Neoplasms
Conditions
Keywords
Niraparib, NSCLC, Pembrolizumab, Dostarlimab, TSR-042
Brief summary
This is a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of niraparib alone and in combination with PD-1 inhibitors in participants with locally advanced and metastatic non-small cell lung cancer (NSCLC). The study will consist of 2 stages. In stage 1, participants from Cohorts 1 and 2 will receive niraparib plus PD-1 inhibitor; pembrolizumab and participants from Cohort 3 will receive niraparib alone. In Stage 2, participants from Cohorts 1A and 2A will receive niraparib plus the PD-1 inhibitor, TSR-042 (Dostarlimab).
Interventions
DRUGNiraparib
Niraparib is an orally available, potent, highly selective poly adenosine diphosphate- ribose (poly ADP-ribose) polymerase-1 (PARP-1) and PARP-2 inhibitor. It will be available as 100 milligrams (mg) capsules and will be administered as 2 X 100 mg capsules (200 mg per day) orally once daily (QD).
BIOLOGICALPembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G-4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands (PD-L1 and PD-L2). It will be available as 50 mg lyophilized powder single-use vials or 100 mg/4 milliliters (mL) (25 mg/mL) solution in a single-dose vial. It will be administered at a dose of 200 mg intravenous (IV) using a 30-minute IV infusion
BIOLOGICALTSR-042 (Dostarlimab)
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.
Sponsors
Tesaro, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This will be an open-label study.
Intervention model description
Participants will receive niraparib either as monotherapy or in combination with pembrolizumab during Stage 1 of the study. Participants will receive niraparib in combination with TSR-042 (dostarlimab) during Stage 2 of the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
General Inclusion Criteria: * Male or female participants at least 18 years of age. * Histological or cytological proven advanced (unresectable) or metastatic NSCLC as defined as stage IIIB (positive supraclavicular lymph nodes) not amenable to definitive chemoradiotherapy or stage IV NSCLC. * Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. * Adequate organ function, defined as: 1. Absolute neutrophil count (ANC) \>= 1500 per microliter (/µL). 2. Platelets \>= 100,000/µL. 3. Hemoglobin \>= 9 grams per deciliter (g/dL) or \>= 5.6 millimoles per liter (mmol/L). 4. Serum creatinine \<= 1.5 times upper limit of normal (ULN) or creatinine clearance \>= 50 milliliters per minute (mL/min) (as calculated using the Cockcroft Gault equation or measured using 24-hour urine creatinine clearance) for participants with creatinine levels \> 1.5 times institutional ULN. 5. Total bilirubin \<= 1.5 times ULN except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin \<= 1.5 times ULN of the direct bilirubin. 6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<= 2.5 times ULN unless liver metastases are present, in which case they must be \<= 5 times ULN. * Participant must have recovered to Grade 1 toxicity from prior cancer therapy (a participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for this study). * Participant agrees to submit formalin fixed paraffin embedded (FFPE) tumor tissue specimen, which may have been collected at any time prior to screening. If no archival FFPE tumor tissue is available, participant agrees to undergo a tumor tissue biopsy before Cycle 1/Day 1. (For Cohort 3 only: if diagnosis was made by cytology and archival tissue is not available, participant will not need to provide tumor tissue). * Participants is able to take oral medications. * Female participant meets the following criteria: a) Female participant (of childbearing potential) is not breastfeeding, has a negative serum pregnancy test within 72 hours prior to taking study drug, and agrees to abstain from activities that could result in pregnancy from enrollment through 180 days after the last dose of study treatment or is of nonchildbearing potential; or b) Female participant is of nonchildbearing potential, other than medical reasons, defined as follows: i) \>=45 years of age and has not had menses for \> 1 year. ii) Amenorrheic for \< 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone (FSH) value in the postmenopausal range upon screening evaluation. iii) Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the participant must be willing to use 2 highly effective contraception methods throughout the study, starting with the screening visit through 180 days after the last dose of study therapy. * Male participant agrees to use an adequate method of contraception and not donate sperm starting with the first dose of study therapy through 120 days after the last dose of study therapy. * Participant is able to understand the study procedures and agree to participate in the study by providing written informed consent. Cohort Specific Inclusion Criteria: * Cohorts 1 and 1A (combination of niraparib and PD-1 inhibitor): participants must have tumors with high PD-L1 expression (TPS \>= 50%) per local assessment; with no known Epidermal Growth Factor Receptor (EGFR)-sensitizing mutation and/or ROS -1 or anaplastic lymphoma kinase (ALK) translocation, and no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLC. * Cohorts 2 and 2A (combination of niraparib and PD-1 inhibitor): participants must have tumors with PD-L1 expression (TPS between 1% and 49%) per local assessment, with no known EGFR-sensitizing mutation and/or ROS-1 or ALK translocation, and no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLC. * Cohort 3 (single agent niraparib): participants must have metastatic squamous non-small cell lung cancer (sqNSCLC) and have progressed after both prior platinum-based chemotherapy and prior PD-1 or PD-L1 inhibitor treatment.
Exclusion criteria
for Cohorts 1, 1A , 2 and 2A: * Participant has received systemic therapy for the treatment of advanced stage NSCLC. Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease. * Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. * Known hypersensitivity to the components of niraparib, pembrolizumab, TSR-042 (Dostarlimab), or their excipients. * Known EGFR (exon 19 and 21) mutations, ALK translocations, and/or ROS-1 translocations. * Participant has a history or current condition (such as transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results, or interfere with the participant's participation for the full duration of the study treatment. * Known diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. * Participant is immunocompromised, in the opinion of the Investigator. * Current participation in a treatment study or past participation in a study of an investigational agent within 4 weeks before the first dose of study treatment. * Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered controlled, central nervous system \[CNS\] disease must have undergone treatment \[example, radiation or chemotherapy\] at least 1 month prior to study entry. The participant must not have any new or progressive signs or symptoms related to the CNS disease and must be taking \<= 10 mg of prednisone or equivalent per day or no steroids.) Participants who have untreated brain metastases and who are not symptomatic may enroll if the Investigator feels that treatment of these metastases is not indicated. A scan to confirm the absence of brain metastases is not required. Participants with spinal cord compression may be considered if they have received definitive treatment for this and evidence of clinically SD for 28 days. * Active autoimmune disease that required systemic treatment in the past 2 years (with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (examples, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. * Major surgery within 3 weeks of starting the study or participant has not recovered from any effects of any major surgery. * Other active concomitant malignancy that warrants systemic therapy. * Poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, uncontrolled hypertension, active uncontrolled coagulopathy or any psychiatric disorder that prohibits obtaining informed consent. * Known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring steroid treatment. * Participant is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and for 180 days (for pregnancy or conception) or 30 days (for breastfeeding) after the last dose of study treatment. * Male participant is expecting to donate sperm or father children while receiving study drug or for 120 days after the last dose of study treatment. * Known active hepatic disease (known hepatic cirrhosis, hepatitis B surface antigen-positive status, or suspected active hepatitis C infection). * Prior treatment with a known poly adenosine diphosphate-ribose (ADP-ribose) polymerase (PARP) inhibitor. * Participant received a live vaccine within 30 days of planned start of study therapy. * Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Cohort 1: Objective Response Rate (ORR) | Up to a maximum of 29 months | 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. |
| Stage 2: Cohort 1A and Cohort 2A: Objective Response Rate | Up to a maximum of 17 months | 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. |
| Stage 1: Cohort 3: Objective Response Rate | Up to a maximum of 6 months | 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. |
| Stage 1: Cohort 2: Objective Response Rate | Up to a maximum of 17 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 2: Cohorts 1A and 2A: Number of Participants With Non-SAEs and SAEs | Up to a maximum of 29 months | An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events. |
| Stage 1: Cohort 1: Number of Participants Discontinuing the Study Due to AEs | Up to a maximum of 45 months | An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized. |
| Stage 1: Cohort 2: Number of Participants Discontinuing the Study Due to AEs | Up to a maximum of 17 months | An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized. |
| Stage 1: Cohort 3: Number of Participants Discontinuing the Study Due to AEs | Up to a maximum of 6 months | An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized. |
| Stage 2: Cohorts 1A and 2A: Number of Participants Discontinuing the Study Due to AEs | Up to maximum 29 months | An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized. |
| Stage 1: Cohort 1: Duration of Response | Up to a maximum of 45 months | Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeter (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. |
| Stage 1: Cohort 2: Duration of Response | Up to a maximum of 17 months | Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; 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. |
| Stage 1 : Cohort 3: Duration of Response | Up to a maximum of 6 months | Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; 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. |
| Stage 2: Cohorts 1A and 2A: Duration of Response | Up to a maximum of 29 months | Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; 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. |
| Stage 1 : Cohort 2: Disease Control Rate | Up to a maximum of 17 months | Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method. |
| Stage 1 : Cohort 3: Disease Control Rate | Up to a maximum of 6 months | Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method. |
| Stage 2: Cohorts 1A and 2A: Disease Control Rate | Up to a maximum of 29 months | Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method. |
| Stage 1 : Cohort 1: Progression-free Survival | Up to a maximum of 45 months | Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions. |
| Stage 1 : Cohort 2: Progression-free Survival | Up to a maximum of 17 months | Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions. |
| Stage 1 : Cohort 3: Progression-free Survival | Up to a maximum of 6 months | Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions. |
| Stage 2: Cohorts 1A and 2A: Progression-free Survival | Up to a maximum of 29 months | Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions. |
| Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1(Pre-dose and 30 Minutes, 1 Hour, 2 Hours, 4 Hours, 8 Hours, 96 Hours, 168 Hours Post-dose); Cycles 2, 4, 8 (Pre-dose and 4 Hours Post-dose) (each cycle of 21 days) | Blood samples were collected at indicated time points. |
| Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1 (Pre-dose and 30 Minutes, 1, 2, 4, 8, 24, 168, 336 Hours Post-dose), Cycles 2, 8 (Pre-dose and 4 Hours Post-dose), Cycle 4 (Pre-dose and 30 Minutes, 1, 2, 4, 8, 24, 96, 168, 336 Hours Post-dose) (each cycle of 21 days) | Blood samples were collected at indicated time points. |
| Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 1 Day 1 (Pre-dose and 4 Hours Post-dose), Cycles 2, 4 and 8 (Pre-dose and 4 Hours Post-dose) (each cycle of 21 days) | Blood samples were collected at indicated time points. |
| Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 1 Day 1 (Pre-dose and 4 Hours Post-dose), Cycles 2, 4 and 9 (Pre-dose and 4 Hours Post-dose) (each cycle of 21 days) | Blood samples were collected at indicated time points. |
| Stage 1 : Cohort 1: Disease Control Rate | Up to a maximum of 45 months | Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method. |
| Stage 1: Cohort 1: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) | Up to a maximum of 45 months | An adverse event (AE) is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events |
| Stage 1: Cohort 2: Number of Participants With Non-SAEs and SAEs | Up to a maximum of 17 months | An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events |
| Stage 1: Cohort 3: Number of Participants With Non-SAEs and SAEs | Up to a maximum of 6 months | An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events |
Other
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Cohort 1: Overall Survival (OS) | Up to a maximum of 45 months | Overall survival was defined as the time from date of first dose to the date of death due to any cause. |
| Stage 2: Cohorts 1A and 2A: Overall Survival | Up to a maximum of 29 months | Overall survival was defined as the time from date of first dose to the date of death due to any cause. |
| Stage 1: Cohort 3: Overall Survival | Up to a maximum of 6 months | Overall survival was defined as the time from date of first dose to the date of death due to any cause. |
| Stage 1: Cohort 2: Overall Survival | Up to a maximum of 17 months | Overall survival was defined as the time from date of first dose to the date of death due to any cause. |
Countries
United States
Participant flow
Recruitment details
This study consisted of two stages; Stage 1 (Cohorts 1, 2, 3) and Stage 2 (Cohorts 1A, 2A).
Pre-assignment details
A total of 69 participants were screened, of which 16 failed screening and 53 participants (41 in Stage 1 and 12 in Stage 2) were enrolled into the study. Data was not collected for Cohort 2A of Stage 2 as the Sponsor decided not to open this Cohort to enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab Participants with locally advanced and metastatic non-small cell lung cancer (NSCLC) (all histologies) with no prior systemic chemotherapy or programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor treatment and whose tumors had high PD-L1 expression (tumor proportion score \[TPS\]: \>= 50 percent \[%\]) received a combination of niraparib and pembrolizumab. Niraparib was given at a dose of 200 milligrams (mg) orally once daily during each 21-day cycle. Pembrolizumab was administered as an intravenous (IV) infusion at a dose of 200 mg on Day 1 of each 21-day cycle. | 17 |
| Stage 1 (Cohort 2): Niraparib + Pembrolizumab Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment and whose tumors had PD-L1 expression (TPS: 1% to 49%) received a combination of niraparib and pembrolizumab. Niraparib was given at a dose of 200 mg orally once daily during each 21-day cycle. Pembrolizumab was administered as an IV infusion at a dose of 200 on Day 1 of each 21-day cycle. | 21 |
| Stage 1 (Cohort 3): Niraparib Participants with locally advanced and metastatic squamous NSCLC who were previously treated with both platinum and either PD-1 or PD-L1 inhibitor received single agent niraparib at a dose of 200 mg orally once daily during each 21-day cycle. | 3 |
| Stage 2 (Cohort 1A): Niraparib + TSR-042 (Dostarlimab) 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%) received a combination of niraparib and TSR-042 (Dostarlimab). Niraparib was given at a dose of 200 mg orally once daily during each 21-day cycle. TSR-042 (Dostarlimab) was administered as an IV infusion at a dose of 500 mg once every 3 weeks for first 4 cycles followed by 1000 mg dose once every 6 weeks for subsequent cycles (each cycle of 21 days). | 12 |
| Stage 2 (Cohort 2A): Niraparib + TSR-042 (Dostarlimab) 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%) were planned to receive a combination of niraparib and TSR-042 (Dostarlimab). Niraparib was planned to be given at a dose of 200 mg orally once daily. TSR-042 (Dostarlimab) was planned to be administered as an IV infusion at a dose of 500 mg once every 3 weeks for first 4 cycles followed by 1000 mg dose once every 6 weeks for all subsequent cycles (each cycle of 21 days). | 0 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Stage 1 (Up to a Maximum of 45 Months) | Death | 11 | 16 | 1 | 0 | 0 |
| Stage 1 (Up to a Maximum of 45 Months) | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 |
| Stage 1 (Up to a Maximum of 45 Months) | Sponsor Decision | 3 | 1 | 0 | 0 | 0 |
| Stage 1 (Up to a Maximum of 45 Months) | Withdrawal by Subject | 3 | 3 | 2 | 0 | 0 |
| Stage 2 (Up to a Maximum of 29 Months) | Death | 0 | 0 | 0 | 6 | 0 |
| Stage 2 (Up to a Maximum of 29 Months) | Sponsor Decision | 0 | 0 | 0 | 3 | 0 |
| Stage 2 (Up to a Maximum of 29 Months) | Withdrawal by Subject | 0 | 0 | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1 (Cohort 2): Niraparib + Pembrolizumab | Stage 1 (Cohort 3): Niraparib | Stage 2 (Cohort 1A): Niraparib + TSR-042 (Dostarlimab) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 70.1 Years STANDARD_DEVIATION 7.55 | 70.9 Years STANDARD_DEVIATION 9.78 | 72.3 Years STANDARD_DEVIATION 10.69 | 68.3 Years STANDARD_DEVIATION 6.74 | 70.1 Years STANDARD_DEVIATION 8.35 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 14 Participants | 19 Participants | 3 Participants | 8 Participants | 44 Participants |
| Sex: Female, Male Female | 6 Participants | 12 Participants | 0 Participants | 6 Participants | 24 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 3 Participants | 6 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 17 | 16 / 21 | 1 / 3 | 6 / 12 | 0 / 0 |
| other Total, other adverse events | 17 / 17 | 20 / 21 | 3 / 3 | 12 / 12 | 0 / 0 |
| serious Total, serious adverse events | 11 / 17 | 14 / 21 | 1 / 3 | 7 / 12 | 0 / 0 |
Outcome results
Primary
Stage 1: Cohort 1: Objective Response Rate (ORR)
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.
Time frame: Up to a maximum of 29 months
Population: Modified intent-to-treat (mITT) Population comprised of all participants who received any study drug and did not withdraw consent prior to having at least one post-Baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Objective Response Rate (ORR) | 56.3 Percentage of participants |
Primary
Stage 1: Cohort 2: Objective Response Rate
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.
Time frame: Up to a maximum of 17 months
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Objective Response Rate | 20.0 Percentage of participants |
Primary
Stage 1: Cohort 3: Objective Response Rate
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.
Time frame: Up to a maximum of 6 months
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Objective Response Rate | 0 Percentage of participants |
Primary
Stage 2: Cohort 1A and Cohort 2A: Objective Response Rate
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.
Time frame: Up to a maximum of 17 months
Population: mITT Population. Data was not collected for Cohort 2A of Stage 2 as no participant was enrolled into this Cohort of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohort 1A and Cohort 2A: Objective Response Rate | 9.1 Percentage of participants |
Secondary
Stage 1 : Cohort 1: Disease Control Rate
Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method.
Time frame: Up to a maximum of 45 months
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1 : Cohort 1: Disease Control Rate | 87.5 Percentage of participants |
Secondary
Stage 1: Cohort 1: Duration of Response
Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeter (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.
Time frame: Up to a maximum of 45 months
Population: mITT Population. Only those participants with confirmed response were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Duration of Response | 22.8 Months |
Secondary
Stage 1: Cohort 1: Number of Participants Discontinuing the Study Due to AEs
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized.
Time frame: Up to a maximum of 45 months
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Number of Participants Discontinuing the Study Due to AEs | 10 Participants |
Secondary
Stage 1: Cohort 1: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
An adverse event (AE) is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events
Time frame: Up to a maximum of 45 months
Population: Safety Population comprised of participants who received at least one dose of either study medications.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) | Any SAE | 11 Participants |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) | Any non-SAE | 17 Participants |
Secondary
Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab
Blood samples were collected at indicated time points.
Time frame: Cycle 1 Day 1(Pre-dose and 30 Minutes, 1 Hour, 2 Hours, 4 Hours, 8 Hours, 96 Hours, 168 Hours Post-dose); Cycles 2, 4, 8 (Pre-dose and 4 Hours Post-dose) (each cycle of 21 days)
Population: Pharmacokinetic Population comprised of participants who had at least one of measurable niraparib concentration. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; Pre-dose | 28.4 Nanograms per milliliter | Standard Deviation 115 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 30 Minutes Post-dose | 201 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 2; Pre-dose | 360 Nanograms per milliliter | Standard Deviation 383 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 2; 4 Hours Post-dose | 959 Nanograms per milliliter | Standard Deviation 506 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; Pre-dose | 600 Nanograms per milliliter | Standard Deviation 505 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 4 Hours Post-dose | 794 Nanograms per milliliter | Standard Deviation 597 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 1 Hour Post-dose | 500 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 2 Hours Post-dose | 733 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 4 Hours Post-dose | 335 Nanograms per milliliter | Standard Deviation 233 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 8 Hours Post-dose | 353 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 96 Hours Post-dose | 1400 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 168 Hours Post-dose | 1440 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 8; Pre-dose | 460 Nanograms per milliliter | Standard Deviation 543 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 1: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 8; 4 Hours Post-dose | 727 Nanograms per milliliter | Standard Deviation 824 |
Secondary
Stage 1 : Cohort 1: Progression-free Survival
Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.
Time frame: Up to a maximum of 45 months
Population: mITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1 : Cohort 1: Progression-free Survival | 8.4 Months |
Secondary
Stage 1 : Cohort 2: Disease Control Rate
Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method.
Time frame: Up to a maximum of 17 months
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1 : Cohort 2: Disease Control Rate | 70.0 Percentage of participants |
Secondary
Stage 1: Cohort 2: Duration of Response
Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; 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.
Time frame: Up to a maximum of 17 months
Population: mITT Population. Only those participants with confirmed response were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Duration of Response | 9.4 Months |
Secondary
Stage 1: Cohort 2: Number of Participants Discontinuing the Study Due to AEs
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized.
Time frame: Up to a maximum of 17 months
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Number of Participants Discontinuing the Study Due to AEs | 9 Participants |
Secondary
Stage 1: Cohort 2: Number of Participants With Non-SAEs and SAEs
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events
Time frame: Up to a maximum of 17 months
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Number of Participants With Non-SAEs and SAEs | Any SAE | 14 Participants |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Number of Participants With Non-SAEs and SAEs | Any non-SAE | 20 Participants |
Secondary
Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab
Blood samples were collected at indicated time points.
Time frame: Cycle 1 Day 1 (Pre-dose and 30 Minutes, 1, 2, 4, 8, 24, 168, 336 Hours Post-dose), Cycles 2, 8 (Pre-dose and 4 Hours Post-dose), Cycle 4 (Pre-dose and 30 Minutes, 1, 2, 4, 8, 24, 96, 168, 336 Hours Post-dose) (each cycle of 21 days)
Population: Pharmacokinetic Population. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 2 Hours Post-dose | 264 Nanograms per milliliter | Standard Deviation 251 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 4 Hours Post-dose | 345 Nanograms per milliliter | Standard Deviation 188 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 8 Hours Post-dose | 238 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 2; Pre-dose | 767 Nanograms per milliliter | Standard Deviation 362 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 1 Hour Post-dose | 1260 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 2 Hours Post-dose | 1290 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 4 Hours Post-dose | 1040 Nanograms per milliliter | Standard Deviation 668 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 8 Hours, Post-dose | 978 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 24 Hours Post-dose | 660 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; Pre-dose | NA Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 30 Minutes Post-dose | 24.5 Nanograms per milliliter | Standard Deviation 42.4 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 1 Hour Post-dose | 189 Nanograms per milliliter | Standard Deviation 302 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 24 Hours Post-dose | 318 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 168 Hours Post-dose | 759 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 1 Day 1; 336 Hours Post-dose | 808 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 2; 4 Hours Post-dose | 1170 Nanograms per milliliter | Standard Deviation 473 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; Pre-dose | 805 Nanograms per milliliter | Standard Deviation 588 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 30 Minutes Post-dose | 841 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 96 Hours | 773 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 168 Hours | 767 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 4; 336 Hours | 924 Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 8; Pre-dose | 342 Nanograms per milliliter | Standard Deviation 123 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 2: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and Pembrolizumab | Cycle 8; 4 Hours post-dose | 602 Nanograms per milliliter | Standard Deviation 290 |
Secondary
Stage 1 : Cohort 2: Progression-free Survival
Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.
Time frame: Up to a maximum of 17 months
Population: mITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1 : Cohort 2: Progression-free Survival | 4.2 Months |
Secondary
Stage 1 : Cohort 3: Disease Control Rate
Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method.
Time frame: Up to a maximum of 6 months
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1 : Cohort 3: Disease Control Rate | 50.0 Percentage of participants |
Secondary
Stage 1 : Cohort 3: Duration of Response
Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; 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.
Time frame: Up to a maximum of 6 months
Population: mITT Population. No participant had confirmed response. Hence, data for duration of response was not collected.
Secondary
Stage 1: Cohort 3: Number of Participants Discontinuing the Study Due to AEs
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized.
Time frame: Up to a maximum of 6 months
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Number of Participants Discontinuing the Study Due to AEs | 1 Participants |
Secondary
Stage 1: Cohort 3: Number of Participants With Non-SAEs and SAEs
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events
Time frame: Up to a maximum of 6 months
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Number of Participants With Non-SAEs and SAEs | Any SAE | 1 Participants |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Number of Participants With Non-SAEs and SAEs | Any non-SAE | 3 Participants |
Secondary
Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy
Blood samples were collected at indicated time points.
Time frame: Cycle 1 Day 1 (Pre-dose and 4 Hours Post-dose), Cycles 2, 4 and 8 (Pre-dose and 4 Hours Post-dose) (each cycle of 21 days)
Population: Pharmacokinetic Population. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 1 Day 1; Pre-dose | NA Nanograms per milliliter |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 1 Day 1; 4 Hours Post-dose | 279 Nanograms per milliliter |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 2; Pre-dose | 469 Nanograms per milliliter |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 2; 4 Hours Post-dose | 717 Nanograms per milliliter |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 4; Pre-dose | 615 Nanograms per milliliter |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 4; 4 Hours Post-dose | 871 Nanograms per milliliter |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 8; Pre-dose | 478 Nanograms per milliliter |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1: Cohort 3: Plasma Concentration of Niraparib Following Niraparib Monotherapy | Cycle 8; 4 Hours Post-dose | 913 Nanograms per milliliter |
Secondary
Stage 1 : Cohort 3: Progression-free Survival
Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.
Time frame: Up to a maximum of 6 months
Population: mITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 1 : Cohort 3: Progression-free Survival | 4.0 Months |
Secondary
Stage 2: Cohorts 1A and 2A: Disease Control Rate
Disease Control Rate was defined as the percentage of participants with a best overall response of CR, PR or SD per RECIST v1.1; 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. Confidence interval was calculated using binomial exact method.
Time frame: Up to a maximum of 29 months
Population: mITT Population. Data was not collected for Cohort 2A of Stage 2 as no participant was enrolled into this Cohort of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Disease Control Rate | 54.5 Percentage of participants |
Secondary
Stage 2: Cohorts 1A and 2A: Duration of Response
Duration of Response was defined as the time from first documented CR or PR until the subsequently documented disease progression by RECIST v1.1 or death, whichever occurs earlier; 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.
Time frame: Up to a maximum of 29 months
Population: mITT Population. Only those participants with confirmed response were analyzed. Data was not collected for Cohort 2A of Stage 2 as no participant was enrolled into this Cohort of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Duration of Response | 21.5 Months |
Secondary
Stage 2: Cohorts 1A and 2A: Number of Participants Discontinuing the Study Due to AEs
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Number of participants discontinuing the study due to AEs have been summarized.
Time frame: Up to maximum 29 months
Population: Safety Population. Data was not collected for Cohort 2A of Stage 2 as no participant was enrolled into this Cohort of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Number of Participants Discontinuing the Study Due to AEs | 2 Participants |
Secondary
Stage 2: Cohorts 1A and 2A: Number of Participants With Non-SAEs and SAEs
An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not Serious Adverse Events were considered as Non-Serious adverse events.
Time frame: Up to a maximum of 29 months
Population: Safety Population. Data was not collected for Cohort 2A of Stage 2 as no participant was enrolled into this Cohort of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Number of Participants With Non-SAEs and SAEs | Any non-SAE | 12 Participants |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Number of Participants With Non-SAEs and SAEs | Any SAE | 7 Participants |
Secondary
Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab)
Blood samples were collected at indicated time points.
Time frame: Cycle 1 Day 1 (Pre-dose and 4 Hours Post-dose), Cycles 2, 4 and 9 (Pre-dose and 4 Hours Post-dose) (each cycle of 21 days)
Population: Pharmacokinetic Population. Data was not collected for Cohort 2A of Stage 2 as no participant was enrolled into this Cohort of the study. Only those participants with data available at specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 2; Pre-dose | 669 Nanograms per milliliter | Standard Deviation 503 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 2; 4 Hours Post-dose | 967 Nanograms per milliliter | Standard Deviation 540 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 4; Pre-dose | 486 Nanograms per milliliter | Standard Deviation 243 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 9; 4 Hours Post-dose | 766 Nanograms per milliliter | Standard Deviation 231 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 1 Day 1; Pre-dose | NA Nanograms per milliliter | — |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 1 Day 1; 4 Hours Post-dose | 328 Nanograms per milliliter | Standard Deviation 254 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 4; 4 Hours Post-dose | 795 Nanograms per milliliter | Standard Deviation 228 |
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Plasma Concentration of Niraparib Following Combination Therapy of Niraparib and TSR-042 (Dostarlimab) | Cycle 9; Pre-dose | 456 Nanograms per milliliter | Standard Deviation 134 |
Secondary
Stage 2: Cohorts 1A and 2A: Progression-free Survival
Progression-free survival was defined as the time from the date of first dose to the date of disease progression or death due to any cause, whichever occurs earlier. Progression was defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.
Time frame: Up to a maximum of 29 months
Population: mITT Population. Data was not collected for Cohort 2A of Stage 2 as no participant was enrolled into this Cohort of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 (Cohort 1): Niraparib + Pembrolizumab | Stage 2: Cohorts 1A and 2A: Progression-free Survival | 4.4 Months |
Other Pre-specified
Stage 1: Cohort 1: Overall Survival (OS)
Overall survival was defined as the time from date of first dose to the date of death due to any cause.
Time frame: Up to a maximum of 45 months
Population: mITT Population. OS was removed as a secondary endpoint through a protocol amendment, following completion of the primary endpoint. OS will not be analyzed and reported for this study.
Other Pre-specified
Stage 1: Cohort 2: Overall Survival
Overall survival was defined as the time from date of first dose to the date of death due to any cause.
Time frame: Up to a maximum of 17 months
Population: mITT Population. OS was removed as a secondary endpoint through a protocol amendment, following completion of the primary endpoint. OS will not be analyzed and reported for this study.
Other Pre-specified
Stage 1: Cohort 3: Overall Survival
Overall survival was defined as the time from date of first dose to the date of death due to any cause.
Time frame: Up to a maximum of 6 months
Population: mITT Population. OS was removed as a secondary endpoint through a protocol amendment, following completion of the primary endpoint. OS will not be analyzed and reported for this study.
Other Pre-specified
Stage 2: Cohorts 1A and 2A: Overall Survival
Overall survival was defined as the time from date of first dose to the date of death due to any cause.
Time frame: Up to a maximum of 29 months
Population: mITT Population. OS was removed as a secondary endpoint through a protocol amendment, following completion of the primary endpoint. OS will not be analyzed and reported for this study.