Clinical trial 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
Official 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Ovarian Neoplasms
Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma
Keywords: FIRST
FIRST trial
Niraparib
Dostarlimab (TSR-042)
Ovarian cancer
Lead sponsor: Tesaro, Inc.
Sponsor class: INDUSTRY
Collaborators: name: European Network of Gynaecological Oncological Trial Groups (ENGOT)
First posted: 2018-07-27
Enrollment: 1402
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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, 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to 6 years
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 7 years
measure: PFS by Blinded Independent Central Review (BICR) per investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) criteria
timeFrame: Up to 6 years
measure: Change from Baseline in the European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) assessment
timeFrame: Baseline and up to 6 years
measure: Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30) assessment
timeFrame: Baseline and up to 6 years
measure: Change from Baseline in the EORTC-QLQ Ovarian Cancer Module OV28 (EORTC-QLQ-OV28) assessment
timeFrame: Baseline and up to 6 years
measure: Time to first subsequent therapy (TFST)
timeFrame: Up to 6 years
measure: Time to second subsequent therapy (TSST)
timeFrame: Up to 6 years
measure: Time to progression on next-line therapy (PFS2)
timeFrame: Up to 6 years
measure: Objective Response Rate (ORR)
timeFrame: Up to 6 years
measure: Duration of response (DOR)
timeFrame: Up to 6 years
measure: Disease control rate (DCR)
timeFrame: Up to 6 years
measure: Plasma concentration of dostarlimab
timeFrame: Up to 6 years
measure: Number of participants with positive antidrug antibodies (ADAs) against dostarlimab
timeFrame: Up to 6 years
measure: Plasma concentration of niraparib
timeFrame: Up to 6 years
measure: Number of participants with treatment-emergent adverse events (TEAEs)
timeFrame: Up to 6 years
measure: Number of participants with serious adverse events (SAEs)
timeFrame: Up to 6 years
measure: Number of participants with treatment discontinuations or dose delays or dose reductions due to adverse events
timeFrame: Up to 6 years
measure: Number participants with immune-related adverse events (irAEs)
timeFrame: Up to 6 years
measure: Number of participants with changes in Eastern Cooperative Oncology Group (ECOG) performance status
timeFrame: Up to 6 years
measure: Number of participants with abnormal hematology results
timeFrame: Up to 6 years
measure: Number of participants with abnormal clinical chemistry results
timeFrame: Up to 6 years
Other outcomes:
Locations:
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country: United States
facility: GSK Investigational Site
state: Alaska
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state: Arizona
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city: Nashville
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city: Nashville
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city: Dallas
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city: Windsor
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city: Praha 8
country: Czechia
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country: Denmark
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country: Finland
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country: Finland
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country: France
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country: France
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facility: GSK Investigational Site
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country: France
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country: France
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country: France
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country: France
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country: France
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country: France
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country: France
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country: France
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city: Lyon
country: France
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city: Lyon
country: France
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city: Nancy
country: France
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country: France
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country: France
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facility: GSK Investigational Site
city: Paris Cedex
country: France
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city: Paris
country: France
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city: Paris
country: France
facility: GSK Investigational Site
city: Pierre Benite
country: France
facility: GSK Investigational Site
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country: France
facility: GSK Investigational Site
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facility: GSK Investigational Site
city: Reims
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city: Rennes Cedex
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city: Saint-Priest-en-Jarez
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facility: GSK Investigational Site
city: Strasbourg
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city: Toulouse Cedex 9
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city: Tours cedex 9
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facility: GSK Investigational Site
city: Villejuif cedex
country: France
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Muenster
country: Germany
facility: GSK Investigational Site
city: Ravensburg
country: Germany
facility: GSK Investigational Site
city: Wolfsburg
country: Germany
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Haidari - Athens
country: Greece
facility: GSK Investigational Site
city: Marousi
country: Greece
facility: GSK Investigational Site
city: Beer-Sheva
country: Israel
facility: GSK Investigational Site
city: Haifa
country: Israel
facility: GSK Investigational Site
city: Haifa
country: Israel
facility: GSK Investigational Site
city: Holon
country: Israel
facility: GSK Investigational Site
city: Petach Tikva
country: Israel
facility: GSK Investigational Site
city: Rehovot
country: Israel
facility: GSK Investigational Site
city: Bologna
country: Italy
facility: GSK Investigational Site
city: Faenza
country: Italy
facility: GSK Investigational Site
city: Lugo RA
country: Italy
facility: GSK Investigational Site
city: Meldola FC
country: Italy
facility: GSK Investigational Site
city: Napoli
country: Italy
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Groningen
country: Netherlands
facility: GSK Investigational Site
city: Maastricht
country: Netherlands
facility: GSK Investigational Site
city: Nijmegen
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Utrecht
country: Netherlands
facility: GSK Investigational Site
city: Kristiansand
country: Norway
facility: GSK Investigational Site
city: Oslo
country: Norway
facility: GSK Investigational Site
city: Tromsoe
country: Norway
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city: Olsztyn
country: Poland
facility: GSK Investigational Site
city: Szczecin
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Bucuresti
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca
country: Romania
facility: GSK Investigational Site
city: Constanta
country: Romania
facility: GSK Investigational Site
city: Craiova
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Avila
country: Spain
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Gerona
country: Spain
facility: GSK Investigational Site
city: JaEn
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Toledo
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Chernihiv
country: Ukraine
facility: GSK Investigational Site
city: Lviv
country: Ukraine
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
city: Portsmouth
country: United Kingdom
facility: GSK Investigational Site
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
city: Truro
country: United Kingdom
facility: GSK Investigational Site
city: Wirral
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: