Phase 3 Randomized Double-Blind Study of Niraparib Tosilate Monohydrate Maintenance in Advanced Ovarian Cancer Post-Platinum Chemotherapy Response
- Trial ID
- 2023-508010-42-00
- Protocol
- PR-30-5017-C
- Sponsor
- Tesaro Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of niraparib versus placebo as maintenance treatment, as measured by progression-free survival (PFS), in patients with Stage III or IV ovarian cancer, including fallopian and peritoneal cancers, who have achieved a complete response (CR) or partial response (PR) following front-line platinum-based chemotherapy. This is clinically relevant as it aims to determine the potential of niraparib to extend the period during which the disease does not worsen, thereby potentially improving patient outcomes and quality of life.
Secondary objectives include:
- To evaluate additional measures of clinical benefit for niraparib versus placebo, such as overall survival (OS), patient-reported outcomes (PROs), time to first subsequent therapy (TFST), and time to progression on the next anticancer therapy (PFS2).
- To evaluate the safety and tolerability of niraparib versus placebo.
Participants
The clinical trial involves a total of **895 participants** who are exclusively **female** and aged **18 years and older**. The study population comprises individuals diagnosed with **Stage III or IV ovarian cancer**, including fallopian and peritoneal cancers, who have achieved a complete or partial response following front-line platinum-based chemotherapy. Participants were selected based on their ability to understand study procedures and provide informed consent, as well as their **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes women who are postmenopausal, surgically sterilized, or using adequate contraception. Participants must have adequate organ function and be able to take oral medications. The trial population is characterized by a requirement for a negative pregnancy test for those of childbearing potential and the ability to provide tumor samples for HRD testing. The study does not include male participants, and the sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is a **Phase 3, randomized, double-blind, placebo-controlled, multicenter study** designed to evaluate the efficacy of **niraparib** as a maintenance treatment in patients with advanced ovarian cancer, including fallopian and peritoneal cancers, who have shown a complete or partial response following front-line platinum-based chemotherapy. The primary objective is to assess progression-free survival (PFS) in these patients. The trial is expected to run until September 2025, with recruitment having started in September 2016.
Participants will be randomly assigned to receive either niraparib or a placebo, both administered orally. The study involves several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor health and treatment response, and an end-of-study visit to conclude participation. The inclusion criteria require participants to be female, aged 18 or older, with adequate organ function and an ECOG performance status of 0 or 1. They must also have histologically confirmed high-grade serous or endometrioid ovarian cancer at Stage III or IV, and have responded to prior chemotherapy.
The expected duration of participant involvement is up to 36 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the time from randomization to disease progression or death, while secondary endpoints include overall survival and changes in patient-reported outcomes. Participants must agree to undergo central tumor homologous recombination deficiency (HRD) testing, which is a stratification factor for randomization. The study is structured to ensure rigorous monitoring and data collection to evaluate the therapeutic potential of niraparib in this patient population.
Treatment
The clinical trial involves the administration of **Niraparib Tosilate Monohydrate**, an investigational medication, as a maintenance treatment for patients with 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 maximum dose of 324,000 mg over a treatment period of up to 36 months. The investigational product is packaged in bottles, differing from the approved commercial product, which is packaged in blisters. The trial aims to evaluate the efficacy of Niraparib Tosilate Monohydrate in prolonging progression-free survival in patients who have shown a complete or partial response to front-line platinum-based chemotherapy.
The study also includes a **placebo** group, which receives a placebo with a matching appearance to the 100 mg Niraparib capsules. The placebo is filled with an excipient blend and is used to maintain the double-blind nature of the trial. The placebo is administered orally, following the same dosing schedule as the active treatment group. This allows for a controlled comparison of the efficacy of Niraparib Tosilate Monohydrate against a non-active treatment, ensuring the reliability of the study results.
Efficacy
The efficacy of niraparib as a maintenance treatment in patients with advanced ovarian cancer will be assessed primarily through **progression-free survival (PFS)**. PFS is defined as the time from treatment randomization to the earlier date of assessment of progression or death by any cause in the absence of progression. This primary endpoint will provide a direct measure of the treatment's ability to delay disease progression compared to placebo.
Secondary endpoints will include overall survival (OS), observed changes from baseline in patient-reported outcomes (PROs) such as the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the EQ-5D-5L, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), and the EORTC-QLQ-OV28. Additionally, time to first subsequent therapy (TFST) and PFS2 will be evaluated. These secondary endpoints will provide a comprehensive understanding of the treatment's impact on both survival and quality of life.
Data collection for these endpoints will occur at specified intervals throughout the study, including at 4 weeks, 8 weeks, 12 weeks, and 24 weeks after the end of treatment (EOT). The use of validated scales and questionnaires will ensure the reliability and accuracy of the PROs. The analysis of these efficacy parameters will be conducted in accordance with the study protocol to ensure robust and scientifically valid results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must be female ≥18 years of age, able to understand the study procedures and agree to participate in the study by providing written informed consent.
- Patients must have adequate organ function, defined as follows (Note: complete blood count [CBC] test should be obtained without transfusion or receipt of stimulating factors within 2 weeks before obtaining screening blood sample): a. Absolute neutrophil count ≥1,500/µL b. Platelets ≥100,000/µL c. Hemoglobin ≥10 g/dL d. Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥60 mL/min using the Cockcroft-Gault equation. e. Total bilirubin ≤1.5 x ULN f. Aspartate aminotransferase and alanine aminotransferase ≤2.5 x ULN unless liver metastases are present, in which case they must be ≤5 x ULN.
- All patients must agree to complete PROs during study and then at 4 weeks, 8 weeks, 12 weeks, and 24 weeks after EOT, regardless of subsequent treatment.
- Patients must have formalin-fixed, paraffin-embedded tumor samples available from the primary cancer or agree to undergo fresh biopsy prior to study treatment initiation.
- Histological and staging criteria: a. Patients must have histologically diagnosed high-grade serous or endometrioid, or high-grade predominantly serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that is Stage III or IV according to FIGO criteria.
- Surgical criteria: a. Patients with inoperable Stage III and IV disease are eligible; b. All Stage IV patients with operable disease are eligible; c. Patients with stage III or IV disease treated with neoadjuvant chemotherapy and interval debulking surgery are eligible; d. Patients with stage III disease who have visible residual disease after primary debulking surgery are eligible.
- Chemotherapy criteria: a. Patients who have received intraperitoneal chemotherapy are eligible; b. All patients must have had ≥6 and ≤9 cycles of platinum-based therapy; Patients must have had ≥2 post-operative cycles of platinum-based therapy following interval debulking surgery; d. Patients must have physician assessed CR or PR after ≥3 cycles of therapy; e. Patients must have either CA-125 in the normal range or CA-125 decrease by more than 90% during their front-line therapy that is stable for at least 7 days (i.e., no increase >15% from nadir).
- Patients must be randomized within 12 weeks of the first day of the last cycle of chemotherapy.
- All patients must agree to undergo central tumor HRD testing. a. The central HRD test result must be available for randomization as it is a stratification factor. Patients with documented gBRCA1 or gBRCA2 mutation or sBRCA1/2 mutation may be randomized without HRD test results. b. The tumor sample may be submitted for HRD testing prior to the screening period if it appears the patient is likely to meet other eligibility requirements. Patients are not required to have repeat HRD testing if HRD result is “not determined” (e.g., due to insufficient tumor specimen). c. Patients with known HRD test results from a commercially available source are allowed to participate in the study; however, they must still agree to submit a tumor sample for central HRD testing. The results of the central HRD testing must be available prior to randomization and must be used for stratification. Additional testing related to HRD may be performed on the sample used for screening and randomization post randomization. If there is inadequate tissue remaining subsequent to the screening analysis, sites may be requested to provide additional tissue from the block used for screening purposes.
- Patients of childbearing potential must have a negative serum or urine pregnancy test (beta human chorionic gonadotropin [hCG]) within 7 days prior to receiving the first dose of study treatment.
- Patients must be postmenopausal, free from menses for >1 year, surgically sterilized, or willing to use adequate contraception to prevent pregnancy or must agree to abstain from activities that could result in pregnancy throughout the study, starting with enrollment through 180 days after the last dose of study treatment.
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Patients must be able to take oral medications.
Exclusion Criteria
- Patient has mucinous or clear cell subtypes of epithelial ovarian cancer, carcinosarcoma or undifferentiated ovarian cancer
- Patients with Stage III disease who have had complete cytoreduction (i.e., no visible residual disease) after primary debulking surgery
- Patient has undergone more than two debulking surgeries
- Patient is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and for up to 180 days after the last dose of study treatment
- Patient has a known hypersensitivity to the components of niraparib or its excipients;
- Patient is simultaneously enrolled in any clinical trial of niraparib or any other investigational therapy
- Patient has received prior treatment with a known PARP inhibitor or has participated in a study where any treatment arm included administration of a known PARP inhibitor
- Patient is planning to donate blood during the study or for 90 days after the last dose of study treatment.
- Patient has been diagnosed and/or treated for invasive cancer less than 5 years prior to study enrollment. Note: Patients with definitively treated uterine cervical or urinary tract carcinoma in situ, non-melanomatous skin cancer or ductal carcinoma in situ (DCIS) of the breast are not excluded.
- Patient has known brain or leptomeningeal metastases that are untreated or uncontrolled (i.e., new or worsening symptom or signs, or unstable steroid requirements)
- Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection
- Patient is to receive bevacizumab as maintenance treatment. Patients who have received bevacizumab with their first-line platinum-based therapy but are unable to receive bevacizumab as maintenance therapy due to adverse events or for any other reason are not excluded from study as long as the last dose of bevacizumab was received ≥28 days prior to signing the main informed consent form
- Patient is immunocompromised (patients with splenectomy are allowed).
- Patient has known, active hepatic disease (i.e., hepatitis B or C).
- Patient has had investigational therapy administered within 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study
- Patient has undergone major surgery (per Investigator judgment) within 3 weeks of starting the study or patient has not recovered from any effects of any major surgery
- Patient has had drainage of ascites within 4 weeks prior to enrollment
- Patient has undergone palliative radiotherapy encompassing >20% of the bone marrow within 1 week of the first dose of study treatment
- Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the patient’s participation for the full duration of the study treatment, including: a. Patient received a transfusion (platelets or red blood cells) within 2 weeks of the first dose of study treatment; b. Patient received colony-stimulating factors (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment.
- Patient has had any known ≥Grade 3 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted >4 weeks
- Patient has any known history or current diagnosis of MDS or AML
- Patient has a corrected QT interval (QTc) prolongation >480 milliseconds at screening
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 14 Sept 2016 | 52 |
 Czechia | Not Recruiting | 14 Sept 2016 | 12 |
 Denmark | Not Recruiting | 14 Sept 2016 | 32 |
 Finland | Not Recruiting | 14 Sept 2016 | 32 |
 France | Not Recruiting | 14 Sept 2016 | 72 |
 Germany | Not Recruiting | 14 Sept 2016 | 68 |
 Hungary | Not Recruiting | 14 Sept 2016 | 7 |
 Ireland | Not Recruiting | 14 Sept 2016 | 28 |
 Italy | Not Recruiting | 14 Sept 2016 | 68 |
 Poland | Not Recruiting | 14 Sept 2016 | 10 |
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 |
|---|---|---|---|---|---|---|
Placebo with a matching appearance to 100 mg niraparib capsules, filled with an excipient blend for clinical development. | Placebo | N/A | — | — | — | N/A |
NIRAPARIB TOSILATE MONOHYDRATE | Test | — | ORAL USE | 300 | 36 | SUB183938 |