A Phase 3 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 (FIRST)

• ClinicalTrials.gov Identifier: NCT03602859
• Recruitment Status: Active, not recruiting
• First Posted: July 27, 2018
• Last Update Posted: January 28, 2021
• Sponsor: Tesaro, Inc.
• Collaborator: European Network of Gynaecological Oncological Trial Groups (ENGOT)
• Information provided by (Responsible Party): Tesaro, Inc.

Tracking Information

• First Submitted Date: June 28, 2018
• First Posted Date: July 27, 2018
• Last Update Posted Date: January 28, 2021
• Actual Study Start Date: October 11, 2018
• Estimated Primary Completion Date: January 20, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 20, 2020)

• PFS for PD-L1 positive participants [ Time Frame: Up to 5 years ]
  To compare the PFS of PD-L1 positive participants with Stage III or IV non-mucinous epithelial ovarian cancer treated with platinum-based combination therapy, dostarlimab, and niraparib to standard of care platinum-based combination therapy as first-line treatment. 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. Progression free survival will be evaluated by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria.
• PFS for all participants [ Time Frame: Up to 5 years ]
  To compare the PFS of all participants with Stage III or IV high-grade nonmucinous epithelial ovarian cancer treated with platinum-based combination therapy, dostarlimab, and niraparib to SOC platinum-based combination therapy. 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. Progression free survival will be evaluated by investigator assessment per RECIST v.1.1 criteria.

Original Primary Outcome Measures (submitted: July 18, 2018)

Progression Free Survival [ Time Frame: Up to 5 years ]

To compare the progression free survival of patients with Stage III or IV nonmucinous epithelial ovarian cancer treated with platinum-based therapy, TSR-042, and niraparib to standard of care platinum-based therapy as first-line treatment. Progression free survival 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. Progression free survival will be evaluated by Investigator assessment per RECIST v.1.1 criteria.

Current Secondary Outcome Measures (submitted: April 20, 2020)

• Blinded Independent Central Review (BICR) for PD-L1 positive participants [ Time Frame: Up to 5 years ]
  BICR determined by PFS will be derived as per RECIST v1.
• BICR for all the participants [ Time Frame: Up to 5 years ]
  BICR determined by PFS will be derived as per RECIST v1.1
• PFS per investigator-assessed immune-related of PD-L1 positive participants [ Time Frame: Up to 5 years ]
  PFS will be assessed as per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria.
• PFS per investigator-assessed immune-related for all the participants [ Time Frame: Up to 5 years ]
  PFS will be assessed as per irRECIST criteria.
• Overall Survival (OS) of PD-L1 positive participants [ Time Frame: Up to 5 years ]
  The OS is defined as the date of randomization to the date of death by any cause.
• OS of all the participants [ Time Frame: Up to 5 years ]
  The OS is defined as the date of randomization to the date of death by any cause.
• Number of PD-L1 positive participants with treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 5 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 overall participants with TEAEs [ Time Frame: Up to 5 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 PD-L1 positive participants with serious adverse events (SAEs) [ Time Frame: Up to 5 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.
• Number of overall participants with SAEs [ Time Frame: Up to 5 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.
• Number of PD-L1 positive participants with treatment discontinuations or dose delays or dose reductions due to adverse events [ Time Frame: Up to 5 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 all the participants with treatment discontinuations or dose delays or dose reductions due to adverse events [ Time Frame: Up to 5 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 PD-L1 positive participants with immune-related adverse events of interest (irAEIs) [ Time Frame: Up to 5 years ]
  Following events are categorized as irAEIs: Diarrhea/colitis, aspartate aminotransferase (AST) or alanine aminotransferase (ALT; >3 and <=5 X upper limit of normal [ULN]), or increased bilirubin, type 1 diabetes mellitus (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 adverse events after resolution to Grade <=1.
• Number of all the participants with irAEIs [ Time Frame: Up to 5 years ]
  Following events are categorized as irAEIs: 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.
• Number of PD-L1 positive participants with changes in Eastern Cooperative Oncology Group (ECOG) performance status [ Time Frame: Up to 5 years ]
  Performance status will be assessed using the ECOG scale
• Number of overall participants with changes in ECOG performance status [ Time Frame: Up to 5 years ]
  Performance status will be assessed using the ECOG scale
• Number of PD-L1 positive participants with abnormal hematology results [ Time Frame: Up to 5 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 all the participants with abnormal hematology results [ Time Frame: Up to 5 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-INR and activated partial thromboplastin time.
• Number of PD-L1 positive participants with abnormal blood chemistry results [ Time Frame: Up to 5 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 of all the participants with abnormal blood chemistry results [ Time Frame: Up to 5 years ]
  Blood samples will be collected for the analysis of clinical chemistry parameters including:: amylase, thyroid function (TSH), urea or blood urea nitrogen, creatinine, albumin, total protein, ALT, AST, total bilirubin, Glucose, Magnesium, Calcium, Chloride, Potassium and Sodium.
• Change from Baseline in the European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) assessment among PD-L1 positive participants [ Time Frame: Baseline and Up to 5 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, one related to each of: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
• Change from Baseline in the EQ-5D-5L assessment among all participants [ Time Frame: Baseline and Up to 5 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, one related to each of: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
• Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30) assessment among PD-L1 positive participants [ Time Frame: Baseline and Up to 5 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).
• Change from Baseline in the EORTC-QLQ-C30 assessment among all the participants [ Time Frame: Baseline and Up to 5 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 GHS/QOL, and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).
• Change from Baseline in the EORTC-QLQ Ovarian Cancer Module OV28 (EORTC-QLQ-OV28) assessment among PD-L1 positive participants [ Time Frame: Baseline and Up to 5 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/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.
• Change from Baseline in the EORTC-QLQ-OV28 assessment among all the participants [ Time Frame: Baseline and Up to 5 years ]
  EORTC QLQ-OV28 is a validated questionnaire to assess the overall he PFS2, 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/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.
• Time to symptom worsening in the EQ-5D-5L assessment among the PD-L1 positive participants [ Time Frame: Up to 5 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, one related to each of: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
• Time to symptom worsening in the EQ-5D-5L assessment among all the participants [ Time Frame: Up to 5 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, one related to each of: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
• Time to symptom worsening in the EORTC-QLQ-C30 assessment among the PD-L1 positive participants [ Time Frame: Up to 5 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 GHS/QOL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).
• Time to symptom worsening in the EORTC QLQ-C30 assessment among all the participants [ Time Frame: Up to 5 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 GHS/QOL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).
• Time to symptom worsening in the EORTC-QLQ-OV28 assessment among the PD-L1 positive participants [ Time Frame: Up to 5 years ]
  EORTC QLQ-OV28 is a validated questionnaire to assess the overall he PFS2, 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/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.
• Time to symptom worsening in the EORTC-QLQ-OV28 assessment among all the participants [ Time Frame: Up to 5 years ]
  EORTC QLQ-OV28 is a validated questionnaire to assess the overall he PFS2, alth-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/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.
• Time to first subsequent therapy (TFST) in PD-L1 positive participants [ Time Frame: Up to 5 years ]
  TFST is defined as the duration between the date of randomization in the current study to the start date of the first subsequent anticancer therapy.
• TFST in all the participants [ Time Frame: Up to 5 years ]
  TFST is defined as the duration between the date of randomization in the current study to the start date of the first subsequent anticancer therapy.
• Time to second subsequent therapy (TSST) in PD-L1 positive participants [ Time Frame: Up to 5 years ]
  TSST, defined as the duration between the date of randomization in the current study to the start date of the second subsequent anticancer therapy.
• TSST in all the participants [ Time Frame: Up to 5 years ]
  TSST, defined as the duration between the date of randomization in the current study to the start date of the second subsequent anticancer therapy.
• Time to progression on next-line therapy (PFS2,) in PD-L1 positive participants [ Time Frame: Up to 5 years ]
  PFS2, defined as the time from randomization to the earlier date of assessment of progression on the next anticancer therapy following study treatment or death by any cause as assessed by the investigator.
• PFS2 in all the participants [ Time Frame: Up to 5 years ]
  PFS2, defined as the time from randomization to the earlier date of assessment of progression on the next anticancer therapy following study treatment or death by any cause as assessed by the investigator.
• Objective Response Rate (ORR) among PD-L1 positive participants [ Time Frame: Up to 5 years ]
  ORR, defined as the percentage of participants with complete response (CR) or partial response (PR) on study treatment as assessed by RECIST v.1.1 criteria for participants with measurable disease. ORR will also be assessed per irRECIST criteria.
• ORR among all the participants [ Time Frame: Up to 5 years ]
  ORR, defined as the percentage of participants with complete response (CR) or partial response (PR) on study treatment as assessed by RECIST v.1.1 criteria for participants with measurable disease. ORR will also be assessed per irRECIST criteria.
• Pathologic complete response (pCR) rate among PD-L1 positive participants [ Time Frame: Up to 5 years ]
  pCR rate, per investigator assessment, defined as the rate of pathologic complete responseas assessed by the evaluation of residual microscopic disease at the time of surgery in neoadjuvant participants.
• pCR rate among all the participants [ Time Frame: Up to 5 years ]
  pCR rate, per investigator assessment, defined as the rate of pathologic complete responseas assessed by the evaluation of residual microscopic disease at the time of surgery in neoadjuvant participants.
• Duration of response (DOR) in PD-L1 positive participants [ Time Frame: Up to 5 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 v.1.1, or death by any cause in the absence of progression, whichever occurs first. DOR will also be assessed per irRECIST criteria.
• DOR in all the participants [ Time Frame: Up to 5 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 v.1.1, or death by any cause in the absence of progression, whichever occurs first. DOR will also be assessed per irRECIST criteria.
• Disease control rate (DCR) in PD-L1 positive participants [ Time Frame: Up to 5 years ]
  DCR, defined as the proportion of participants with a best overall response of CR, PR, or stable disease, as assessed by RECIST v.1.1 criteria. DCR will also be assessed per irRECIST criteria.
• DCR in all the participants [ Time Frame: Up to 5 years ]
  DCR, defined as the proportion of participants with a best overall response of CR, PR, or stable disease, as assessed by RECIST v.1.1 criteria. DCR will also be assessed per irRECIST criteria.
• Maintenance progression-free survival (MPFS) in PD-L1 positive participants [ Time Frame: Up to 5 years ]
  MPFS, defined as the time from the date of the first maintenance period dose to the date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first, as determined by the investigator. Progression will be assessed by RECIST v.1.1 criteria. MPFS will also be assessed per irRECIST criteria.
• MPFS in all the participants [ Time Frame: Up to 5 years ]
  MPFS, defined as the time from the date of the first maintenance period dose to the date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first, as determined by the investigator. Progression will be assessed by RECIST v.1.1 criteria. MPFS will also be assessed per irRECIST criteria.

Original Secondary Outcome Measures (submitted: July 18, 2018)

• Overall Survival [ Time Frame: Up to 5 years ]
  The time from the date of randomization until the date of death by any cause.
• Assessment of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: Up to 5 years ]
  Assessment of the percentage of participants with adverse events and serious adverse events observed throughout the study, and for 30 days (adverse events), 90 days (serious adverse events) after cessation of study treatment, or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy.
• Time to deterioration in the European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) [ Time Frame: Up to 5 years ]
  EQ-5D-5L is a validated questionnaire to assess the overall health-related quality of life in patients across diseases. EQ-5D-5L consists of a descriptive section of 5 questions, one related to each of: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Questions use a 5-point scale ("no problems", "slight problems", "moderate problems", "severe problems", "unable/extreme problems"). Scores are converted to an index value based on country-specific value sets, with a value of 0 representing "death" and 1 representing "perfect health"). The EQ-5D-5L also includes a visual-analogue scale of overall health on a 100-point scale (from "Worst imaginable health state" to "Best imaginable health state").
• Time to deterioration in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) [ Time Frame: Up to 5 years ]
  EORTC QLQ-C30 is a validated questionnaire to assess the overall health-related quality of life in patients 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). The QLQ-C30 employs a week recall period for all items and a 4-point scale for the functional and symptom scales/items with response categories "Not at all", "A little", "Quite a bit" and "Very much". The two items assessing GHS/QOL utilize a 7-point scale ranging from 1 ("Very Poor") to 7 ("Excellent"). Scores are averaged, and transformed to a 0-100 scale. A higher score on functional scales represents better function, and on symptom scales represents more severe symptoms.
• Time to deterioration in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Ovarian Cancer (EORTC QLQ-OV28) [ Time Frame: Up to 5 years ]
  EORTC QLQ-OV28 is a validated questionnaire to assess the overall health-related quality of life in patients with local or advanced ovarian cancer. EORTC QLQ-OV28 consists of 28 questions evaluated across eight multi-item and 4 single item scales: abdominal/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. Questions use a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores are averaged, and transformed to a 0-100 scale; a higher score represents a more severe overall side effect of treatment.
• Objective Response Rate [ Time Frame: Up to 5 years ]
  The percentage of patients with complete response or partial response on study treatment as assessed by RECIST v.1.1 criteria for patients with measurable disease. Objective response rate will also be assessed per irRECIST criteria.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 3 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
• Official Title: ENGOT-0V44 The FIRST (First-line Ovarian Cancer Treatment With Niraparib Plus TSR-042) Study: A Randomized, Double-blind, Phase 3 Comparison of Platinum-based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-based Therapy as First-line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer
• 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 progressive survival rate of PD-L1 positive patients and also to compare progression-free survival (PFS) of all participants with Stage III or IV high-grade nonmucinous epithelial ovarian cancer treated with platinum-based combination therapy, dostarlimab, 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. Approximately 1228 participants will be enrolled into the study and the duration of the study will be approximately 78 months.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Ovarian Neoplasms
• Ovarian Cancer

Intervention

• Drug: Niraparib
  Participants in each arm will receive oral capsules of niraparib as a unit dosage strength of 100 milligrams (mg).
  Other Name: ZEJULA
• Drug: Dostarlimab (TSR-042)
  Participants will receive 30 minutes intravenous (IV) infusions of 1000 mg dostarlimab on Day 1 every 6 weeks.
• Drug: Placebo
  Capsule with no active drug to mimic Niraparib, or IV fluid with no active drug to mimic Dostarlimab (TSR-042)
• Drug: Standard of care
  Participants will receive SOC that includes paclitaxel 175 milligrams per square meter (mg/m^2) on day 1 every 21 days + area under the curve (AUC) of 5 to 6 milligrams per milliliter per minute (mg/mL/min) on day 1 every 21 days + bevacizumab 7.5 milligrams per kilograms (mg/kg) every 21 days or 15 mg/kg every 21 days for a total of 15 months.
• Drug: Dostarlimab/Placebo
  Participants will receive 1000 mg of dostarlimab/placebo on day 1 every 6 weeks to continue up to 3 years in the absence of disease progression, unacceptable toxicity, patient withdrawal, or investigator decision
• Drug: Niraparib/Placebo
  Participants in each arm will receive oral capsules of niraparib/placebo as a unit dosage strength of 100 mg.

Study Arms

• Placebo Comparator: Participants receiving SOC+placebo
  Participants in this arm will receive SOC (carboplatin+paclitaxel+bevacizumab) in cycle 1 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.
  Interventions:

  • Drug: Placebo
  • Drug: Standard of care
  • Drug: Dostarlimab/Placebo
  • Drug: Niraparib/Placebo
• Active Comparator: Participants receiving SOC+niraparib
  Participants in this arm will receive SOC in cycle 1 followed by SOC with chemotherapy treatment dostarlimab placebo from cycles 2 to 6 and maintenance treatment of bevacizumab with niraparib and dostarlimab placebo.
  Interventions:

  • Drug: Niraparib
  • Drug: Placebo
  • Drug: Standard of care
  • Drug: Dostarlimab/Placebo
• Experimental: Participants receiving SOC+dostarlimab
  Participants in this arm will receive SOC in cycle 1 followed by SOC with chemotherapy treatment dostarlimab, and maintenance treatment of bevacizumab with niraparib and dostarlimab.
  Interventions:

  • Drug: Niraparib
  • Drug: Dostarlimab (TSR-042)
  • Drug: Standard of care

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 14, 2021): 1405
• Original Estimated Enrollment (submitted: July 18, 2018): 960
• Estimated Study Completion Date: June 22, 2026
• Estimated Primary Completion Date: January 20, 2023 (Final data collection date for primary outcome measure)

Eligibility 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, an mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria.
• All participants with Stage IV disease are eligible. This includes those with inoperable disease, those who undergo primary debulking surgery (PDS); (complete cytoreduction [CC0] or macroscopic disease), or those for whom neoadjuvant chemotherapy (NACT) is planned.

• Participants with Stage III are eligible if they meet one or more of the following criteria:

  1. Stage IIIC participants with CC0 resection if they meet the following criteria: Aggregate >=5 cm extra-pelvic disease during PDS as assessed by the investigator
  2. All participants with inoperable Stage III disease.
  3. All Stage III participants with macroscopic residual tumor (per investigator judgement) following PDS.
  4. All Stage III participants for whom NACT is planned..
• Participants must provide a blood sample for circulating tumor deoxyribonucleic acid (ctDNA) homologous recombinant repair (HRR) testing at pre-screening or screening.
• Participant must provide a minimum of formalin-fixed paraffin embedded (FFPE) block at pre-screening or screening for PD-L1, homologous recombinant deficiency (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: Absolute neutrophil count ANC >=1500/micro liter (μL;) Platelet count >=100000/μL; Hemoglobin >=9 grams per deciliter (g/dL); Serum creatinine <=1.5 × upper limit of normal (ULN) or calculated creatinine clearance >=60 milliliters per minute (mL/min) using the Cockcroft-Gault equation; total bilirubin <=1.5 × ULN or direct bilirubin <=1.5 × ULN; AST and ALT <=2.5 × ULN unless liver metastases are present, in which case they must be <=5 × ULN.
• Participants must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
• Participants must have normal blood pressure (BP) or adequately treated and controlled hypertension (systolic BP <=140 millimeters of mercury (mmHg) and/or diastolic BP <=90 mmHg).
• Participants must agree to complete health related quality of life (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 R0 resection after PDS (i.e., no macroscopic residual disease, unless the participant has aggregate 5cm extra-pelvic disease during primary debulking surgery.
• 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 (example, 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 computed tomography (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 grams (g) of protein in 24 hours to be eligible).
• 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 IA 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. Participants with splenectomy are allowed. Participants with well-controlled known HIV are allowed if they meet all of the following criteria: Cluster of differentiation 4 >=350/μL and viral load <400 copies/mL; No history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrolment; No history of HIV-associated malignancy for the past 5 years; Concurrent anti-retroviral therapy as per the most current National Institutes of Health (NIH) Guidelines for the Use of Anti-retroviral Agents in Adults and Adolescents Living with HIV started >4 weeks prior to study enrolment.
• 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 active, uncontrolled infection. Specific examples include, but are not limited to, history of non-infectious pneumonitis that required steroids, current pneumonitis, uncontrolled autoimmune disease, uncontrolled ventricular arrhythmia, recent myocardial infarction within 90 days of consent, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).
• 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.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belarus, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Israel, Italy, Netherlands, Norway, Poland, Romania, Spain, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03602859
• Other Study ID Numbers: 213350; 3000-03-005 ( Other Identifier: Tesaro )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Tesaro, Inc.
• Study Sponsor: Tesaro, Inc.
• Collaborators: European Network of Gynaecological Oncological Trial Groups (ENGOT)

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: Tesaro, Inc.
• Verification Date: January 2021