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NCT Number: NCT03602859

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

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.

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This study is active but is not currently recruiting participants.

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Key information

Conditions

Ovarian Neoplasms Adnexal Diseases Endocrine Gland Neoplasms Endocrine System Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genital Diseases Genital Diseases, Female Genital Neoplasms, Female Gonadal Disorders Neoplasms Neoplasms by Site Ovarian Diseases Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma Urogenital Diseases Urogenital Neoplasms

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 3

Primary location

GSK Investigational Site, Minsk, Belarus

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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 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) (R0 or macroscopic disease), or those for whom neoadjuvant chemotherapy (NACT) is planned.
  • Participants with Stage III are eligible if they meet protocol defined criteria.
  • 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 1 formalin-fixed paraffin embedded (FFPE) block slide 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 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.
  • 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.

Treatment and study plan

Niraparib

Drug

Participants will receive oral capsules of niraparib as a unit dosage strength of 100 milligrams (mg)

Other names: ZEJULA

Dostarlimab (TSR-042)

Drug

Participants will receive 500 mg dostarlimab on day 1 every 3 weeks from cycle 2 to 6 followed by 1000mg of dostarlimab on day 1 every 6 weeks to continue up to 3 years in the absence of disease progression, unacceptable toxicity, participant withdrawal, or investigator decision

Standard of care

Drug

Participants will receive SOC that includes paclitaxel 175 milligrams per square meter (mg/m^2) on day 1 every 21 days + carboplatin 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.

Dostarlimab-Placebo

Drug

Participants will receive 500 mg of dostarlimab-placebo on day 1 every 3 weeks from cycle 2 to 6 followed by 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, participant withdrawal, or investigator decision

Niraparib-Placebo

Drug

Participants will receive oral capsules of niraparib-placebo as a unit dosage strength of 100 mg.

Primary outcomes

  1. Progression Free Survival (PFS)

    Time frame: Up to approximately 316 weeks

    Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documented progressive disease (PD) or death due to any cause, whichever occurs first by the Investigator assessment according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST) version 1.1. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeter (mm).

Secondary outcomes

  1. Overall Survival (OS)

    Time frame: Up to approximately 316 weeks

    Overall Survival (OS) is defined as the time from the date of randomization to the date of death by any cause.

  2. PFS Determined by Blinded Independent Central Review (BICR) Per RECIST v1.1 Criteria

    Time frame: Up to approximately 316 weeks

    Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documented progressive disease (PD) or death due to any cause, whichever occurs first determined by the BICR according to RECIST version 1.1. Progressive Disease was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.

  3. Time to First Subsequent Therapy (TFST)

    Time frame: Up to approximately 316 weeks

    Time to First Subsequent Therapy (TFST) is defined as the time from randomization until the start date of the first subsequent anticancer therapy or death by any cause, whichever occurs first. First subsequent anticancer therapy is defined as the earliest anticancer therapy on the follow-up anticancer therapy form.

  4. Time to Second Subsequent Therapy (TSST)

    Time frame: Up to approximately 316 weeks

    Time to Second Subsequent Therapy (TSST) is defined as the time from the date of randomization to the start date of the second subsequent anticancer therapy or death of any cause, whichever occurs first. Second subsequent anticancer therapy is defined as an anticancer therapy with a start date after the first subsequent anticancer therapy and a recorded PD on first subsequent anticancer therapy, as captured on the follow-up anticancer therapy eCRF form.

  5. Time to Second Progression (PFS2)

    Time frame: Up to approximately 316 weeks

    PFS2 is defined as the time from the date of randomization to the date of first Progressive Disease per Investigator's assessment after initiation of subsequent anticancer therapy or death due to any cause, whichever occurs first.

    Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeter (mm).

  6. Objective Response Rate (ORR)

    Time frame: Up to approximately 316 weeks

    Objective Response Rate (ORR) is defined as the percentage of participants with measurable disease at baseline achieving a best overall response (BOR) of complete response (CR) or partial response (PR) by Investigator assessment per RECIST v1.1 criteria for participants with measurable disease at baseline. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 mm.

  7. Duration of Response (DOR)

    Time frame: Up to approximately 316 weeks

    DOR is defined as the time from the first documented response (complete response (CR) OR partial response (PR) ) to the first documented disease progression per Investigator assessed RECIST v1.1 or death by any cause in participants with measurable disease at baseline who responded to treatment. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

  8. Disease Control Rate (DCR)

    Time frame: Up to approximately 316 weeks

    Disease Control Rate (DCR) is defined as the percentage of participants with measurable disease at baseline achieving a best overall response (BOR) of complete response (CR), partial response (PR) or stable disease (SD) by Investigator assessment per RECIST v1.1 criteria for participants with measurable disease at baseline. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR is defined as the disappearance of all target lesions. SD defined as any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 mm.

  9. Number of Participants With Treatment Emergent Positive Antidrug Antibodies (ADAs) of Dostarlimab

    Time frame: Up to approximately 316 weeks

    Serum samples were collected for the analysis of Anti-drug antibody (ADAs) of dostarlimab.

  10. Change From Baseline (CFB) for the Visual Analogue Score (VAS) and Health Utility Index (HUI) of European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) Questionnaire

    Time frame: Day1 of Chemo Cycles 2(baseline), 4&6; Day1 of Maintenance Cycles 1,2,3,6,9,12,15,17,23,29,35,41,47,53,59,65,71,77,83,89; EOT visit up to a maximum of 63 months; LTFU visit up to a maximum of 69 months(including SFU visit up to a maximum of 61 months)

    EQ-5D-5L is a standardized, participant-rated health outcomes questionnaire covering five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each of dimensions, participant self-assigned score: 1 (no problems); 2 (slight problems); 3 (moderate problems); 4 (severe problems); 5 (extreme problems). VAS is collected separately and recorded from 0 (Worst imaginable health state) to 100 (Best imaginable health state). HUI values summarize how good or bad each health state is on a scale of 1 (full health) to 0 (worse health/dead). High HUI value indicates a good HRQoL. Baseline is defined as the latest, non-missing collected value, excluding end of treatment, safety follow-up, long term follow-up visits records and unscheduled visits after end of treatment (EOT).

  11. Number of Participants With Improvement and Worsening in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30)

    Time frame: Day1 of Chemo Cycles 2(baseline), 4&6; Day1 of Maintenance Cycles 1,2,3,6,9,12,15,17,23,29,35,41,47,53,59,65,71,77,83,89; EOT visit up to a maximum of 63 months; LTFU visit up to a maximum of 69 months(including SFU visit up to a maximum of 61 months)

    The EORTC QLQ-C30 includes 30-items with single and multi-item scales. These included five functional scales (physical functioning [PF], role functioning [RF], cognitive functioning [CF], emotional functioning [EF] and social functioning [SF]), three symptom scales (fatigue, pain and nausea/vomiting [N/V]), a global health status (GHS)/ Quality-of-Life (QoL) scale, and six single items (constipation, diarrhoea, insomnia, dyspnoea, appetite loss [AL] and financial difficulties [FD]). Response options are 1 to 4. Scores were averaged and transformed to 0 to 100, a high score for functional scales/ GHS/QoL represent better functioning ability or health-related quality-of-life (HRQoL), whereas a high score for symptom scales/ single items represent significant symptomatology.

  12. Number of Participants With Change in Status in EORTC-QLQ Ovarian Cancer Module (EORTC-QLQ-OV28) Questionnaire

    Time frame: Day1 of Chemo Cycles 2(baseline), 4&6; Day1 of Maintenance Cycles 1,2,3,6,9,12,15,17,23,29,35,41,47,53,59,65,71,77,83,89; EOT visit up to a maximum of 63 months; LTFU visit up to a maximum of 69 months(including SFU visit up to a maximum of 61 months)

    The EORTC QLQ-OV28 supplements the QLQ-C30. It includes three functional scales (body image (BI), sexuality (S), attitude to disease/treatment(ATD)) and five symptom scales/items (abdominal/GI symptoms (AS), peripheral neuropathy (PN), hormonal/menopausal symptoms (MS), other chemotherapy side effects (CSE), and hair loss (HS)). Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much). Higher scores represent better functioning (better quality of life). For functional scales: improved (worsened) is defined as >=10 points increase (decrease) from baseline. For symptom scales: improved (worsened) is defined as >=10 points decrease (increase) from baseline. Baseline is defined as the latest, non-missing collected value, excluding end of treatment, safety follow-up, long term follow-up visits records and unscheduled visits after end of treatment.

Sponsors and collaborators

Lead sponsor

Tesaro, Inc.

Industry

Collaborators

  • European Network of Gynaecological Oncological Trial Groups (ENGOT)

Registry information

Official study title

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

Acronym: FIRST

Important dates

Study start
2018
Primary completion
2024
Study completion
2029
First posted
Jul 27, 2018
Registry last updated
Dec 31, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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