Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Niraparib · 21 trials · 42 indications
Overall survival, defined as the time from the date of randomization to the date of death due to any cause.
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, is life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, is a congenital anomaly/birth defect, other situations and is associated with liver injury or impaired liver function. SAEs are subsets of AEs. TEAE is an event that emerged during treatment having been absent pretreatment or worsened relative to the pretreatment state. AESI is any AE (serious or nonserious) that is of scientific and medical concern specific to niraparib for which ongoing monitoring and rapid communication by the Investigator to the Sponsor is warranted. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is an event that emerged during treatment having been absent pretreatment or worsened relative to the pretreatment state.Number of participants with TEAEs leading to death were reported.
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is an event that emerged during treatment having been absent pretreatment or worsened relative to the pretreatment state. Number of participants with TEAEs leading to dose modifications (reduction and interruption/delay) and permanent discontinuation of study treatment were reported.
Number of participants with ECOG Performance Status was reported and was measured on 6-point grade scale 0: Fully active, able to carry on all pre-disease performance without restriction. Grade 1: Restricted in physically strenuous activity but ambulatory \& able to carry out work of light or sedentary nature; Grade 2 - Ambulatory \& capable of all self-care but unable to carry out any work activities. Up and about more than (\>) 50% of waking hours; Grade 3 -Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; Grade 4 -Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; Grade 5 -Dead. Data is presented as baseline grade, best case on-therapy, and worst-case on-therapy for the available participants.
Blood samples were collected for the analysis of hematology parameters. The summaries of worst-case change from baseline with respect to normal range was analyzed for only those laboratory tests that were not gradable by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. The number of participants with decreases to low from baseline, changes to normal or no changes from baseline, and increases to high values have been presented. Baseline is defined as the latest non-missing pre-dose value, including those from unscheduled visits.
Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Baseline is defined as the latest non-missing pre-dose value, including those from unscheduled visits.
The abnormal vital sign ranges are: Pulse Rate (PR): Low \[\<60 beats per minute (bpm)\], Normal (60 bpm to 100 bpm), High (\>100 bpm); Temperature: Low (\<35 degree Celsius (°C)), Normal (35 C and 38 C), High (\>38 C); Systolic Blood Pressure (SBP): Low (\<90 millimeter of mercury (mmHg)), Normal (\>90 mmHg to \<120 mmHg), High (\>120 mmHg); Diastolic Blood Pressure (DBP): Low (\<60 mmHg), Normal (60 mmHg to 79 mmHg), High (\>80 mmHg). Participants were counted in the maximum worst case increase category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category.
Number of participants who used concomitant medications is presented.
PFS is defined as the time from the date of randomization to the date of first objectively documented disease progression (PD) as determined by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or death from any cause in the absence of progression, whichever occurs first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
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).
Progression free survival was defined as the time from the date of treatment randomization to the date of first documentation of disease progression or death due to any cause in the absence of documented progression, whichever occurs first. It was assessed by the blinded independent central review (BICR). Median and 95% confidence interval (CI) are presented.
Measured by assessing best overall response using RECIST 1.1 in subjects in recurrent and/or metastatic HNSCC patients receiving combination of niraparib and dostarlimab.
The CBR as best response, defined as the percentage of patients who experience a complete response, partial response or stable disease for at least 24 weeks and assessed by modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria
AEs, SAEs and AESI will be collected.
The performance status will be assessed using ECOG scale, where Grade 0 (fully active), Grade 1 (restricted in physically strenuous activity), Grade 2 (ambulatory and capable of all self-care), Grade 3 (capable of only limited self-care) and Grade 4 (completely disabled). Number of participants with clinically significant changes in ECOG performance status will be summarized.
Blood samples will be collected for the analysis of hematology and clinical chemistry parameters.
Number of participants with clinically significant changes in vital signs will be assessed.
Number of participants with clinically significant changes in physical examination will be assessed.
The primary evaluation of change in TILs within each arm will be based on a Wilcoxon signed rank test (absolute difference) using a one-sided alpha = 0.05 for each arm
The number and proportion of participants achieving pCR among all participants who initiate protocol therapy will be summarized with a two-sided 90% exact confidence interval.
RR is defined as the proportion of patients with a partial response or complete response 4 months after randomization
OS is the time from the date of the randomization until death due to any cause
Number of Participants enrolled across cohorts are presented.
PFS rate at 18 months is defined as the percentage of participants who have not progressed or died within 18 months after niraparib combined with bevacizumab treatment initiation. Progression was assessed by response evaluation criteria in solid tumors (RECIST) version (v) 1.1 criteria per Investigator assessment and defined as a 20 percent (%) increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions. Survival rate is the percentage of participants without progression assessed by RECIST v1.1 or death by the landmark timepoint. Confidence intervals was constructed using exact method.
ORR is the percentage of participants with a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) in the analysis population where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters (mm) in the short axis. PR=At least a 30 percent (%) decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. Tumor assessment was done by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Data has been presented for participants with NSCLC whose tumors have high PD-L1 expression (TPS\>=50%). Confidence interval was calculated using binomial exact method.
ORR is the percentage of participants with a confirmed BOR of CR or PR in the analysis population where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. Tumor assessment was done by the Investigator per RECIST v1.1. Data has been presented for participants with NSCLC having PD-L1 expression in tumors (TPS: 1 to 49%). Confidence interval was calculated using binomial exact method.
ORR is the percentage of participants with a confirmed BOR of CR or PR in the analysis population where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. Tumor assessment was done by the Investigator per RECIST v1.1. Data is presented for participants with locally advanced and metastatic squamous NSCLC. Confidence interval was calculated using binomial exact method.
ORR is the percentage of participants with a confirmed BOR of CR or PR in the analysis population where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. Tumor assessment was done by the Investigator per RECIST v1.1. Confidence interval was calculated using binomial exact method.
The ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters (mm) in the short axis, PR=At least a 30 percent (%) decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. Primary Analysis Population comprised of participants who received 3 or 4 prior lines of therapy (LOT), had homologous recombination deficiency positive (HRDpos) tumors, had platinum-sensitive disease, and were poly(adenosine 5'-diphosphate \[ADP\]-ribose) polymerase inhibitors (PARPi) naïve.
The percentage of participants with treatment-emergent adverse events as classified and graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be reported
The MTD is defined as the highest dose studied for which the observed incidence of DLT is less than 33% or occurs within at most one out of six patients treated at any given dose level.
The percentage of participants with documented dose-limiting toxicities will be reported by dose level.
The RP2D will be selected based on the evaluation of dose-limiting toxicities and adverse events measured using CTCAE v5.0.
Tumor response measured by breast MRI is defined as \>=30 percent (%) reduction of tumor volume from Baseline based on primary lesion after niraparib treatment without any new lesion development. Tumor volume was calculated as (length × width × height × pi \[π\])/6. Responses were assessed as Clinical complete response (CR): A complete disappearance of all tumor signs in the breast as assessed by imaging test. Clinical partial response (PR): A reduction in the tumor volume of the primary tumor size by \>=30% assessed by palpation or imaging test. Clinical stable disease (SD): No significant change in tumor volume during treatment. Clinical progressive disease (cPD): The development of new, previously undetected lesions, or an estimated increase in the size of the primary lesion by greater than 20%. Percentage of participants with tumor response and its 95 percent confidence interval (CI) has been presented. The 95% CI was the binomial exact CI based on Clopper-Pearson method.
Blood samples were collected at indicated time points to evaluate AUC (last) of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.
Blood samples were collected at indicated time points to evaluate AUC (0-infinity) of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.
Blood samples were collected at indicated time points to evaluate Cmax of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.
Blood samples were collected at indicated time points to evaluate tmax of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.
Blood samples were collected at indicated time points to evaluate t1/2 of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.
CL/F is calculated as Dose/(AUC 0-inf). Blood samples were collected at indicated time points to evaluate CL/F of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. Not applicable (NA) indicates that CL/F could not be measured for M1 since the dose of metabolite is unknown and only known dose is that of parent niraparib.
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Blood samples were collected at indicated time points for pharmacokinetic assessment of tlag. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of adverse event(AE) onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were collected during first cycle to establish recommended phase 2 dose (RP2D).
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were collected during first cycle to establish RP2D.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were collected during first cycle to establish RP2D.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were collected during first cycle to establish RP2D.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were collected during first cycle to establish RP2D.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were collected during first cycle to establish RP2D.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were planned to be collected during first cycle to establish RP2D.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were planned to be collected during first cycle to establish RP2D.
An event was considered a DLT if it occurred within the first 21 days of treatment, and met one of following DLT criteria:hematologic toxicity- Grade4 thrombocytopenia persists for \>=7 days from the time of AE onset, Grade 4 neutropenia, Grade 4 or Grade 3 febrile neutropenia persists for \>=7 days, Grade4 or Grade3 anemia requiring blood transfusion, Grade 3 thrombocytopenia associated with clinically significant bleeding, Grade 3 neutropenia associated with infection as described in CTCAE version 4.0, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 3 or 4 nonhematologic laboratory abnormality if any of the following also occur: abnormality leads to hospitalization and abnormality persists for \>=7 days from the time of AE onset; drug related toxicity leading to prolonged delay (\>2 weeks) in initiating Cycle 2. DLTs were planned to be collected during first cycle to establish RP2D.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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 participants with TEAEs, SAEs and AESIs are reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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 participants with TEAEs, SAEs and AESIs are reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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 participants with TEAEs, SAEs and AESIs are reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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 participants with TEAEs, SAEs and AESIs are reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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 participants with TEAEs, SAEs and AESIs are reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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 participants with TEAEs, SAEs and AESIs are reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as 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 or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is 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.
DLTs are defined as: Any treatment-related Grade \>=3 non-hematologic clinical (non-laboratory) adverse event (AE); Any treatment-related Grade 3 or Grade 4 non-hematologic laboratory (lab) abnormality if Medical intervention is required to treat the participant or the abnormality leads to hospitalization or the abnormality persists for \>=7 days; Any treatment-related hematologic toxicity specifically defined as: Thrombocytopenia Grade 4 for \>=7 days, or Grade 3 or 4 associated with bleeding or requiring platelet transfusion, Neutropenia Grade 4 for \>=7 days, or Grade 3 or 4 associated with infection or febrile neutropenia, Anemia Grade 4, or Grade 3 or 4 requiring blood transfusion; Any treatment-related AE leading to niraparib dose interruption per the following criteria: A dose interruption for a non-DLT lab abnormality lasting \>=14 days, A dose in interruption per dose modification rules for non-hematologic AE leading to \<80 percent (%) of an intended dose being administered.
ORR is defined as the percentage of participants with a confirmed best overall response of Complete Response (CR) or Partial Response (PR), RECIST v1.1 for target lesions as assessed by the Investigator. CR is defined as disappearance of all target lesions, Any pathological lymph nodes must be \<10 millimeters (mm) in the short axis; 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.
Absolute bioavailability of niraparib will be calculated as the ratio of dose normalized oral to IV niraparib exposure
| Arm | Type | Description |
|---|---|---|
| Arm A: Niraparib | EXPERIMENTAL | - |
| Arm B: Temozolomide | ACTIVE_COMPARATOR | - |
| Cohort1:Participants with tBRCAmut HER2-breast cancer(Independent of HR status,including HR+andTNBC) | EXPERIMENTAL | Eligible participants will receive either Niraparib or Placebo. |
| Cohort 2: Participants with tBRCAwt TNBC | EXPERIMENTAL | Eligible participants will receive either Niraparib or Placebo. |
| Participants receiving niraparib plus pembrolizumab | EXPERIMENTAL | Eligible participants will receive niraparib along with pembrolizumab. |
| Participants receiving placebo plus pembrolizumab | PLACEBO_COMPARATOR | Eligible participants will receive matching placebo along with pembrolizumab. |
| Participants receiving SOC+placebo | PLACEBO_COMPARATOR | Participants in this arm will receive SOC (carboplatin+paclitaxel+/-bevacizumab) in cycle 1 (each cycle is of 21 days) 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 |
| Participants receiving SOC+niraparib | ACTIVE_COMPARATOR | Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/- bevacizumab with niraparib and dostarlimab placebo |
| Participants receiving SOC+dostarlimab+niraparib | EXPERIMENTAL | Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab, and maintenance treatment of +/-bevacizumab with niraparib and dostarlimab |
| Participants receiving Niraparib | EXPERIMENTAL | - |
| Participants receiving Placebo | PLACEBO_COMPARATOR | - |
| Niraparib & Dostarlimab | EXPERIMENTAL | Niraparib starting on Day 0. Niraparib will be administered as continuous daily dose, orally 200 or 300 mg. Dostarlimab IV administered via a 30-minute infusion on Day 1 of every 21 day cycle. 500mg for first 4 doses followed by 1000 mg every 6 weeks. |
| Niraparib in combination with Aromatase Inhibitors | EXPERIMENTAL | Upon meeting all selection criteria, patients enrolled in the study will receive the combination of niraparib orally, once daily, flat- fixed, continuously in 28-day cycles plus aromatase Inhibitors. |
| Arm A Triple Negative Breast Cancer (TNBC) | EXPERIMENTAL | Participants will be randomized 1:1 to treatment with the combination (Arm A) * Niraparib-Daily beginning with week 1, day 1 * Dostarlimab-Once every three weeks beginning with week 1, day 1 |
| Arm B TNBC | EXPERIMENTAL | Participants will be randomized 1:1 to treatment with the combination (Arm B) * 3-week lead-in of niraparib monotherapy followed by treatment with the combination * Niraparib Daily beginning with week 1, day 1 * Dostarlimab Once every three weeks beginning with week 4, day 1 |
| Arm C ER+/HER2- | EXPERIMENTAL | exploratory cohort of estrogen receptor (ER) positive HER2-negative participants will be enrolled to Arm C. * Niraparib Daily beginning with week 1, day 1 * Dostarlimab Once every three weeks beginning with week 1, day 1 |
| Arm A - Niraparib | EXPERIMENTAL | Niraparib, 200 mg or 300 mg, daily dose |
| Arm B - Niraparib + TSR-042 (Dostarlimab) | EXPERIMENTAL | Niraparib, 200 mg or 300 mg, daily dose TSR042, intravenous infusion on Day 1 of every 21-day cycle at 500 mg for the 4 first cycles, followed by 1,000 mg on Day 1 of every 42-day cycle thereafter |
| Arm C - Chemotherapy drugs | ACTIVE_COMPARATOR | Chemotherapies (Standard of care) For Ovarian Cancer Patients Paclitaxel, 80 mg/m², Intravenous, Day 1, 8, 15 every 28 days Pegylated Liposomal Doxorubicin, 40 mg/m², Intravenous, every 28 days Topotecan, 4mg/m², Intravenous, Day 1, 8, 15 every 28 days For Endometrial Cancer Patients Doxorubicin, 60 mg/m², Intravenous, every 21 days Paclitaxel, 80 mg/m², Intravenous, Day 1, 8, 15 every 28 days Gemcitabine, 800 mg/m², Intravenous, Day 1, 8 every 21 days |
| Cohort A: 1-2 prior lines of therapy (TSR-042, Bevacizumab, and Niraparib) | EXPERIMENTAL | PARP Inhibitor-Naive Platinum-Resistant Ovarian Cancer Treatment Cohort with TSR-042, Bevacizumab, and Niraparib. TSR-042 administered 500 milligrams (mg) on Day 1 every 3 weeks (Q3W) for 4 cycles (each cycle is 21 days), followed by 1000 mg every 6 weeks (Q6W) beginning on Cycle 5 Day 1 until progressive disease (PD) or toxicity. Bevacizumab administered 15 milligram per kilogram (mg/kg) every 3 weeks for up to 15 months. Niraparib 200 or 300 mg per day until PD or toxicity. |
| Cohort C: Arm 1: Participants receiving platinum plus taxane | ACTIVE_COMPARATOR | Participants are expected to receive 1 run-in cycle (up to 5 weeks) of carboplatin-paclitaxel during pre-screening. After confirmation that the tumor is homologous recombination-deficient (HRd). Participants will then be randomized to three 21-day cycles of platinum-taxane doublet chemotherapy (carboplatin plus paclitaxane). After interval debulking surgery (IDS), all participants will receive up to three 21-day cycles of adjuvant platinum-taxane doublet chemotherapy (and optional bevacizumab for participants deemed high-risk; third cycle is optional) followed by niraparib (and optional bevacizumab or bevacizumab biosimilar for participants deemed high- risk) maintenance treatment. |
| Cohort C: Arm 2: Participants receiving neoadjuvant Niraparib | EXPERIMENTAL | Participants are expected to receive 1 run-in cycle (up to 5 weeks) of carboplatin-paclitaxel during pre-screening. After confirmation that the tumor is HRd, participants will be randomized to three 21-day cycles of neoadjuvant niraparib therapy. After IDS, all participants will receive up to three 21-day cycles of adjuvant platinum-taxane doublet chemotherapy (and optional bevacizumab for participants deemed high-risk; third cycle is optional) followed by niraparib (and optional bevacizumab or bevacizumab biosimilar for participants deemed high- risk) maintenance treatment. |
| Participants receiving niraparib+ bevacizumab | EXPERIMENTAL | Participants will be administered bevacizumab 15 milligram per kilogram (mg/kg) via a 30 minute (min) intravenous (IV) infusion on Day 1 of each 21-day cycle. Niraparib will be administered orally once a day continuously throughout each 21-day cycle (84-day cycle after amendment 2). On Day 1 of each cycle, niraparib will be administered upon completion of bevacizumab infusion. The starting dose of niraparib will be based on the participant's Baseline actual body weight or platelet count. |
| Stage 1 (Cohort 1): Niraparib plus Pembrolizumab | EXPERIMENTAL | Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/programmed death-ligand 1 (PD-L1) inhibitor treatment and whose tumors have high PD-L1 expression (tumor proportion score \[TPS\]: \>= 50 percent \[%\]) will receive combination of niraparib and a PD-1 inhibitor; pembrolizumab. |
| Stage 1 (Cohort 2): Niraparib plus Pembrolizumab | EXPERIMENTAL | Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment and whose tumors have PD-L1 expression (TPS: 1% to 49%) will receive combination of niraparib and a PD-1 inhibitor; pembrolizumab. |
| Stage 1 (Cohort 3): Niraparib | EXPERIMENTAL | Participants with locally advanced and metastatic squamous NSCLC who have been previously treated with both platinum and either PD-1 or PD-L1 inhibitor will receive single agent niraparib. |
| Stage 2 (Cohort 1A): Niraparib plus TSR-042 (Dostarlimab) | EXPERIMENTAL | Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment and whose tumors have high PD-L1 expression (TPS: \>= 50%) will receive combination of niraparib and a PD-1 inhibitor; TSR-042 (Dostarlimab). |
| Stage 2 (Cohort 2A): Niraparib plus TSR-042 (Dostarlimab) | EXPERIMENTAL | Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment and whose tumors have PD-L1 expression (TPS: 1% to 49%) will receive combination of niraparib and a PD-1 inhibitor; TSR-042 (Dostarlimab). |
| Niraparib | EXPERIMENTAL | - |
| Cohort 1 (Niraparib, Irinotecan) | EXPERIMENTAL | Participants will receive a starting dose of 100 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal. |
| Cohort 2 (Niraparib, Irinotecan) | EXPERIMENTAL | Participants will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal. |
| Cohort 3a (Niraparib, Irinotecan) | EXPERIMENTAL | Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal. |
| Cohort 3b (Niraparib, Irinotecan) | EXPERIMENTAL | Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal. |
| Cohort 4a (Niraparib, Irinotecan) | EXPERIMENTAL | Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal. |
| Cohort 4b (Niraparib, Irinotecan) | EXPERIMENTAL | Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal. |
| Participants with HER2-negative and BRCAmut breast cancer | EXPERIMENTAL | Participants with HER2-negative and BRCAmut localized breast cancer (primary tumor \>=1 cm) will receive niraparib (200 mg PO). |
| Normal hepatic function (Group 1): | EXPERIMENTAL | To evaluate the pharmocokinetics and safety of niraparib |
| Moderate hepatic impairment (Group 2): | EXPERIMENTAL | To evaluate the pharmocokinetics and safety of niraparib |
| Stage 1: Tablet-Capsule Sequence | EXPERIMENTAL | Single dose niraparib tablet followed by single dose niraparib capsule followed by optional daily dosing extension phase |
| Stage 1: Capsule-Tablet Sequence | EXPERIMENTAL | Single dose niraparib capsule followed by single dose niraparib tablet followed by optional daily dosing extension phase |
| Stage 2: Tablet-Capsule Sequence | EXPERIMENTAL | Single dose niraparib tablet followed by single dose niraparib capsule followed by optional daily dosing extension phase. |
| Stage 2: Capsule-Tablet Sequence | EXPERIMENTAL | Single dose niraparib capsule followed by single dose niraparib tablet followed by optional daily dosing extension phase |
| Stage 3: High fat meal-fasted sequence | EXPERIMENTAL | Single dose niraparib tablet with a high fat meal followed by single dose of niraparib tablet in a fasted state. |
| Stage 3: Fasted-high fat meal sequence | EXPERIMENTAL | Single dose niraparib tablet in a fasted state followed by single dose Niraparib tablet with a high fat meal. |
| Part A: TSR-042 and niraparib 200 mg QD | EXPERIMENTAL | Patients will receive TSR-042 500 milligram (mg), intravenous (IV) infusion on Day 1 of every cycle (every 3 weeks \[Q3W\]) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (every 6 weeks \[Q6W\]) beginning on Day 1 of Cycle 5 along with niraparib 200 mg, once daily (QD), orally on Days 1 to 21 repeated Q3W. |
| Part A: TSR-042 and niraparib 300 mg QD | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with niraparib 300 mg, QD, orally on Days 1 to 21 repeated Q3W. |
| Part B: TSR-042 and carboplatin-paclitaxel | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with carboplatin, IV infusion on Day 1 Q3W and paclitaxel 175 milligram per square meter (mg/m\^2), IV infusion on Day 1 Q3W administered for 4 to 6 cycles. |
| Part C: TSR-042, niraparib 200 mg QD and bevacizumab | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with niraparib 200 mg administered orally on Days 1 to 21 repeated Q3W and bevacizumab 15 mg/kilogram (kg), IV infusion on Day 1 of every 21-day cycle Q3W for up to 15 months. |
| Part C: TSR-042, niraparib 300 mg QD and bevacizumab | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with niraparib 300 mg administered orally on Days 1 to 21 repeated Q3W and bevacizumab 15 mg/kg, IV infusion on Day 1 of every 21-day cycle Q3W for up to 15 months. |
| Part D: TSR-042, carboplatin-paclitaxel and bevacizumab | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with carboplatin, IV infusion on Day 1 Q3W and paclitaxel 175 mg/m\^2, IV infusion on Day 1 Q3W administered for 4 to 6 cycles; and bevacizumab 15 mg/kg, IV infusion on Day 1 of every 21-day cycle Q3W for up to 15 months. |
| Part E: TSR-042 and carboplatin-pemetrexed | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) along with carboplatin, IV infusion on Day 1 Q3W and pemetrexed 500 mg/m\^2, IV infusion on Day 1 Q3W (with vitamin supplementation) administered for 6 cycles (each cycle is 21 days). |
| Part F: TSR-042, TSR-022, and carboplatin-pemetrexed | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W); and TSR-022 900 mg, IV infusion on Day 1 Q3W along with carboplatin, IV infusion on Day 1 Q3W administered for 5 cycles (each cycle is 21 days); and pemetrexed 500 mg/m\^2, IV infusion on Day 1 Q3W (with vitamin supplementation). |
| Part G: TSR-042 and carboplatin-nab-paclitaxel | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) along with carboplatin, IV infusion on Day 1 Q3W for 4 to 6 cycles (each cycle is 21 days) and nab-paclitaxel 100 mg/m\^2, IV infusion on Days 1, 8 and 15 (every week \[Q1W\]) of every 3 week cycle for 4 to 6 cycles. |
| Part H: TSR-042, TSR-022, and carboplatin-nab-paclitaxel | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W); followed by TSR-022 900 mg, IV infusion on Day 1 Q3W along with carboplatin, IV infusion on Day 1 Q3W for 4 to 6 cycles (each cycle is 21 days) and nab-paclitaxel 100 mg/m\^2, IV infusion on Days 1, 8 and 15 (Q1W) of every 3 week cycle for 4 to 6 cycles. |
| Part I: TSR-042, TSR-022, and carboplatin-paclitaxel | EXPERIMENTAL | Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W); followed by TSR-022 900 mg, IV infusion on Day 1 Q3W along with carboplatin, IV infusion on Day 1 Q3W and paclitaxel 175 mg/m\^2, IV infusion on Day 1 Q3W for 4 to 6 cycles (each cycle is 21 days). |
| niraparib plus pembrolizumab | EXPERIMENTAL | Phase 1: Dose-escalation: ascending doses of niraparib up to 300mg/day orally (PO) on Days 1-21 and pembrolizumab 200mg intravenously (IV) on Day 1 of each 21-day cycle Phase 2: niraparib (recommended Phase 2 dose) in combination with pembrolizumab 200mg IV on Day 1 of each 21-day cycle |
| Niraparib Oral and IV | EXPERIMENTAL | Single Oral dose of Niraparib capsules (unlabeled active pharmaceutical ingredient) orally and a 15-minute IV infusion of Niraparib (labeled active pharmaceutical ingredient) |
| Niraparib Oral | EXPERIMENTAL | Single Oral dose of Niraparib capsules (labeled active pharmaceutical ingredient) |
| Name | Type | Description |
|---|---|---|
| Niraparib | DRUG | Participants will receive niraparib 200 mg orally once daily starting on Day 1 of RT. Following completion of RT, participants will continue niraparib adjuvant therapy orally once daily on Days 1 to 28 of each 28-day cycle until progression by BICR |
| Temozolomide | DRUG | Participants randomized to the comparator arm (Arm B) will receive SOC TMZ 75 mg/m2 orally once daily with RT starting on Day 1 of RT. Following completion of RT, participants will complete a 4-week rest period, and then receive adjuvant TMZ 150 to 200 mg/m2 orally once daily on Days 1 to 5 of each 28-day cycle until progression by BICR or for a maximum of 6 cycles. |
| Placebo | DRUG | Matching placebo will be administered |
| Pembrolizumab | BIOLOGICAL | Pembrolizumab will be administered |
| 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. |
| Dostarlimab | DRUG | Niraparib \& Dostarlimab combination |
| Aromatase Inhibitors | DRUG | Aromatase Inhibitors beginning on Day 1 and continuing through Day 28 of every 28-day cycle. |
| Niraparib + TSR-042 (Dostarlimab) | COMBINATION_PRODUCT | Combination of 2 drugs, a PARP Inhibitor and an Anti-PD-1 |
| Chemotherapy Drugs | DRUG | Chemotherapies given in standard of care |
| TSR-042 | BIOLOGICAL | TSR-042 is a humanized monoclonal antibody that binds with high affinity to Programmed cell death protein 1 (PD-1) resulting in inhibition of binding to programmed death receptor ligands 1 and 2 (PD-L1 and PD-L2). |
| Bevacizumab | BIOLOGICAL | Bevacizumab is an Food Drug and Administration (FDA) approved antiangiogenic recombinant humanized monoclonal Immunoglobulin (Ig) G1 antibody against the vascular endothelial growth factor protein, which has been shown to be efficacious against a variety of different cancer types, including colon cancer, lung cancer, glioblastoma, and renal-cell carcinoma. |
| Carboplatin | DRUG | Carboplatin will be infused intravenously over 60 minutes at the prescribed dose of area under the concentration versus time curve of 5 to 6 mg/milliliters (mL) per minute on Day 1 of every 21-day cycle |
| Paclitaxel | DRUG | Paclitaxel will be administered intravenously over 180 minutes at the prescribed dose of 175 mg/meter square (m\^2) on Day 1 of every 21-day cycle |
| TSR-042 (Dostarlimab) | BIOLOGICAL | TSR-042 (Dostarlimab) is a humanized mAb of the IgG4/kappa isotype that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. It will be administered at a dose of 500 mg for every 3 weeks (Q3W) for first 4 cycles followed by 1000 mg for every 6 weeks (Q6W) for all subsequent cycles using a 30-minute IV infusion. TSR-042 (dostarlimab) will be supplied as a solution of 160 mg (20 mg/mL) or 500 mg (50 mg/mL) in a single-dose vial. |
| Irinotecan | DRUG | Given intravenously (IV) |
| Niraparib Tablet | DRUG | Niraparib tablet formulation |
| Niraparib Capsule | DRUG | Niraparib capsule formulation |
| Carboplatin-Paclitaxel | DRUG | Carboplatin in combination with paclitaxel is a chemotherapy treatment that has been shown to be efficacious against a variety of different tumor types, including non-small cell lung cancer \[NSCLC\], ovarian cancer, endometrial cancer, and head and neck cancer. |
| TSR-022 | DRUG | TSR-022 is a monoclonal antibody against TIM-3 (also called HAVCR2), an immune checkpoint receptor. Immune checkpoint proteins are molecules that help to regulate the immune system so it does not mistakenly attack healthy cells. However, they can also keep immune cells from recognizing and killing cancer cells. TIM-3 is found on the surface of certain T-cells, including tumor-infiltrating T-cells, that have left the bloodstream and migrated into the tumor environment. By binding to and blocking TIM-3, TRS-022 allows for T-cells to become activated so as to enhance T-cell-mediated attacks on tumors. These attacks reduce their growth. |
| Carboplatin-Pemetrexed | DRUG | Pemetrexed and platinum therapy in combination with pembrolizumab (anti-PD-1 antibody) has proven to be efficacious in a first line setting for nonsquamous NSCLC patients |
| Carboplatin-Nab-Paclitaxel | DRUG | Nab-paclitaxel is a formulation of paclitaxel that is indicated for locally advanced or metastatic NSCLC, as first-line treatment in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy. Nab-paclitaxel has shown increased ORR and time to progression in metastatic breast cancer compared with solvent-based paclitaxel and has shown antitumor activity and improved ORR compared with solvent-based paclitaxel as first-line therapy in patients with NSCLC. |
| Niraparib Oral Capsules (Labeled) | DRUG | Single 300 mg dose of niraparib |
| Niraparib IV (Labeled) | DRUG | Intravenous (IV) infusion of 100 μg niraparib (containing approximately 1 μCi of \[14C\]-niraparib) |
| Niraparib Oral Capsules (Unlabeled) | DRUG | Single 300 mg dose of niraparib (unlabeled active pharmaceutical ingredient) |
Inclusion Criteria: * 1\. Histologic documentation of a newly-diagnosed intracranial GBM, per 2021 WHO classification guidelines through local pathology review. * 2\. Age ≥18 years at the time of signing informed consent. * 3\. Sufficient tissue available for retrospective central pathology review,...