Study to Evaluate the Efficacy and Safety of the Combination of Niraparib and Dostarlimab (TSR-042) in Participants With Platinum Resistant Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
This is an open-label, single-arm Phase 2 study to evaluate the efficacy and safety of combination of niraparib and dostarlimab (TSR-042) in participants with advanced, relapsed, high-grade ovarian, fallopian tube, endometrioid, clear cell ovarian or primary peritoneal cancer without known breast cancer susceptibility gene (BRCA) mutation who have platinum-resistant disease and who have also been previously treated with bevacizumab.

Official Title
-----------------
A Phase 2 Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of the Combination of Niraparib and Dostarlimab (TSR-042) in Patients With Platinum-Resistant Ovarian Cancer (MOONSTONE)

Conditions
-----------------
Ovarian Neoplasms

Intervention / Treatment
-----------------
* Drug: Niraparib
* Drug: Dostarlimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Participant must be female >=18 years of age, able to understand the study procedures, and subsequently agreed to participate in the study by providing written informed consent. Participants must have recurrent high-grade serous, endometrioid, or clear cell ovarian, fallopian tube, or primary peritoneal cancer. Participants must be considered resistant to the last administered platinum therapy. Participants must have completed at least 1 but no more than 3 prior lines of therapy for advanced or metastatic ovarian cancer. Participants must have been previously treated with platinum-based regimen, taxane agent(s), and bevacizumab. Participant has measurable disease according to RECIST v.1.1. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participant has adequate organ function. Females with childbearing potential have a serum pregnancy test that is negative 72 prior first dose and are not breastfeeding. Participant must also agree to abstain from activities that could result in pregnancy from enrollment through 180 days after the last dose of study treatment. Participant must provide formalin fixed paraffin embedded (FFPE) tumor tissue block(s) with sufficient tumor content (as confirmed by the Sponsor's designated central laboratory) during screening to enable BRCA testing and PD-L1 testing. The use of slides created from paraffin-embedded tissue as opposed to FFPE blocks must be approved by the Sponsor. Participant must agree to complete health-related quality of life (HRQoL) questionnaires throughout the study. Exclusion Criteria: Participant who experienced disease progression within 3 months (12 weeks or 84 days) of first-line platinum therapy. Participants with a known deleterious or suspected BRCA 1 or 2 mutation. Participant has received prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent. Participant has received prior therapy with a PARP-1/PARP-2 inhibitor. Participant has a known hypersensitivity to dostarlimab (TSR-042), Niraparib, their components, or their excipients. Participant has a known history of myelodysplastic syndrome or acute myeloid leukemia. Participant has not recovered from prior chemotherapy induced adverse events. Participant has a known diagnosis of immunodeficiency or is receiving systemic steroid therapy exceeding an equivalent of prednisone 10 mg daily or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Participant is currently participating in a treatment study or has participated in a study of an investigational agent within 4 weeks of the first dose of treatment. Participant has received prior systemic anticancer therapy including cytotoxic chemotherapy, hormonal therapy given with the intention to treat ovarian cancer, or biological therapy within 3 weeks of the first dose of study treatment. Participant has received live vaccine within 14 days of planned start of study therapy Participant has symptomatic uncontrolled brain or leptomeningeal metastases. (If investigator feels participant symptoms are not symptomatic, participants can undergo a scan to confirm for eligibility). Participant had major surgery with 4 weeks of starting the first dose of the study treatment or participant has not recovered from any effects of any major surgery. Participant has a known additional malignancy that progressed or required active treatment within the last 2 years. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active controlled infection. Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study. Participant has known active hepatitis B (hepatitis B surface antigen reactive) or hepatitis C (hepatitis C virus ribonucleic acid, qualitative). Participant with a known history of human immunodeficiency virus (HIV) are allowed if they meet all of the following criteria: Cluster of differentiation 4 >=350/microliter (μL) and viral load <400 copies/milliliter (mL) No history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrollment No history of HIV-associated malignancy for the past 5 years Concurrent antiretroviral therapy as per the most current National Institutes of Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV started >4 weeks prior to study enrollment Participant is immunocompromised. Participants with splenectomy are allowed. Participant has an ongoing bowel obstruction or has other conditions that would lead to impaired absorption of oral niraparib. Participant has active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Niraparib+Dostarlimab (TSR-042)<br>Participants with body weight ≥77 kilogram (kg) and platelet count ≥150,000/microliter (μL) at baseline were administered Niraparib 300 milligram (mg) once daily (QD) and participants with body weight <77 kg or platelet count <150,000/μL at baseline were administered Niraparib 200 mg QD. Niraparib was administered continuously until Progressive disease (PD) or toxicity. Dostarlimab (TSR-042) was administered as an intravenous (IV) infusion of 500 mg once every three weeks (Q3W) from Cycle 1 Day 1 through Cycle 4. Beginning at Cycle 5, Dostarlimab (TSR-042) was administered via an IV infusion of 1000 mg on Day 1 of each 6-week cycle until PD or toxicity, up to 27 months. | Drug: Niraparib<br>* Niraparib is a potent, orally active poly (adenosine diphosphate-ribose) polymerase (PARP)-1 and PARP2 inhibitor being developed as a treatment for participants with tumors that harbor defects in the homologous recombination deoxyribonucleic acid (DNA) repair pathway or that are driven by PARP-mediated transcription factors.<br>* Other names: ZEJULA;Drug: Dostarlimab<br>* TSR-042 is a humanized monoclonal antibody that binds with high affinity to programmed cell death-1 (PD-1) resulting in inhibition of binding to programmed cell-death receptor ligands 1 and 2 (PD-L1 and PD-L2).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) in Participants With Platinum-resistant Ovarian Cancer (PROC) | ORR is defined as the percentage of participants who have achieved confirmed complete response (CR) or partial response (PR), as determined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria based on Investigator assessment and computed tomography (CT) scans were commonly used for tumor imaging. | Up to approximately 22 months | 
| ORR in Participants With PROC Who Have Programmed Cell Death-ligand 1 (PD-L 1) Positive Status | ORR is defined as the percentage of participants who have achieved confirmed CR or PR, as determined by RECIST v1.1 criteria based on Investigator assessment and CT scans were commonly used for tumor imaging. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with combined positive score (vCPS) >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) in Participants With PROC | DOR is defined as the time from first documentation of response (CR or PR) until the time of first documentation of disease progression or death by any cause in the absence of progression by RECIST v.1.1 based on Investigator assessment. | Up to approximately 22 months | 
| DOR in Participants With PROC Who Have PD-L 1 Positive Status | DOR is defined as the time from first documentation of response (CR or PR) until the time of first documentation of disease progression or death by any cause in the absence of progression by RECIST v.1.1 based on Investigator assessment. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with vCPS >=5% was used as specified cut-point for the assessment of PD-L1 patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| Progression-free Survival (PFS) in Participants With PROC | PFS is defined as the time from the date of the first dose of study treatment to the earlier date of assessment of progression or death by any cause in the absence of progression by RECIST v.1.1 based on Investigator assessment. | Up to approximately 22 months | 
| PFS in Participants With PROC Who Have PD-L 1 Positive Status | PFS is defined as the time from the date of the first dose of study treatment to the earlier date of assessment of progression or death by any cause in the absence of progression by RECIST v.1.1 based on Investigator assessment. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with a vCPS >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| Overall Survival (OS) in Participants With PROC | OS is defined as the time from the date of the first dose of study treatment to the date of death by any cause. | Up to approximately 22 months | 
| OS in Participants With PROC Who Have PD-L 1 Positive Status | OS is defined as the time from the date of the first dose of study treatment to the date of death by any cause. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with vCPS >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| Disease Control Rate (DCR) in Participants With PROC | DCR is defined as the percentage of participants who have achieved best overall response (BOR) of CR, PR, or stable disease (SD) per RECIST v.1.1 based on the investigator's assessment. | Up to approximately 22 months | 
| DCR in Participants With PROC Who Have PD-L 1 Positive Status | DCR is defined as the percentage of participants who have achieved BOR of CR, PR, or SD per RECIST v.1.1 based on the investigator's assessment. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with vCPS >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| ORR in Participants With PROC Based on Independent Review Committee (IRC) Assessment | ORR is defined as the percentage of participants who have achieved confirmed CR or PR per RECIST v1.1 based on the independent review committee assessment. | Up to approximately 22 months | 
| ORR in Participants With PROC Who Have PD-L 1 Positive Status Based on IRC Assessment | ORR is defined as the percentage of participants who have achieved confirmed CR or PR per RECIST v1.1 based on the independent review committee assessment. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with a vCPS >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| DOR in Participants With PROC Based on IRC Assessment | DOR is defined as the time from first documentation of response (CR or PR) until the time of first documentation of disease progression or death by any cause in the absence of progression by RECIST v.1.1 based on Independent Review Committee assessment. | Up to approximately 22 months | 
| DOR in Participants With PROC Who Have PD-L 1 Positive Status Based on IRC Assessment | DOR is defined as the time from first documentation of response (CR or PR) until the time of first documentation of disease progression or death by any cause in the absence of progression by RECIST v.1.1 based on Independent Review Committee assessment. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with a vCPS >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| PFS in Participants With PROC Based on IRC Assessment | PFS is defined as the time from the date of the first dose of study treatment to the earlier date of assessment of progression or death by any cause in the absence of progression by RECIST v.1.1 based on Independent Review Committee Assessment. | Up to approximately 22 months | 
| PFS in Participants With PROC Who Have PD-L 1 Positive Status Based on IRC Assessment | PFS is defined as the time from the date of the first dose of study treatment to the earlier date of assessment of progression or death by any cause in the absence of progression by RECIST v.1.1 based on IRC Assessment. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with a vCPS >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| DCR in Participants With PROC Based on IRC Assessment | DCR is defined as the percentage of participants who have achieved BOR of CR, PR, or SD per RECIST v.1.1 based on IRC Assessment. | Up to approximately 22 months | 
| DCR in Participants With PROC Who Have PD-L 1 Positive Status Based on IRC Assessment | DCR is defined as the percentage of participants who have achieved BOR of CR, PR, or SD per RECIST v.1.1 based on Independent Review Committee Assessment. PD-L1 is a ligand that binds to PD-L1 protein on tumor infiltrating T cells and renders the T cells inactive. Any PD-L1 positive tissue sample with vCPS >=5% was used as specified cut-point for the assessment of PD-L1 positive patient subset with PROC. vCPS was defined as the percentage of tumor cells and immune cells staining positive within the total tumor area. | Up to approximately 22 months | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-emergent Adverse Events (TEAEs) and Adverse Event of Special Interest (AESI) | An AE is any untoward medical occurrence in a patient administered with a medicinal product and that does which may or may not have a causal relationship with this treatment. A SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. TEAEs are any event that occurred between first dose of study drug up to 22 months, which were absent before treatment or that had worsened relative to pretreatment state. AESI were any AE (serious or non-serious) that is of scientific and medical concern specific to the study treatment, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor was done. | Up to approximately 27 months | 
| Number of Participants With Grade Shift From Baseline in Hematology | Blood samples were collected for the analysis of hematology parameters and each parameter was graded according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.3. Grade 0: Normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent measurement prior to the first administration of study treatment. Data has been presented for the number of participants with hematology grade shifts from baseline grade to grade 3 and 4 for each parameter. | Up to approximately 27 months | 
| Number of Participants With Grade Shift From Baseline in Plasma Chemistry | Blood samples were collected and the clinical chemistry parameters assessed were Albumin (Alb), alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), alkaline phosphatase (ALP), sodium, total bilirubin (TB), creatinine, glucose, magnesium and potassium. The Grade shift post baseline data of each parameter from Grade 0 through Grade 4 was based on the CTCAE version 4.03, grading scale, as per intensity, namely Grade 0: Normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent measurement prior to the first administration of study treatment. Data has been presented for the number of participants with plasma chemistry grade shifts from baseline grade to grade 3 and 4 for each parameter. | Up to approximately 27 months | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline was defined as the most recent measurement prior to the first administration of study treatment. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. The minimum (min) and maximum (max) change from baseline values have been reported. | Up to approximately 27 months | 
| Change From Baseline in Pulse Rate | Baseline was defined as the most recent measurement prior to the first administration of study treatment. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. The minimum (min) and maximum (max) change from baseline values have been reported. | Up to approximately 27 months | 
| Change From Baseline in Temperature | Baseline was defined as the most recent measurement prior to the first administration of study treatment. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. The minimum (min) and maximum (max) change from baseline values have been reported. | Up to approximately 27 months | 
| Change From Baseline in Prothrombin International Normalized Ratio | Blood samples were collected to evaluate Prothrombin International Normalized Ratio (INR). Baseline was defined as the most recent measurement prior to the first administration of study treatment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. | Baseline and up to approximately 27 months | 
| Change in Baseline in Activated Partial Thromboplastin Time | Blood samples were planned to be collected to evaluate activated partial thromboplastin time (APTT). Baseline was defined as the most recent measurement prior to the first administration of study treatment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. | Baseline and up to approximately 27 months | 
| Change From Baseline in Thyrotropin | Blood samples were collected to evaluate thyrotropin at indicated time points. Baseline was defined as the most recent measurement prior to the first administration of study treatment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. | Baseline and up to approximately 27 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Open-label, Single-arm, Efficacy and Safety, Platinum-resistant ovarian cancer, Niraparib, dostarlimab