A Study to Evaluate Dostarlimab Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Participants With Recurrent or Primary Advanced Endometrial Cancer

Study Overview
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Brief Summary
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This is a 2 part study. Part 1 is to evaluate the efficacy and safety of dostarlimab plus carboplatin-paclitaxel followed by dostarlimab versus placebo plus carboplatin-paclitaxel followed by placebo; and Part 2 is to evaluate the efficacy and safety of dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib versus placebo plus carboplatin-paclitaxel followed by placebo in participants with recurrent or primary advanced (Stage III or IV) endometrial cancer.

Official Title
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A Phase 3, Randomized, Double-blind, Multicenter Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)

Conditions
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Neoplasms

Intervention / Treatment
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* Biological: Dostarlimab
* Drug: Placebo matching dostarlimab
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Niraparib
* Drug: Placebo matching Niraparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1 and Part 2: Female participant is at least 18 years of age. Participant has histologically or cytologically proven endometrial cancer with recurrent or advanced disease. Participant must have primary Stage III or Stage IV disease or first recurrent endometrial cancer with a low potential for cure by radiation therapy or surgery alone or in combination and meet at least one of the following criteria; Participant has primary Stage IIIA to IIIC1 disease with presence of evaluable or measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v).1.1 based on Investigator's assessment. Lesions that are equivocal or can be representative of post-operative change should be biopsied and confirmed for the presence of tumor; Participant has primary Stage IIIC1 disease with carcinosarcoma, clear cell, serous, or mixed histology (containing greater than or equal to [>=] 10 percent carcinosarcoma, clear cell, or serous histology) regardless of presence of evaluable or measurable disease on imaging; Participant has primary Stage IIIC2 or Stage IV disease regardless of the presence of evaluable or measurable disease; Participant has first recurrent disease and is naïve to systemic anticancer therapy; Participant has received prior neo-adjuvant/adjuvant systemic anticancer therapy and had a recurrence or progression of disease (PD) >=6 months after completing treatment (first recurrence only). Participant has an ECOG performance status of 0 or 1. Participant has adequate organ function. Part 2 only: Participants must have normal blood pressure (BP) or adequately treated and controlled hypertension (systolic BP lesser than or equal to [<=] 140 millimeter of mercury [mmHg] and diastolic BP <=90 mmHg). Participants must be able to take medication orally, by mouth (PO). Exclusion Criteria: Part 1 and Part 2: Participant has received neo-adjuvant/adjuvant systemic anticancer therapy for primary Stage III or IV disease and: has not had a recurrence or PD prior to first dose on the study OR has had a recurrence or PD within 6 months of completing systemic anticancer therapy treatment prior to first dose on the study. Participant has had >1 recurrence of endometrial cancer. Participant has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), or anti-PD-ligand 2 (anti-PD-L2) agent. Participant has received prior anticancer therapy (chemotherapy, targeted therapies, hormonal therapy, radiotherapy, or immunotherapy) within 21 days or <5 times the half-life of the most recent therapy prior to Study Day 1, whichever is shorter. Participant has a concomitant malignancy, or participant has a prior non-endometrial invasive malignancy who has been disease-free for <3 years or who received any active treatment in the last 3 years for that malignancy. Non-melanoma skin cancer is allowed. Participant has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both. Participant has not recovered (that is [i.e.], to Grade <=1 or to Baseline) from cytotoxic therapy induced AEs or has received transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 21 days prior to the first dose of study drug. Participant has not recovered adequately from AEs or complications from any major surgery prior to starting therapy. Participant is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection requiring systemic therapy. Participant has received, or is scheduled to receive, a live vaccine within 30 days before first dose of study treatment, during study treatment, and for up to 180 days after receiving the last dose of study treatment. Part 2 only: Participant has received prior therapy with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. Participant has clinically significant cardiovascular disease. Participant has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Participant is at increased bleeding risk due to concurrent conditions. Participant has participated in Part 1 of this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Participants receiving dostarlimab + Carboplatin-paclitaxel followed by dostarlimab<br> | Biological: Dostarlimab<br>* Participants will be administered dostarlimab<br>* Other names: TSR-042;Drug: Carboplatin<br>* Participants will be administered carboplatin<br>Drug: Paclitaxel<br>* Participants will be administered paclitaxel<br>|
| Placebo Comparator: Arm 2: Participants receiving placebo + carboplatin-paclitaxel followed by placebo<br> | Drug: Placebo matching dostarlimab<br>* Participants will be administered placebo matching dostarlimab<br>Drug: Carboplatin<br>* Participants will be administered carboplatin<br>Drug: Paclitaxel<br>* Participants will be administered paclitaxel<br>|
| Active Comparator: Arm 3: Participants receiving dostarlimab + carboplatin-paclitaxel followed by dostarlimab+niraparib<br> | Biological: Dostarlimab<br>* Participants will be administered dostarlimab<br>* Other names: TSR-042;Drug: Carboplatin<br>* Participants will be administered carboplatin<br>Drug: Paclitaxel<br>* Participants will be administered paclitaxel<br>Drug: Niraparib<br>* Participants will be administered niraparib<br>|
| Placebo Comparator: Arm 4: Participants receiving placebo + carboplatin-paclitaxel followed by placebo<br> | Drug: Placebo matching dostarlimab<br>* Participants will be administered placebo matching dostarlimab<br>Drug: Carboplatin<br>* Participants will be administered carboplatin<br>Drug: Paclitaxel<br>* Participants will be administered paclitaxel<br>Drug: Placebo matching Niraparib<br>* Participants will be administered placebo matching Niraparib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 2: Progression-Free Survival (PFS) - investigator assessment |  | Up to 6 years | 
| Part 1: Overall survival |  | Up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Overall survival |  | Up to 6 years | 
| Parts 1 and 2: Progression free survival (PFS) blinded independent central review (BICR) |  | Up to 6 years | 
| Parts 1 and 2: Objective response rate (ORR) - BICR and Investigator assessment |  | Up to 6 years | 
| Parts 1 and 2: Duration of response (DOR) - BICR and Investigator assessment |  | Up to 6 years | 
| Parts 1 and 2: Disease control rate (DCR) - BICR and Investigator assessment |  | Up to 6 years | 
| Parts 1 and 2: Patient-reported outcomes (PROs) in the European Quality of Life scale, 5-Dimensions, 5-Levels (EQ-5D-5L) | EQ-5D-5L is a validated questionnaire to assess the overall health-related quality of life in participants across diseases. | Up to 6 years | 
| Parts 1 and 2: PROs in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30 [Core]) | EORTC QLQ-C30 is validated questionnaire to assess overall health-related quality of life in participants with cancer. | Up to 6 years | 
| Parts 1 and 2: PROs in the EORTC Quality of Life Questionnaire (Endometrial Cancer Module [QLQ-EN24]) | EORTC QLQ-EN24 is a validated questionnaire to assess the overall health-related quality of life in participants with all stages of endometrial cancer. | Up to 6 years | 
| Parts 1 and 2: Progression-free survival 2 (PFS2) |  | Up to 6 years | 
| Parts 1 and 2: Number of participants with adverse events (AEs), Serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) |  | Up to 6 years | 
| Parts 1 and 2: Number of participants with clinically significant changes in clinical laboratory parameters, physical examination, electrocardiogram (ECG) and participants reporting the intake of concomitant medication |  | Up to 6 years | 
| Parts 1 and 2: Change from Baseline in vital sign: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) (Millimeters of mercury) |  | Baseline and up to 6 Years | 
| Parts 1 and 2: Change from Baseline in vital sign: Heart Rate |  | Baseline and up to 6 Years | 
| Parts 1 and 2: Change from Baseline in vital sign: Respiratory rate |  | Baseline and up to 6 Years | 
| Parts 1 and 2: Change from Baseline in vital sign: Body temperature |  | Baseline and up to 6 Years | 
| Parts 1 and 2: Number of participants with Eastern Cooperative Oncology Group (ECOG) Performance Status Scores | Performance status will be assessed using the ECOG scale, with status score ranging from 0 to 5. | Up to 6 years | 
| Parts 1 and 2: Minimum observed concentration (Cmin) and maximum observed concentration (Cmax) of dostarlimab (micrograms per milliliter) |  | Predose (Day 1) and postdose (Day 1) of Cycles 1, 2, 6, 7, 10, 15, and 20 (Cycle 1, 2, 6 is 21 days and Cycle 7, 10, 15, 20 is 42 days) | 
| Parts 1 and 2: Cmin and Cmax at steady state of dostarlimab (micrograms per milliliter) |  | Predose (Day 1) and postdose (Day 1) of Cycles 1, 2, 6, 7, 10, 15, and 20 (Cycle 1, 2, 6 is 21 days and Cycle 7, 10, 15, 20 is 42 days) | 
| Part 2: Cmin and Cmax of niraparib (nanograms per milliliter) |  | Predose (Day 1) and 3 hours postdose (Day 1) of Cycles 7 and 8 and Predose (Day 1) of Cycles 10 and 14 (each cycle is 42 days) | 
| Part 2: Cmin and Cmax at steady state of niraparib (nanograms per milliliter) |  | Predose (Day 1) and 3 hours postdose (Day 1) of Cycles 7 and 8 and Predose (Day 1) of Cycles 10 and 14 (each cycle is 42 days) | 
| Parts 1 and 2: Number of participants with anti-drug antibodies (ADA) against dostarlimab |  | Predose (Day 1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dostarlimab, Carboplatin, Paclitaxel, Niraparib, Recurrent or primary advanced endometrial cancer, TSR-042