A Phase II randomized, open label non-inferiority study of NiraParib maintenance after 3 vs. 6 cycles of platinum-based chemotherapy in completeLy debUlked advanced HRDpositive high-grade ovarian cancer patientS in first line therapy
- Trial ID
- 2022-502559-69-01
- Protocol
- NOGGO-ov53
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that the **recurrence-free survival** (RFS) in patients with advanced HRD-positive high-grade ovarian cancer, who receive three cycles of platinum-based chemotherapy followed by maintenance with niraparib, is not inferior to those receiving six cycles of chemotherapy followed by niraparib. This is clinically relevant as it may offer a less intensive treatment regimen without compromising efficacy, potentially reducing treatment-related toxicity and improving patient quality of life.
Secondary objectives include:
- Comparison of overall survival between both treatment arms.
- Comparison of the time to first subsequent treatment (TFST).
- Comparison of the time without symptoms of disease or toxicity of treatment.
- Estimation and comparison of progression-free survival 2 (PFS2).
- Estimation and comparison of patient-reported outcomes (PROs).
- Safety assessments.
- Evaluation of cost-effectiveness.
Participants
The clinical trial involves a study population consisting exclusively of **female** participants aged 18 years and older, diagnosed with advanced HRD-positive high-grade ovarian cancer, fallopian tube cancer, primary peritoneal cancer, or clear cell carcinoma of the ovary, with no residual tumor mass following primary tumor debulking. The trial does not include male participants or vulnerable populations. Participants are required to have a good general health status, as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and must be capable of taking oral medications. The selection criteria necessitate that participants have normal organ and bone marrow function, and they must be postmenopausal or have evidence of non-childbearing status. The trial does not provide specific information on the total number of participants or any lifestyle considerations such as diet or physical activity. The sponsor has not disclosed the total number of participants involved in the study.
Plans and Procedures
The clinical trial is a **Phase II randomized, open-label, non-inferiority study** designed to evaluate the efficacy of **niraparib tosylate monohydrate** as maintenance therapy following three versus six cycles of platinum-based chemotherapy in patients with advanced HRD-positive high-grade ovarian cancer. The trial aims to demonstrate that recurrence-free survival (RFS) in patients receiving three cycles of chemotherapy followed by maintenance with niraparib is not inferior to those receiving six cycles. The study will involve a total estimated duration from recruitment start in January 2024 to completion in March 2032.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, cancer stage, and HRD status. Following randomization, participants will receive either three or six cycles of chemotherapy, including **carboplatin** and **paclitaxel**, administered intravenously. Maintenance therapy with niraparib, administered orally, will follow the chemotherapy cycles. Follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events, with assessments including laboratory evaluations, vital signs, and physical examinations. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoint of RFS and secondary endpoints such as overall survival and time to first subsequent treatment.
The expected length of participant involvement will vary depending on the assigned treatment arm, with a maximum treatment period of 36 months for those receiving niraparib. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, may jeopardize the participant's safety or compliance with the protocol. The study will adhere to rigorous ethical standards, ensuring informed consent and the protection of participant rights throughout the trial.
Treatment
The clinical trial involves the administration of **Niraparib Tosilate Monohydrate**, an investigational medication provided in the form of a tablet. This pharmaceutical is administered orally with a maximum daily dose of 300 mg. The total maximum dose over the treatment period is 324,000 mg, with a treatment duration of up to 36 months. Niraparib Tosilate Monohydrate is a highly selective poly adenosine diphosphate (ADP)-ribose polymerase inhibitor, developed by GlaxoSmithKline. The investigational product differs from the approved commercial medicinal product in several minor aspects, including the absence of tablet debossing, differences in packaging, labeling, importation, and Qualified Person (QP) release sites. The investigational product is packaged in high-density polyethylene (HDPE) bottles, whereas the approved product is packaged in blisters.
**Carboplatin** is used as a comparator treatment in this study. It is provided as a solution for infusion and administered intravenously. The maximum daily dose is 400 mg/m², with a total maximum dose of 1200 mg/m² over a treatment period of up to 9 months. Carboplatin is a chemotherapy agent and is not a pediatric formulation.
**Paclitaxel** is another comparator treatment in the study, also provided as a solution for infusion and administered intravenously. The maximum daily dose is 175 mg/m², with a total maximum dose of 1050 mg/m² over a treatment period of up to 18 months. Paclitaxel is a chemotherapy agent and is not a pediatric formulation.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the efficacy of Niraparib maintenance therapy following different cycles of platinum-based chemotherapy in patients with advanced HRD-positive high-grade ovarian cancer.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Recurrence Free Survival (RFS)**, defined as the time from treatment randomization to the earliest date of assessment of first relapse or death by any cause. This primary endpoint will provide a direct measure of the treatment's effectiveness in preventing disease recurrence in patients with advanced HRD-positive high-grade ovarian cancer.
Secondary endpoints will include **Overall Survival (OS)**, which will be evaluated as time to event and rate at 3 and 5 years, and **Time to First Subsequent Treatment (TFST)**. Additionally, **TWIST (Time Without Symptoms of disease progression or Toxicity of treatment)** will be assessed at baseline, 3, 6, and 12 months. **PFS2 (Time from randomization until the date of second objective disease progression or death by any cause)** will also be measured. Patient-reported outcomes (PROs) will be collected using the EORTC QLQ-C30 and EORTC QLQ-OV28 instruments to evaluate the impact of treatment on quality of life. Safety assessments will include monitoring of adverse events (AEs/SAEs), laboratory evaluations, vital signs, and physical examinations. The cost-effectiveness of the treatment will also be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent and obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
- Female patient, age ≥ 18 years.
- FIGO Stage III-IV high-grade ovarian cancer (all histological types, except mucinous histology)
- Complete primary debulked patients (without any macroscopic residuals), confirmed by CT-Scan postoperatively.
- Patients must have formalin-fixed, paraffin-embedded tumor samples available from the primary cancer for central NGS analysis and must be HRD positive defined as BRCAmut independent of NOGGO GIS Score OR NOGGO GIS Score >83 independent of BRCA status, based on these results
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Patients must be able to take oral medications.
- Synchronous and secondary malignancies are allowed if the prognosis of the ovarian cancer is not affected. The investigator must contact the medical monitoring team before enrolling the patient in the clinical trial.
- Patients must have normal organ and bone marrow function: a. Hemoglobin ≥ 10.0 g/dL independent of transfusion ≤ 14 days prior to screening hemoglobin assessment b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L c. Platelet count ≥ 100 x 109/L d. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); < 2 × ULN if hyperbilirubinemia is due to Gilbert’s syndrome e. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2,5 x ULN f. Serum creatinine ≤ 1.5 x institutional ULN and creatinine clearance > 30 mL/min.
- Postmenopausal or evidence of non-childbearing status for women of childbearing potential prior to the first dose of study treatment. Female patients of childbearing potential must have a negative serum pregnancy test result ≤3 days prior to administration of the first dose of study treatment. Patients are considered to be of childbearing potential unless 1 of the following applies: a. Considered to be permanently sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy; or b. Is postmenopausal, defined as no menses for at least 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level consistently in the postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausal state. Female patients of reproductive potential must practice highly effective methods (failure rate < 1% per year) of contraception with their partners, if of reproductive potential, during treatment and for 6 months following the last dose of chemotherapy or the last dose of niraparib, whichever occurs later, or longer if requested by local authorities. Highly effective contraception includes: Ongoing use of progesterone only injectable or implantable contraceptives; Placement of an intrauterine device (IUD) or intrauterine system (IUS); Bilateral tubal occlusion; Sexual abstinence as defined as complete or true abstinence, acceptable only when it is the usual and preferred lifestyle of the patient; periodic abstinence (e.g., calendar, symptothermal, post-ovulation methods) is not acceptable; or Sterilization of the male partner, with appropriate post-vasectomy documentation of absence of sperm in ejaculate.
Exclusion Criteria
- Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e., germ cell tumors) and Ovarian tumors of low malignant potential (e.g., borderline tumors), or mucinous carcinoma of the ovary.
- Low-grade ovarian, fallopian tube or peritoneal cancer.
- Has known hypersensitivity to any of the study drugs or any of the excipients of any of the study drugs.
- Has known hypersensitivity to platin-containing compounds other than carboplatin.
- Patients posttransplant, including previous allogeneic bone marrow transplant.
- Has undergone interval debulking of the tumor.
- Has received any anti-cancer therapy for ovarian cancer other than primary surgery.
- Administration of other simultaneous chemotherapy drugs, any other anti-cancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are steroidal antiemetics).
- Has received prior treatment with a PARP inhibitor or has participated in a trial where any treatment arm included the administration of a PARP inhibitor.
- Bevacizumab is planned to be given together with first line chemotherapy or as maintenance.
- Clinically significant cardiovascular disease: a. Cerebrovascular accident or myocardial infarction or unstable angina ≤6 months before start of study treatment b. Severe cardiac arrhythmia (recent event or active or uncontrolled) c. New York Heart Association grade ≥2 congestive heart failure d. Uncontrolled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy or posterior reversible encephalopathy syndrome e. History of stroke or transient ischemic attack ≤6 months before start of study treatment f. Coronary/peripheral artery bypass graft ≤6 months before start of study treatment g. Deep vein thrombosis or thromboembolic events ≤1 month before start of study treatment
- History or evidence of brain metastases or spinal cord compression.
- Known history of MDS or a pre-treatment cytogenetic testing result at risk for a diagnosis of MDS/AML.
- Current, clinically relevant bowel obstruction at the time of randomization.
- Patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
- Pregnant or lactating women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (see inclusion criteria) starting with the screening visit through at least 6 months after the last dose of chemotherapy treatment or through at least 1 month after the last dose of niraparib, whichever occurs later.
- Participation in another clinical study with an investigational product immediately prior to randomization. Earliest time point for randomization is after the time required for the investigational product to undergo 5 half-lives has passed.
- Has a known history of Human Immunodeficiency Virus (HIV) infection (known HIV1/HIV2 antibodies positive) or acquired immunodeficiency syndrome (AIDS) related illness.
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] has been detected) infection.
- Has active infection with SARS-CoV-2 (antigen test).
- Patient who might be dependent on the sponsor, CRO, site or the investigator.
- In Germany: Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40a S. 1 Nr. 2 AMG.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Jan 2024 | 20 |
 Belgium | Recruiting | 01 Jan 2024 | 50 |
 Czechia | Recruiting | 01 Jan 2024 | 30 |
 Germany | Recruiting | 01 Jan 2024 | 300 |
 Italy | Recruiting | 01 Jan 2024 | 120 |
 Spain | Recruiting | 01 Jan 2024 | 120 |
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 |
|---|---|---|---|---|---|---|
PACLITAXEL | Comparator | — | INTRAVENOUS | 175 | 18 | SUB09583MIG |
CARBOPLATIN | Test | — | INTRAVENOUS | 400 | 9 | SUB06614MIG |
NIRAPARIB TOSILATE MONOHYDRATE | Comparator | — | ORAL | 300 | 36 | SUB183938 |
PACLITAXEL | Test | — | INTRAVENOUS | 175 | 9 | SUB09583MIG |
CARBOPLATIN | Comparator | — | INTRAVENOUS | 400 | 18 | SUB06614MIG |