This is a multi-center, open-label, first-in-human Phase 1 study evaluating the anti-programmed death receptor 1 (anti-PD-1) antibody dostarlimab (also known as TSR-042) n participants with advanced solid tumors who have limited available treatment options. The study will be conducted in 2 parts with Part 1 consisting of safety evaluation, pharmacokinetics (PK), and pharmacodynamics (PDy) of escalating doses of dostarlimab. Dose escalation will be based on ascending weight-based dose levels (DLs) of dostarlimab and will continue until the maximum tolerated dose (MTD) is reached or may be stopped at any dose level up to the highest dose of 20 milligrams per kilograms (mg/kg) based on emerging safety and PK/PDy data. Part 2 will be conducted in two subparts, Part 2A (fixed-dose safety evaluation cohorts) and Part 2B (expansion cohorts). Part 2A of the study will evaluate the safety and tolerability of dostarlimab at fixed doses of 500 mg administered every 3 weeks (Q3W) and 1000 mg administered every 6 weeks (Q6W). Part 2B of the study will examine the safety and clinical activity of dostarlimab in cohorts of participants with specific types of advanced solid tumors.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
730
Dostarlimab (160 mg, 20 mg/mL; or 500 mg, 50 mg/mL) is a humanized monoclonal antibody that binds with high affinity to PD-1 resulting in inhibition of binding to programmed death receptor ligands 1 and 2 (PD-L1 and PD-L2). Dostarlimab will be administered via a 30 minute IV infusion on Day 1 and Day 15 of each cycle in Part 1. For additional patients enrolled specifically to better characterize the PK/PDy profile in Part 1, dostarlimab administration during Cycle 1 will only occur on Day 1 with the second dose administered on Cycle 2/Day 1 and Q2W thereafter. For Part 2A and 2B, dostarlimab will be administered on Day 1 of each treatment cycle. Cycle duration for Q3W dosing is 21 days and Q6W dosing is 42 days.
GSK Investigational Site
Birmingham, Alabama, United States
GSK Investigational Site
Goodyear, Arizona, United States
GSK Investigational Site
Scottsdale, Arizona, United States
GSK Investigational Site
Fayetteville, Arkansas, United States
GSK Investigational Site
Encinitas, California, United States
Part 1: Number of participants with treatment emergent AEs (TEAEs)
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. An AE can therefore be any unfavorable and unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the product. TEAEs defined as any AE either reported for the first time or worsening of a pre-existing event after first dose of study treatment.
Time frame: Up to 2 years
Part 1: Number of participants with immune mediated AEs of interest
Participants with immune related AEs of interest will be assessed.
Time frame: Up to 2 years
Part 1: Number of participants with abnormal hematology parameters
Blood samples will be collected to assess the following hematology parameters: hemoglobin, Mean corpuscular (MCV), white blood cell count (WBC count), platelets, mean platelet volume, differential WBC count and coagulation factors including International normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Time frame: Up to 2 years
Part 1: Number of participants with abnormal clinical chemistry parameters
Blood samples will be collected to assess the following chemistry parameters: sodium, potassium, calcium, magnesium, creatinine, bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin.
Time frame: Up to 2 years
Part 1, Part 2A, and Part 2B: Number of participants with a change from baseline in urinalysis parameters
Number of participants will be assessed.
Time frame: Up to 2 years
Part 1, Part 2A, and Part 2B: Number of participants with a change from baseline in vital signs
Number of participants will be assessed.
Time frame: Up to 2 years
Part 1: Number of participants with abnormal electrocardiogram (ECG) parameters
Participants will be supine or in a semi-recumbent position and rested for approximately 2 minutes before ECGs are recorded.
Time frame: Up to 2 years
Part 1: Number of participants receiving concomitant medications
Concomitant medications will be recorded.
Time frame: Up to 2 years
Part 2A: Number of participants with TEAEs
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. An AE can therefore be any unfavorable and unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the product. TEAEs defined as any AE either reported for the first dose of study treatment.
Time frame: Up to 2 years
Part 2A: Number of participants with immune mediated AEs of interest
Participants with immune related AEs of interest will be assessed.
Time frame: Up to 2 years
Part 2A: Number of participants with abnormal hematology parameters
Blood samples will be collected to assess the following hematology parameters: hemoglobin, MCV, white WBC count, platelets, mean platelet volume, differential WBC count and coagulation factors including INR, aPTT and PT.
Time frame: Up to 2 years
Part 2A: Number of participants with abnormal clinical chemistry parameters
Blood samples will be collected to assess the following chemistry parameters: sodium, potassium, calcium, magnesium, creatinine, bilirubin, AST, ALT, and albumin.
Time frame: Up to 2 years
Part 2A: Number of participants with abnormal ECG
Participants will be supine or in a semi-recumbent position and rested for approximately 2 minutes before ECGs are recorded.
Time frame: Up to 2 years
Part 2A: Number of participants receiving concomitant medications
Concomitant medications will be recorded.
Time frame: Up to 2 years
Part 2B: Number of participants with TEAEs
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. An AE can therefore be any unfavorable and unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the product. TEAEs defined as any AE either reported for the first dose of study treatment.
Time frame: Up to 2 years
Part 2B: Number of participants with immune related AEs of interest
Participants with immune related AEs of interest will be assessed.
Time frame: Up to 2 years
Part 2B: Number of participants with abnormal hematology parameters
Blood samples will be collected to assess the following hematology parameters: hemoglobin, MCV, white WBC count, platelets, mean platelet volume, differential WBC count and coagulation factors including INR, aPTT and PT.
Time frame: Up to 2 years
Part 2B: Number of participants with abnormal clinical chemistry parameters
Blood samples will be collected to assess the following chemistry parameters: sodium, potassium, calcium, magnesium, creatinine, bilirubin, AST, ALT, and albumin.
Time frame: Up to 2 years
Part 2B: Number of participants with abnormal ECG parameters
Participants will be supine or in a semi-recumbent position and rested for approximately 2 minutes before ECGs are recorded.
Time frame: Up to 2 years
Part 2B: Number of participants receiving concomitant medications
Concomitant medications will be recorded.
Time frame: Up to 2 years
Part 2B: Cohort A1 Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
ORR is defined as the proportion of participants achieving complete response (CR) or partial response (PR) as evaluated by independent blinded central review using RECIST version 1.1.
Time frame: Up to 2 years
Part 2B: Cohort F ORR by RECIST version 1.1
ORR is defined as the proportion of participants achieving CR or PR as evaluated by independent blinded central review using RECIST version 1.1.
Time frame: Up to 2 years
Part 2B: Cohort A2 ORR by RECIST version 1.1
ORR is defined as the proportion of participants achieving CR or PR as evaluated by independent blinded central review using RECIST version 1.1.
Time frame: Up to 2 years
Part 2B: Cohort G ORR by RECIST version 1.1
ORR is defined as the proportion of participants achieving CR or PR as evaluated by independent blinded central review using RECIST version 1.1.
Time frame: Up to 2 years
Part 2B: Cohort E ORR by immune related Response Evaluation Criteria in Solid Tumors per irRECIST
ORR is defined as the proportion of participants achieving CR or PR as assessed by investigator per irRECIST will be evaluated.
Time frame: Up to 2 years
Part 2B: Cohort A1 Duration of response (DOR)
DOR is defined as the time from first documentation of CR or PR by RECIST version 1.1 until the time of first documentation of progressive disease (PD) evaluated using RECIST version 1.1 based on independent blinded central review, or death due to any cause.
Time frame: Up to 2 years
Part 2B: Cohort F Duration of response (DOR)
DOR is defined as the time from first documentation of CR or PR by RECIST version 1.1 until the time of first documentation of PD evaluated using RECIST version 1.1 based on independent blinded central review, or death due to any cause.
Time frame: Up to 2 years
Part 2B: Cohort A2 Duration of response (DOR)
DOR is defined as the time from first documentation of CR or PR by RECIST version 1.1 until the time of first documentation of PD evaluated using RECIST version 1.1 based on independent blinded central review, or death due to any cause.
Time frame: Up to 2 years
Part 1: Immune-related objective response rate (irORR) by irRECIST
Immune-related objective response rate will be evaluated based on investigator's assessment using irRECIST.
Time frame: Up to 2 years
Part 2B: Cohort A1 ORR by independent blinded central review using RECIST version 1.1
ORR is defined as the proportion of participants achieving CR or PR as evaluated by independent blinded central review using RECIST version 1.1.
Time frame: Up to 2 years
Part 2B: Cohort F ORR by independent blinded central review using RECIST version 1.1
ORR is defined as the proportion of participants achieving CR or PR as evaluated by independent blinded central review using RECIST version 1.1.
Time frame: Up to 2 years
Part 2B: Cohort A1 Immune-related objective response rate (irORR) by irRECIST
Immune related objective response rate will be evaluated based on investigator's assessment using irRECIST.
Time frame: Up to 2 years
Part 2B: Cohort A2 irORR by irRECIST
Immune related objective response rate will be evaluated based on investigator's assessment using irRECIST.
Time frame: Up to 2 years
Part 2B: Cohort F irORR by irRECIST
Immune related objective response rate will be evaluated based on investigator's assessment using irRECIST.
Time frame: Up to 2 years
Part 2B: Cohort G irORR by irRECIST
Immune related objective response rate will be evaluated based on investigator's assessment using irRECIST.
Time frame: Up to 2 years
Part 2B: Cohort A1 Duration of response (DOR) based on independent blinded central review using RECIST version 1.1
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GSK Investigational Site
La Jolla, California, United States
GSK Investigational Site
Los Angeles, California, United States
GSK Investigational Site
Newport Beach, California, United States
GSK Investigational Site
San Francisco, California, United States
GSK Investigational Site
San Marcos, California, United States
...and 95 more locations
DOR is defined as the time from first documentation of CR or PR by RECIST version 1.1 until the time of first documentation of progressive disease (PD) evaluated using RECIST version 1.1 based on independent blinded central review, or death due to any cause.
Time frame: Up to 2 years
Part 2B: Cohort F DOR based on independent blinded central review using RECIST version 1.1
DOR is defined as the time from first documentation of CR or PR by RECIST version 1.1 until the time of first documentation of PD evaluated using RECIST version 1.1 based on independent blinded central review, or death due to any cause.
Time frame: Up to 2 years
Part 2B: Cohort G DOR based on independent blinded central review using RECIST version 1.1
DOR is defined as the time from first documentation of CR or PR by RECIST version 1.1 until the time of first documentation of PD evaluated using RECIST version 1.1 based on independent blinded central review, or death due to any cause.
Time frame: Up to 2 years
Part 2B: Cohort A1 Disease control rate
Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.
Time frame: Up to 2 years
Part 2B: Cohort A2 Disease control rate
Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.
Time frame: Up to 2 years
Part 2B: Cohort F Disease control rate
Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.
Time frame: Up to 2 years
Part 2B: Cohort G Disease control rate
Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.
Time frame: Up to 2 years
Immune related disease control rate
The proportion of participants achieving CR, PR, or SD per irRECIST based on Investigators assessment.
Time frame: Up to 2 years
Immune related duration of response
The time from first documentation of CR or PR by irRECIST until the time of first documentation of PD (subsequently confirmed) per irRECIST based on Investigators assessment.
Time frame: Up to 2 years
Progression free survival
The time from date of first dose to the earlier date of assessment of progression or death by any cause in the absence of progression based on: (1) the time of first documentation of PD per RECIST v1.1 (for Cohorts A1, A2, F, and G only); and (2) the time of first documentation of PD (subsequently confirmed) per irRECIST.
Time frame: Up to 2 years
Overall survival
The time from date of first dose of study treatment to the date of death by any cause.
Time frame: Up to 2 years
Part 1: Area under the concentration-time curve from time 0 to last (AUC,0-last) assessment of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504 and 672 hours post dose
Part 1: Area under the concentration-time curve from time 0 to infinity (AUC, 0-infinity) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672 hours post dose
Part 1: Minimum concentration (Cmin) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672 hours post dose
Part 1: Maximum concentration (Cmax) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672 hours post dose
Part 1: Clearance (CL) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672 hours post dose
Part 1: Volume of distribution (Vz) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672 hours post dose
Part 1: Area under the concentration-time curve at steady state (AUC,ss) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672 hours post dose
Part 1: Minimum concentration at steady state (Cmin,ss) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose.
Part 1: Maximum concentration at steady state (Cmax,ss) of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672 hours post dose
Part 2A: AUC,0-last assessment of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years
Part 2A: AUC, 0-infinity of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years
Part 2A: Cmin of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504,hours post dose Q3W upto 2 years
Part 2A: Cmax of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504,hours post dose Q3W upto 2 years
Part 2A: CL of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504,hours post dose Q3W upto 2 years
Part 2A: Vz of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years.
Part 2A: AUC,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years
Part 2A: Cmin,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years
Part 2A: Cmax,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years
Part 2A : AUC,0-last assessment of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: AUC, 0-infinity of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: Cmin of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: Cmax of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: CL of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: Vz of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: AUC,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: Cmin,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840, and 1008 hours post dose Q6W upto 2 years
Part 2A: Cmax,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504, 672, 840 and 1008 hours post dose Q6W upto 2 years
Part 2B: Cmax of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.5 and 1.5 hours post dose
Part 2B: AUC,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.5 and 1.5 hours post dose
Part 2B: Cmax,ss of dostarlimab
Blood samples for determination of serum levels of dostarlimab will be collected.
Time frame: Predose, 0.5 and 1.5 hours post dose
Part 1, Part 2A, and Part 2B: Number of participants with antidrug antibodies (ADA) against dostarlimab
Time frame: Up to 2 years