Phase 3 Randomized, Double-Blind Study of Platinum-Based Therapy with Dostarlimab and Niraparib vs. Standard Care in Stage III/IV Non-Mucinous Epithelial Ovarian Cancer
- Trial ID
- 2024-510605-28-00
- Protocol
- 213350/3000-03-005
- Sponsor
- Tesaro Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival** (PFS) of a treatment regimen consisting of platinum-based combination therapy, **dostarlimab**, and **niraparib** (Arm 3) with a regimen of platinum-based combination therapy and niraparib (Arm 2) in participants diagnosed with Stage III or IV high-grade non-mucinous epithelial ovarian cancer. This comparison is clinically relevant as it aims to determine the efficacy of adding dostarlimab to the existing treatment protocol, potentially improving patient outcomes by delaying disease progression.
Secondary objectives include evaluating the following parameters for the comparison between Arm 3 and Arm 2: - **Overall survival** (OS) - Blinded Independent Central Review (BICR) determined PFS per RECIST v1.1 criteria - Health-related quality of life (HRQoL) - Time to first subsequent therapy (TFST) - Time to second subsequent therapy (TSST) - Time from randomization to the earliest date of assessment of progression after initiation of subsequent anticancer therapy following study treatment or death by any cause (PFS2) - Objective response rate (ORR) per RECIST v1.1 for participants with measurable disease at baseline - Duration of response (DOR) per RECIST v1.1 for participants with measurable disease at baseline - Disease control rate (DCR) per RECIST v1.1 for participants with measurable disease at baseline - Pharmacokinetics (PK) and immunogenicity of dostarlimab - PK of niraparib
Additionally, secondary objectives for all participants across the three treatment arms (platinum-based combination therapy alone, with niraparib, and with both dostarlimab and niraparib) will assess the **safety and tolerability** of these regimens. These evaluations are crucial for understanding the overall benefit-risk profile of the treatments, ensuring that any potential improvements in efficacy do not come at the cost of increased adverse effects.
Participants
The clinical trial involves a total of **708 participants** diagnosed with **Stage 3 or 4 Non-mucinous Epithelial Ovarian Cancer**. The study population is exclusively female, aged 18 years and older, and includes individuals with a histologically confirmed diagnosis of high-grade nonmucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer. Participants are required to have an 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 population was selected based on specific inclusion criteria, including the ability to understand study procedures and provide informed consent, as well as having normal or controlled blood pressure. Participants must be able to take oral medication and agree to complete health-related quality of life questionnaires throughout the study. Lifestyle considerations such as diet and physical activity are not specified, but participants must have adequate organ function and, if of childbearing potential, must use effective contraception or abstain from activities that could result in pregnancy. The trial does not include male subjects and involves a vulnerable population, as indicated by the selection criteria. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of a combination therapy involving **dostarlimab** and **niraparib tosilate monohydrate** compared to standard platinum-based therapy in patients with Stage III or IV non-mucinous epithelial ovarian cancer. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS) and various health-related quality of life (HRQoL) assessments. The trial is expected to span approximately eight years, with an estimated recruitment start date in September 2018 and an anticipated end date in June 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and organ function. Following randomization, participants will receive either the investigational combination therapy or the standard therapy. Study visits will include regular follow-up assessments to monitor treatment response, adverse events, and compliance with the study protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
The expected length of participant involvement is up to 72 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events that compromise participant safety, or voluntary withdrawal by the participant. Throughout the trial, participants will be required to complete HRQoL questionnaires and provide blood and tumor tissue samples for biomarker analysis. The trial's design ensures that all participants, including those receiving placebo, are blinded to the treatment allocation to maintain the integrity of the study results.
Treatment
The clinical trial involves the administration of **Niraparib Tosilate Monohydrate**, a chemical compound provided in the form of a hard capsule. The pharmaceutical product, identified by the sponsor product code GSK3985771, is manufactured by GlaxoSmithKline. The maximum daily dose is 300 mg, administered orally. The treatment period extends up to 72 weeks. Participants' compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
**Dostarlimab**, marketed under the name JEMPERLI, is another investigational product used in this trial. It is a concentrate for solution for infusion, containing 500 mg of the active substance. Dostarlimab is administered intravenously, with a maximum daily dose of 1000 mg. The treatment duration is also set for a maximum of 72 weeks. The product is a monoclonal antibody targeting the Programmed Cell Death Protein 1 (PD-1) and is produced by GlaxoSmithKline (Ireland) Limited. The administration of dostarlimab is conducted under controlled conditions, with compatibility and transfer protocols detailed in the study's documentation.
A **placebo** is utilized in this study to maintain blinding. The placebo is designed to be identical in appearance to the active drugs but lacks the active drug substances. It is available in the form of Niraparib placebo tablets and Dostarlimab placebo infusion bags. The placebo administration follows the same route and schedule as the active treatments to ensure the integrity of the double-blind study design.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from the date of randomization to the date of first documentation of disease progression or death by any cause, whichever occurs first. This endpoint will provide a direct measure of the treatment's impact on delaying disease progression in participants with Stage III or IV high-grade nonmucinous epithelial ovarian cancer.
Secondary efficacy endpoints include Overall Survival (OS), which measures the time from randomization to death by any cause, and PFS as determined by Blinded Independent Central Review (BICR) per RECIST v1.1 criteria. Additional secondary endpoints involve patient-reported outcomes such as the EQ-5D-5L Visual Analogue Score (VAS) and Health Utility Index (HUI) for Health-Related Quality of Life (HRQoL) assessments, as well as the EORTC QLQ C30 and EORTC QLQ OV28 HRQoL assessments. Other secondary endpoints include Time to First Subsequent Therapy (TFST), Time to Second Subsequent Therapy (TSST), PFS2, Objective Response Rate (ORR), Duration of Response (DOR), and Disease Control Rate (DCR).
The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on disease progression and patient quality of life. The use of validated scales and criteria, such as RECIST v1.1, ensures the reliability and accuracy of the efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants 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.
- Participants with a histologically confirmed diagnosis of high-grade nonmucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the FIGO or tumor, node and metastasis staging criteria [i.e., American Joint Committee on Cancer].
- All participants with Stage IV disease are eligible. This includes those with inoperable disease, those who undergo PDS (R0 or macroscopic disease), or those for whom NACT is planned.
- Participants with Stage III are eligible if they meet one or more of the following criteria: a. Stage IIIC participants CC0 resection if they meet the following criteria: aggregate ≥ 5 cm extra-pelvic disease during PDS as assessed by the Investigator. b. All participants with inoperable Stage III disease. c. All Stage III participants with macroscopic residual tumor (per Investigator judgment) following PDS. d. All Stage III participants for whom NACT is planned.
- Participant must provide a blood sample for ctDNA HRR testing at PreScreening or Screening.
- Participant must provide sufficient tumor tissue sample (a minimum of 1 FFPE block or slide at Pre-Screening or Screening) for programmed death ligand 1 (PD-L1), HRD testing.
- Participants of childbearing potential must have a negative serum or urine pregnancy test (beta human chorionic gonadotropin) within 3 days prior to receiving the first dose of study treatment.
- Participants must be postmenopausal, free from menses for >1 year, surgically sterilized, or willing to use highly effective 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.
- Participants must have adequate organ function, defined as follows (Note: 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. Platelet count ≥100,000/µL c. Hemoglobin ≥9 g/dL d. Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≥60 mL/min using the Cockcroft Gault equation e. Total bilirubin ≤1.5 × ULN or direct bilirubin ≤1.5 × ULN f. Aspartate aminotransferase and alanine aminotransferase (ALT) ≤2.5 × ULN unless liver metastases are present, in which case they must be ≤5 × ULN
- Participants must have an ECOG score of 0 or 1.
- Participants must have normal BP or adequately treated and controlled hypertension (systolic BP ≤140 mmHg and/or diastolic BP ≤90 mmHg).
- Participants must agree to complete HRQoL questionnaires throughout the study.
- Participants must be able to take oral medication.
Exclusion Criteria
- Participant has mucinous, germ cell, transitional cell, or undifferentiated tumor.
- Participant has low grade or Grade 1 epithelial ovarian cancer.
- Stage III participant with CC0 resection after PDS (i.e., no macroscopic residual disease, unless inclusion criterion #4a is met).
- Participant has not adequately recovered from prior major surgery.
- Participant has a known condition, therapy, or laboratory abnormality that might confound the study results or interfere with the participant's participation for the full duration of the study treatment in the opinion of the Investigator.
- Participant is pregnant or is expecting to conceive children while receiving study drug or for up to 180 days after the last dose of study drug. Participant is breastfeeding or is expecting to breastfeed within 30 days of receiving the final dose of study drug (women should not breastfeed or store breastmilk for use, during niraparib treatment and for 30 days after receiving the final dose of study treatment).
- Participant has known active central nervous system metastases, carcinomatous meningitis, or both.
- Participant has clinically significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, uncontrolled cardiac arrhythmia or unstable angina <6 months to enrollment, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident within 6 months).
- Participant has a bowel obstruction by clinical symptoms or CT scan, subocclusive mesenteric disease, abdominal or gastrointestinal fistula, gastrointestinal perforation, or intra abdominal abscess.
- Participant initiating bevacizumab as SOC has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at Screening or urine dipstick for proteinuria ≥2 (participants discovered to have ≥2 proteinuria on dipstick at baseline should undergo a 24 hour urine collection and must demonstrate <2 g of protein in 24 hours to be eligible).
- Participant has any known history or current diagnosis of MDS or AML.
- Participant has been diagnosed and/or treated with any therapy for invasive cancer <5 years from study enrollment, completed adjuvant chemotherapy and/or targeted therapy (e.g., trastuzumab) less than 3 years from enrollment, or completed adjuvant hormonal therapy less than 4 weeks from enrollment. Participants with definitively treated non- invasive malignancies such as cervical carcinoma in situ, ductal carcinoma in situ, Grade 1 or 2, Stage I endometrial cancer, or nonmelanomatous skin cancer are allowed.
- Participant is at increased bleeding risk due to concurrent conditions (e.g., major injuries or major surgery within the past 28 days prior to start of study treatment and/or history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
- Participant is immunocompromised. Participants with splenectomy are allowed. Participants with known HIV are allowed if they meet all criteria as listed in the protocol. a. Cluster of differentiation 4 ≥350/µL and viral load <400 copies/mL b. No history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrollment c. No history of HIV associated malignancy for the past 5 years d. Concurrent antiretroviral therapy as per the most current National Institutes of Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV started >4 weeks prior to study enrollment.
- Participant has known active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative] is detected).
- Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non- malignant systemic disease, or uncontrolled infection.
- Participant 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.
- Participant has received a live vaccine within 14 days of planned start of study therapy. Seasonal influenza vaccines that do not contain live viruses are allowed.
- Participant has a known contraindication or uncontrolled hypersensitivity to the components of paclitaxel, carboplatin, niraparib, bevacizumab, dostarlimab, or their excipients.
- Prior treatment for high-grade nonmucinous epithelial ovarian, fallopian tube, or peritoneal cancer (immunotherapy, anticancer therapy, radiation therapy).
- Participant has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone or insulin).
- Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 03 Sept 2018 | 34 |
 Czechia | Not Recruiting | 03 Sept 2018 | 18 |
 Denmark | Not Recruiting | 03 Sept 2018 | 40 |
 Finland | Not Recruiting | 03 Sept 2018 | 40 |
 France | Not Recruiting | 03 Sept 2018 | 400 |
 Germany | Not Recruiting | 03 Sept 2018 | 45 |
 Greece | Not Recruiting | 03 Sept 2018 | 50 |
 Italy | Not Recruiting | 03 Sept 2018 | 80 |
 The Netherlands | Not Recruiting | 03 Sept 2018 | — |
 Norway | Not Recruiting | 03 Sept 2018 | 26 |
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 is identical to the active drugs but without the active drug substance to maintain study blinding. Niraparib placebo tablets, Dostarlimab placebo infusion bags | Placebo | N/A | — | — | — | N/A |
JEMPERLI 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1000.00 | 72 | PRD8877508 |