has been definitively treated and synchronous grade 1 stage 1 endometrial cancer) Patient with history of primary triple negative breast cancer may be eligible provided she completed her definitive anticancer treatment more than 3 years ago and she remains breast cancer disease free prior to start of study treatment.
- Participant has a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
- Patient with synchronous high grade serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium is not eligible.
- Patient with myelodysplastic syndrome/acute myeloid leukemia history.
- Patient receiving radiotherapy within 6 weeks prior to study treatment.
- Previous allogenic bone marrow transplant
- Any previous treatment with PARP inhibitor.
- Administration of other simultaneous chemotherapy drugs – except during a HIPEC procedure with cisplatin at PDS, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are steroid antiemetics).
- History of Posterior Reversible Encephalopathy Syndrome (PRES).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Jan 2022 | 20 |
 France | Recruiting | 01 Jan 2022 | 211 |
 Italy | Recruiting | 01 Jan 2022 | 75 |
 Spain | Recruiting | 01 Jan 2022 | 30 |
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 |
|---|---|---|---|---|---|---|
MVASI 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 15 | 15 | PRD5803005 |
Zejula 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 300 | 24 | PRD9709363 |
Zejula 100 mg hard capsules | Test | HARD CAPSULE | ORAL USE | 300 | 24 | PRD5625301 |