A Comparison of Platinum-based Therapy With TSR-042 and Niraparib Versus Standard of Care (SOC) Platinum-based Therapy as First-line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer

Phase 3

Active, not recruiting

• Conditions: Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma; Ovarian Neoplasms
• Interventions: Drug: Standard of care; Drug: Niraparib; Drug: Dostarlimab (TSR-042); Drug: Dostarlimab-Placebo; Drug: Niraparib-Placebo

• Registration Number: NCT03602859
• Lead Sponsor: Tesaro, Inc.

Brief Summary

Ovarian cancer is a heterogeneous disease, characterized by complex molecular and genetic changes. The high expression of vascular endothelial growth factor (VEGF) receptor, programmed death receptor ligands 1 (PD-L1) expression, and deoxyribonucleic acid (DNA) damage in ovarian tumors provide several targets for treatment and maintenance of disease response. Given the unmet medical need of participants with advanced or metastatic ovarian cancer, this study design will enable investigators to provide participants with current SOC for ovarian cancer for the duration of the study. This is a global, multicenter, randomized, double-blind, controlled Phase 3 study that will primarily compare the progression-free survival (PFS) for participants receiving dostarlimab with SOC chemotherapy +/- bevacizumab followed by niraparib and dostarlimab maintenance +/- bevacizumab versus participants receiving SOC with chemotherapy followed by niraparib maintenance. This comparison will be investigated in participants of newly diagnosed stage III or IV advanced non-mucinous epithelial ovarian cancer participants and also to compare PFS of all participants with Stage III or IV high-grade non-mucinous epithelial ovarian cancer treated with platinum-based combination therapy, dostarlimab (TSR-042), and niraparib to SOC platinum-based combination therapy. The currently recommended SOC therapy for the first line treatment of Stage III or IV ovarian cancer is the combination of paclitaxel and carboplatin, with or without concurrent and maintenance bevacizumab. Participants will receive SOC during the chemotherapy Run-In period (cycle 1) before randomization to study treatment (cycle 2). Concurrent bevacizumab use must be determined prior to randomization at cycle 2.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-06-28
• Study First Submitted QC: 2018-07-18
• Study First Posted: 2018-07-27
• Study Start: 2018-10-11
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-14
• Last Update Posted: 2024-08-16
• Primary Completion: 2024-10-25
• Study Completion: 2026-06-22

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Female
• Target Recruitment: 1402

Inclusion Criteria

Not provided

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Exclusion Criteria

• Participant has mucinous, germ cell, transitional cell, or undifferentiated tumor.
• Participant has low-grade or Grade 1 epithelial ovarian cancer.
• Participant has not adequately recovered from prior major surgery.
• 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.
• Participant has a bowel obstruction by clinical symptoms or computed tomography (CT) scan, subocclusive mesenteric disease, abdominal or gastrointestinal fistula, gastrointestinal perforation, or intra-abdominal abscess.
• Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (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 (example, 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 non-melanomatous skin cancer are allowed.
• Participant is at increased bleeding risk due to concurrent conditions (example, 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.
• Participant has known active hepatitis B (example, hepatitis B surface antigen reactive) or hepatitis C (example, 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, anti-cancer 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 (example, 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Participants receiving SOC+niraparib	Dostarlimab-Placebo	Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/- bevacizumab with niraparib and dostarlimab placebo
Participants receiving SOC+dostarlimab+niraparib	Dostarlimab (TSR-042)	Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab, and maintenance treatment of +/-bevacizumab with niraparib and dostarlimab
Participants receiving SOC+placebo	Standard of care	Participants in this arm will receive SOC (carboplatin+paclitaxel+/-bevacizumab) in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment with dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/-bevacizumab along with niraparib placebo and dostarlimab placebo
Participants receiving SOC+dostarlimab+niraparib	Standard of care	Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab, and maintenance treatment of +/-bevacizumab with niraparib and dostarlimab
Participants receiving SOC+placebo	Dostarlimab-Placebo	Participants in this arm will receive SOC (carboplatin+paclitaxel+/-bevacizumab) in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment with dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/-bevacizumab along with niraparib placebo and dostarlimab placebo
Participants receiving SOC+placebo	Niraparib-Placebo	Participants in this arm will receive SOC (carboplatin+paclitaxel+/-bevacizumab) in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment with dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/-bevacizumab along with niraparib placebo and dostarlimab placebo
Participants receiving SOC+niraparib	Standard of care	Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/- bevacizumab with niraparib and dostarlimab placebo
Participants receiving SOC+niraparib	Niraparib	Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/- bevacizumab with niraparib and dostarlimab placebo
Participants receiving SOC+dostarlimab+niraparib	Niraparib	Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab, and maintenance treatment of +/-bevacizumab with niraparib and dostarlimab

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Up to 6 years	To compare the PFS of all participants with Stage III or IV high-grade nonmucinous epithelial ovarian cancer given first-line treatment with the combination of dostarlimab with SOC chemotherapy +/- bevacizumab followed by niraparib and dostarlimab maintenance +/- bevacizumab versus SOC chemotherapy +/- bevacizumab followed by niraparib maintenance +/- bevacizumab. 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. PFS will be evaluated by investigator assessment per RECIST v1.1 criteria.

Secondary Outcome Measures

Name	Time	Method
Disease control rate (DCR)	Up to 6 years	DCR, defined as the proportion of participants with a best overall response of CR, PR, or stable disease (SD), as assessed by RECIST v1.1 criteria.
Number of participants with positive antidrug antibodies (ADAs) against dostarlimab	Up to 6 years	Serum samples will be collected for the analysis of the presence of ADAs using validated immunoassays.
Overall Survival (OS)	Up to 7 years	OS is defined as the date of randomization to the date of death by any cause
Time to second subsequent therapy (TSST)	Up to 6 years	TSST is defined as the time from randomization until the start date of the second subsequent anti-cancer therapy or death, whichever occurs first
Time to progression on next-line therapy (PFS2)	Up to 6 years	PFS2 is defined as the time from randomization until PD per investigator's assessment after starting follow-up anti-cancer therapy or death due to any cause, whichever occurs first
Number of participants with serious adverse events (SAEs)	Up to 6 years	SAEs are any adverse event that may result in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital abnormality or birth defect, is an important medical event.
PFS by Blinded Independent Central Review (BICR) per investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) criteria	Up to 6 years	BICR determined PFS will be assessed as per RECIST criteria.
Change from Baseline in the European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) assessment	Baseline and up to 6 years	EQ-5D-5L is a validated questionnaire to assess the overall health-related quality of life in participants across diseases. EQ-5D-5L consists of a descriptive section of 5 questions/dimensions, one related to each of: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is measured by 5-point Likert scale (no problems, slight problems, moderate problems, severe problems and extreme problems)
Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30) assessment	Baseline and up to 6 years	EORTC QLQ-C30 is a validated questionnaire to assess the overall health-related quality of life in participants with cancer and is composed of 30 questions including multi-item scales and single item measures. These include five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/quality of life scale (GHS/QOL), and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). Response options are 1 to 4. Higher score indicates better health-related quality of life.
Time to first subsequent therapy (TFST)	Up to 6 years	TFST is defined as the time from randomization until the start date of the first subsequent anti-cancer therapy or death, whichever occurs first
Duration of response (DOR)	Up to 6 years	DOR, defined as the time from first documentation of CR or PR until the time of first documentation of PD as assessed by RECIST v1.1, or death by any cause in the absence of progression, whichever occurs first.
Plasma concentration of dostarlimab	Up to 6 years	Blood samples will be collected for pharmacokinetic analysis of dostarlimab
Change from Baseline in the EORTC-QLQ Ovarian Cancer Module OV28 (EORTC-QLQ-OV28) assessment	Baseline and up to 6 years	EORTC QLQ-OV28 is a validated questionnaire to assess the overall health-related quality of life in participants with local or advanced ovarian cancer. EORTC QLQ-OV28 consists of 28 questions evaluated across eight multi-item and 4 single item scales: abdominal/ gastrointestinal (GI) symptoms, peripheral neuropathy, hormonal symptoms, body image, attitude to disease/treatment, chemotherapy side effects, and sexuality, and single items scales for indigestion/heartburn, hair loss, upset due to hair loss, and taste. All questions are rated on a 4 point verbal rating scale: "Not at all," "A little," "Quite a bit," and "Very much."
Objective Response Rate (ORR)	Up to 6 years	ORR, defined as the percentage of participants with complete response (CR) or partial response (PR) on study treatment as assessed by RECIST v1.1 criteria for participants with measurable disease.
Number of participants with treatment discontinuations or dose delays or dose reductions due to adverse events	Up to 6 years	Adverse events are any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment.
Number of participants with abnormal hematology results	Up to 6 years	Blood samples will be collected for the analysis of hematologic parameters including: hemoglobin, platelet count, white blood cell count, differential white blood cell count, coagulation factors-International normalized ratio (INR) and activated partial thromboplastin time.
Number of participants with abnormal clinical chemistry results	Up to 6 years	Blood samples will be collected for the analysis of clinical chemistry parameters including: amylase, thyroid function (thyroid stimulating hormone \[TSH\]), urea or blood urea nitrogen, creatinine, albumin, total protein, ALT, AST, total bilirubin, Glucose, Magnesium, Calcium, Chloride, Potassium and Sodium.
Number participants with immune-related adverse events (irAEs)	Up to 6 years	Following events are categorized as irAEs: Diarrhea/colitis, AST or ALT (\>3 and \<=5 X ULN), or increased bilirubin, T1DM or hyperglycemia, immune-related encephalitis, uveitis, myositis, hypophysitis, adrenal insufficiency, hypo- and hyperthyroidism, infusion-related reaction, pneumonitis, immune-related rash, renal failure or nephritis and recurrence of AEs after resolution to Grade \<=1.
Plasma concentration of niraparib	Up to 6 years	Blood samples will be collected for pharmacokinetic analysis of niraparib.
Number of participants with treatment-emergent adverse events (TEAEs)	Up to 6 years	TEAEs are defined as, any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment.
Number of participants with changes in Eastern Cooperative Oncology Group (ECOG) performance status	Up to 6 years	Performance status will be assessed using the ECOG performance status scale: ranging from Grade 0 to 5, Grade 0 denoting fully active and Grade 5 denoting death.

Trial Locations

Locations (1)

GSK Investigational Site; 🇬🇧 Wirral, United Kingdom