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Trial record 1 of 1 for:    Tesaro 4010-01-001
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Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)

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ClinicalTrials.gov Identifier: NCT02715284
Recruitment Status : Recruiting
First Posted : March 22, 2016
Last Update Posted : May 15, 2020
Sponsor:
Information provided by (Responsible Party):
Tesaro, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neoplasms Biological: Dostarlimab Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 740 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors
Actual Study Start Date : March 7, 2016
Estimated Primary Completion Date : November 30, 2023
Estimated Study Completion Date : November 30, 2023

Arm Intervention/treatment
Experimental: Part 1: Participants receiving dostarlimab
Part 1 will evaluate dostarlimab at ascending weight-based doses 1 mg/kg, 3 mg/kg and 10 mg/kg. Higher dose levels 15 mg/kg and/or 20 mg/kg may also be explored. Dostarlimab will be administered intravenously (IV) on Day 1 and Day 15 of each cycle; cycle length is 28 days. Cohorts will be enrolled sequentially and will initially follow a 3+3 design.
Biological: Dostarlimab
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.

Experimental: Part 2A: Participants receiving dostarlimab
In Part 2A, participants will receive fixed dose of 500 mg administered Q3W or 1000 mg administered Q6W dose on Day 1 of each cycle. Cycle duration for Q3W dosing is 21 days and Q6W dosing is 42 days. Cohorts will enroll participants with advanced solid tumor using a modified 6+6 design and will follow a 6+6 design.
Biological: Dostarlimab
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.

Experimental: Part 2B: Cohort A1 dMMR/MSI-H
Part 2B: Cohort A1 will include participants with mismatch repair deficient microsatellite instability high (dMMR/MSI-H) endometrial cancer who have progressed on or after platinum doublet therapy. These participants will receive dostarlimab 500 mg for Q3W for the first 4 cycles followed by 1000 mg Q6W for all subsequent cycles. Participants have received no more than 2 lines of anti-cancer therapy for recurrent or advanced (Stage >= IIIB) disease.
Biological: Dostarlimab
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.

Experimental: Part 2B: Cohort A2 MMR-proficient/MSS endometrial cancer
Part 2B: Cohort A2 will include participants with MMR-proficient/MSS endometrial cancer who have progressed on or after platinum doublet therapy. These participants will receive dostarlimab 500 mg for Q3W for the first 4 cycles followed by 1000 mg Q6W for all subsequent cycles. Participants have received no more than 2 lines of anti-cancer therapy for recurrent or advanced (Stage >=IIIB) disease.
Biological: Dostarlimab
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.

Experimental: Part 2B: Cohort E NSCLC
Part 2B: Cohort E NSCLC will include participants with non-small cell lung cancer (NSCLC) who progressed after at least 1 prior platinum-based systemic chemotherapy regimen for recurrent or advanced disease. These participants will receive dostarlimab 500 mg for Q3W for the first 4 cycles followed by 1000 mg Q6W for all subsequent cycles.
Biological: Dostarlimab
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.

Experimental: Part 2B:Cohort F non-endometrial dMMR/MSI-H & POLE-Mut cancers
Participants with recurrent or advanced dMMR/MSI-H solid tumors or polymerase ɛ mutated (POLE -mut) solid tumors , except endometrial cancers, that have progressed following up to 2 prior lines of systemic therapy for recurrent or advanced (>=Stage IIIB) disease and who have no alternative treatment options. These participants will receive dostarlimab 500 mg for Q3W for the first 4 cycles followed by 1000 mg Q6W for all subsequent cycles.
Biological: Dostarlimab
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.

Experimental: Part 2B: Cohort G PROC without known BRCA
Participants with advanced, relapsed, high-grade serous, endometrioid, or clear cell ovarian, fallopian tube, or primary peritoneal cancer without known breast cancer susceptibility gene (BRCA) mutation who have platinum-resistant disease receiving dostarlimab and who have also been previously treated with bevacizumab. These participants will receive dostarlimab 500 mg for Q3W for the first 4 cycles followed by 1000 mg Q6W for all subsequent cycles.
Biological: Dostarlimab
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.




Primary Outcome Measures :
  1. Part 1: Number of participants with treatment emergent AEs (TEAEs) [ Time Frame: Up to 2 years ]
    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.

  2. Part 1: Number of participants with immune related AEs of interest [ Time Frame: Up to 2 years ]
    Participants with immune related AEs of interest will be assessed.

  3. Part 1: Number of participants with abnormal hematology parameters [ Time Frame: Up to 2 years ]
    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).

  4. Part 1: Number of participants with abnormal clinical chemistry parameters [ Time Frame: Up to 2 years ]
    Blood samples will be collected to assess the following chemistry parameters: sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, urea or blood urea nitrogen (BUN), amylase, bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, lactate dehydrogenase.

  5. Part 1: Number of participants with abnormal thyroid function [ Time Frame: Up to 2 years ]
    Blood samples will be collected to assess the levels of thyroid-stimulating hormone (TSH); triiodothyronine (T3), or free triiodothyronine (FT3) and free thyroxine (FT4).

  6. Part 1: Number of participants with abnormal urine parameters [ Time Frame: Up to 2 years ]
    Urine samples will be collected to evaluate specific gravity, leucocyte esterase, nitrite, blood, protein, glucose, and ketones.

  7. Part 1: Number of participants with abnormal vital signs [ Time Frame: Up to 2 years ]
    Blood pressure, pulse rate, respiratory rate and temperature will be assessed.

  8. Part 1: Number of participants with abnormal electrocardiogram (ECG) parameters [ Time Frame: Up to 2 years ]
    Participants will be supine or in a semi-recumbent position and rested for approximately 2 minutes before ECGs are recorded.

  9. Part 1: Number of participants with abnormal physical examination. [ Time Frame: Up to 2 years ]
    Physical examinations including weight will be assessed.

  10. Part 1: Number of participants receiving concomitant medications [ Time Frame: Up to 2 years ]
    Concomitant medications will be recorded.

  11. Part 2A: Number of participants with TEAEs [ Time Frame: Up to 2 years ]
    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.

  12. Part 2A: Number of participants with immune related AEs of interest [ Time Frame: Up to 2 years ]
    Participants with immune related AEs of interest will be assessed.

  13. Part 2A: Number of participants with abnormal hematology parameters [ Time Frame: Up to 2 years ]
    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.

  14. Part 2A: Number of participants with abnormal clinical chemistry parameters [ Time Frame: Up to 2 years ]
    Blood samples will be collected to assess the following chemistry parameters: sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, urea or BUN, amylase, bilirubin, AST, ALT, total protein, albumin, lactate dehydrogenase.

  15. Part 2A: Number of participants with abnormal thyroid function [ Time Frame: Up to 2 years ]
    Blood samples will be collected to assess the levels of TSH, T3, or FT3 and FT4.

  16. Part 2A: Number of participants with abnormal urine parameters [ Time Frame: Up to 2 years ]
    Urine samples will be collected to evaluate specific gravity, leucocyte esterase, nitrite, blood, protein, glucose, and ketones.

  17. Part 2A: Number of participants with abnormal vital signs [ Time Frame: Up to 2 years ]
    Blood pressure, pulse rate, respiratory rate and temperature will be assessed.

  18. Part 2A: Number of participants with abnormal ECG [ Time Frame: Up to 2 years ]
    Participants will be supine or in a semi-recumbent position and rested for approximately 2 minutes before ECGs are recorded.

  19. Part 2A: Number of participants with abnormal physical examination [ Time Frame: Up to 2 years ]
    Physical examination including weight will be assessed.

  20. Part 2A: Number of participants receiving concomitant medications [ Time Frame: Up to 2 years ]
    Concomitant medications will be recorded.

  21. Part 2B: Number of participants with TEAEs [ Time Frame: Up to 2 years ]
    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.

  22. Part 2B: Number of participants with immune related AEs of interest [ Time Frame: Up to 2 years ]
    Participants with immune related AEs of interest will be assessed.

  23. Part 2B: Number of participants with abnormal hematology parameters [ Time Frame: Up to 2 years ]
    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.

  24. Part 2B: Number of participants with abnormal clinical chemistry parameters [ Time Frame: Up to 2 years ]
    Blood samples will be collected to assess the following chemistry parameters: sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, urea or BUN, amylase, bilirubin, AST, ALT, total protein, albumin, lactate dehydrogenase.

  25. Part 2B: Number of participants with abnormal thyroid function [ Time Frame: Up to 2 years ]
    Blood samples will be collected to assess the levels of TSH, T3, or FT3 and FT4.

  26. Part 2B: Number of participants with abnormal urine parameters [ Time Frame: Up to 2 years ]
    Urine samples will be collected to evaluate specific gravity, leucocyte esterase, nitrite, blood, protein, glucose, and ketones.

  27. Part 2B: Number of participants with abnormal vital signs [ Time Frame: Up to 2 years ]
    Blood pressure, pulse rate, respiratory rate and temperature will be assessed.

  28. Part 2B: Number of participants with abnormal ECG parameters [ Time Frame: Up to 2 years ]
    Participants will be supine or in a semi-recumbent position and rested for approximately 2 minutes before ECGs are recorded.

  29. Part 2B: Number of participants with abnormal physical examination [ Time Frame: Up to 2 years ]
    Physical examinations including weight will be assessed.

  30. Part 2B: Number of participants receiving concomitant medications [ Time Frame: Up to 2 years ]
    Concomitant medications will be recorded.

  31. Part 2B: Cohort A1 Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ Time Frame: Up to 2 years ]
    ORR is defined as the proportion of participants achieving complete response (CR) or partial response (PR) as assessed by investigator per RECIST version 1.1 will be evaluated.

  32. Part 2B: Cohort F ORR by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    ORR is defined as the proportion of participants achieving CR or PR as assessed by investigator per RECIST version 1.1 will be evaluated.

  33. Part 2B: Cohort A2 ORR by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    ORR is defined as the proportion of participants achieving CR or PR as assessed by investigator per RECIST version 1.1 will be evaluated.

  34. Part 2B: Cohort G ORR by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    ORR is defined as the proportion of participants achieving CR or PR as assessed by investigator per RECIST version 1.1 will be evaluated.

  35. Part 2B: Cohort E ORR by immune related Response Evaluation Criteria in Solid Tumors per irRECIST [ Time Frame: Up to 2 years ]
    ORR is defined as the proportion of participants achieving CR or PR as assessed by investigator per irRECIST will be evaluated.

  36. Part 2B: Cohort A1 Duration of response (DOR) [ Time Frame: Up to 2 years ]
    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.

  37. Part 2B: Cohort F Duration of response (DOR) [ Time Frame: Up to 2 years ]
    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.

  38. Part 2B: Cohort A2 Duration of response (DOR) [ Time Frame: Up to 2 years ]
    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.


Secondary Outcome Measures :
  1. Part 2B: Cohort A1 ORR by independent blinded central review using RECIST version 1.1 [ Time Frame: Up to 2 years ]
    ORR is defined as the proportion of participants achieving CR or PR as assessed by investigator per RECIST version 1.1 will be evaluated.

  2. Part 2B: Cohort F ORR by independent blinded central review using RECIST version 1.1 [ Time Frame: Up to 2 years ]
    ORR is defined as the proportion of participants achieving CR or PR as assessed by investigator per RECIST version 1.1 will be evaluated.

  3. Part 2B: Cohort A1 Immune-related objective response rate (irORR) by irRECIST [ Time Frame: Up to 2 years ]
    Immune related objective response rate will be evaluated.

  4. Part 2B: Cohort A2 irORR by irRECIST [ Time Frame: Up to 2 years ]
    Immune related objective response rate will be evaluated.

  5. Part 2B: Cohort F irORR by irRECIST [ Time Frame: Up to 2 years ]
    Immune related objective response rate will be evaluated.

  6. Part 2B: Cohort G irORR by irRECIST [ Time Frame: Up to 2 years ]
    Immune related objective response rate will be evaluated.

  7. Part 2B: Cohort A1 Duration of response (DOR) based on independent blinded central review using RECIST version 1.1 [ Time Frame: Up to 2 years ]
    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.

  8. Part 2B: Cohort F DOR based on independent blinded central review using RECIST version 1.1 [ Time Frame: Up to 2 years ]
    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.

  9. Part 2B: Cohort G DOR based on independent blinded central review using RECIST version 1.1 [ Time Frame: Up to 2 years ]
    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.

  10. Part 2B: Cohort A1 Disease control rate [ Time Frame: Up to 2 years ]
    Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.

  11. Part 2B: Cohort A2 Disease control rate [ Time Frame: Up to 2 years ]
    Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.

  12. Part 2B: Cohort F Disease control rate [ Time Frame: Up to 2 years ]
    Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.

  13. Part 2B: Cohort G Disease control rate [ Time Frame: Up to 2 years ]
    Disease control rate is the proportion of participants achieving CR, PR, or SD per RECIST v1.1 based on independent blinded central review.

  14. Part 2B: Immune related disease control rate [ Time Frame: Up to 2 years ]
    The proportion of participants achieving CR, PR, or SD per irRECIST based on Investigators' assessment.

  15. Part 2B: Immune related duration of response [ Time Frame: Up to 2 years ]
    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.

  16. Part 2B: Progression free survival [ Time Frame: Up to 2 years ]
    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.

  17. Part 2B: Overall survival [ Time Frame: Up to 2 years ]
    The time from date of first dose of study treatment to the date of death by any cause.

  18. Part 1: Area under the concentration-time curve from time 0 to last (AUC,0-last) assessment of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504 and 672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  19. Part 1: Area under the concentration-time curve from time 0 to infinity (AUC, 0-infinity) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  20. Part 1: Minimum concentration (Cmin) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  21. Part 1: Maximum concentration (Cmax) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  22. Part 1: Clearance (CL) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  23. Part 1: Volume of distribution (Vz) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  24. Part 1: Area under the concentration-time curve at steady state (AUC,ss) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  25. Part 1: Minimum concentration at steady state (Cmin,ss) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose. ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  26. Part 1: Maximum concentration at steady state (Cmax,ss) of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, 504,672 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  27. Part 2A : AUC,0-last assessment of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  28. Part 2A: AUC, 0-infinity of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  29. Part 2A: Cmin of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504,hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected

  30. Part 2A: Cmax of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504,hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  31. Part 2A: CL of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504,hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  32. Part 2A: Vz of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years. ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  33. Part 2A: AUC,ss of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  34. Part 2A: Cmin,ss of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  35. Part 2A: Cmax,ss of dostarlimab [ Time Frame: Predose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336, and 504 hours post dose Q3W upto 2 years ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  36. Part 2A : AUC,0-last assessment of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  37. Part 2A: AUC, 0-infinity of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  38. Part 2A: Cmin of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  39. Part 2A: Cmax of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  40. Part 2A: CL of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  41. Part 2A: Vz of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  42. Part 2A: AUC,ss of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  43. Part 2A: Cmin,ss of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  44. Part 2A: Cmax,ss of dostarlimab [ 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 ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  45. Part 2B : AUC,0-last assessment of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  46. Part 2B: AUC, 0-infinity of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  47. Part 2B: Cmin of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  48. Part 2B: Cmax of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  49. Part 2B: CL of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  50. Part 2B: Vz of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  51. Part 2B: AUC,ss of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  52. Part 2B: Cmin,ss of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.

  53. Part 2B: Cmax,ss of dostarlimab [ Time Frame: Predose, 0.5 and 1.5 hours post dose ]
    Blood samples for determination of serum levels of dostarlimab will be collected.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant is at least 18 years of age.
  • Participant has proven recurrent or advanced solid tumor and has disease progression after treatment with available anti cancer therapies, or is intolerant to treatment that meets the following requirements for the part of the study they will participate in:
  • a. Part 1: Any histologically or cytologically proven recurrent advanced solid tumor
  • b. Part 2A: : Any histologically or cytologically proven recurrent advanced solid tumor
  • c. Part 2B: Histologically of cytologically proven recurrent or advanced solid tumor with measurable lesion(s) per RECIST version 1.1 and meets one of the following disease types:
  • The criteria below should be met for participant participating in:
  • Cohort A1 (dMMR/MSI-H endometrial cancer) and
  • Cohort A2 (MMR-proficient/MSS endometrial cancer)
  • Participants who have progressed on or after platinum doublet therapy
  • Participants have received no more than 2 lines of anti-cancer therapy for recurrent or advanced (>=Stage IIIB) disease. Prior treatment with hormone therapies is acceptable and does not count towards the number of anti-cancer therapies noted in the criterion above for this cohort.
  • All endometrial cancer histologies are allowed except endometrial sarcoma (including carcinosarcoma).
  • Participants must submit 2 scans demonstrating increase in tumor measurement that meet criteria for PD on or after the latest systemic anti-cancer therapy based on RECIST 1.1 to Central Radiology prior to the first dose of dostarlimab.
  • Presence of at least 1 measurable lesion on Baseline scan will be confirmed by central radiology review.
  • Status of tumor MMR/MSI: Participants can be screened based on local MMR/MSI testing results using immunohistochemistry (IHC), polymerase chain reaction (PCR), or next generation sequencing (NGS) performed in a certified local laboratory, but participant eligibility needs to be determined by MMR IHC results. For participant with available local MMR IHC results for the respective cohort(s), tumor samples have to be submitted to a central IHC laboratory and its quality has to be checked and cleared prior to Cycle 1 Day 1 (C1D1). For participants without available local MMR IHC test results (participants with local PCR or NGS test results), central IHC results have to confirm eligibility prior to proceeding with other screening procedures. After the central IHC test is completed, remaining tumor tissue may be tested for further exploratory biomarkers or may be sent to a central NGS laboratory for further testing.
  • Cohort E - Participants with NSCLC who progressed after at least 1 prior platinum-based systemic chemotherapy regimen for recurrent or advanced disease.
  • Chemotherapy regimen in the adjuvant or neoadjuvant setting following surgery and/or radiation is acceptable if recurrent or advanced disease develops within 6 months from completion of therapy.
  • Participants with a known epidermal growth factor receptor (EGFR) mutation must have received a chemotherapy regimen and an EGFR tyrosine-kinase inhibitor (TKI) (e.g., erlotinib, gefitinib, afatinib, or experimental)
  • Participants with a known anaplastic lymphoma kinase (ALK) translocation must have received a chemotherapy regimen and an ALK inhibitor (e.g., crizotinib, ceritinib or experimental)
  • Cohort F - Participants with recurrent or advanced dMMR/MSI-H solid tumors or POLE-mut solid tumors, except endometrial cancers, that have progressed following up to 2 prior lines of systemic therapy for recurrent or advanced (>=Stage IIIB) disease and who have no alternative treatment options. Prior treatment with hormone therapies alone given for recurrent or advanced disease is acceptable and does not count towards the number of anti-cancer therapies.
  • dMMR/MSI-H colorectal cancer (CRC) participants must have progressed after or been intolerant to treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Progression following up to 3 prior lines of therapy is allowed.
  • Ovarian cancer participants with platinum-resistant disease (i.e., progression occurred <6 months on or after platinum doublet chemotherapy): receipt of up to 1 line of systemic therapy after becoming platinum-resistant is allowed.
  • Participants must submit 2 scans demonstrating increase in tumor measurement that meet criteria for PD based on RECIST 1.1 to Central Radiology prior to the first dose of dostarlimab.
  • Tumor MMR/MSI or POLE status: Participants can be screened based on local MMR/MSI testing results using immunohistochemistry (IHC), polymerase chain reaction (PCR), or next generation sequencing (NGS) performed in a certified local laboratory, but participant eligibility needs to be determined by MMR IHC results. For participants with available local MMR IHC results for the respective cohort(s), tumor samples have to be submitted to a central IHC laboratory and its quality has to be checked and cleared prior to C1D1. For participants without available local MMR IHC test results (participants with local PCR or NGS test results), central IHC results have to confirm eligibility prior to proceeding with other screening procedures. After the central IHC test is completed, remaining tumor tissue may be tested for further exploratory biomarkers or may be sent to a central NGS laboratory for further testing.
  • Participants who are considered for the study based on POLE mutation must have the local results available showing tumor mutation(s) in the exonuclease domain of the POLE gene (amino acid residues 268-471) to begin screening. Participants must have the quality of submitted tumor samples checked and cleared by a central IHC laboratory prior to receiving study treatment.
  • Cohort G: Participants must have recurrent high-grade serous, endometrioid, or clear cell ovarian, fallopian tube, or primary peritoneal cancer.
  • Participants must have presence of at least 1 measurable lesion on Baseline scan that will be confirmed by central radiology review.
  • Participants must be considered resistant to the last administered platinum therapy, that is, the time from the last administered platinum dose until the initial documented progression (as evidenced by radiographic progression per RECIST) must be less than 6 months.
  • Participants must have completed at least 1 but no more than 3 prior lines of therapy for advanced or metastatic ovarian cancer. Neoadjuvant, adjuvant, and the combination of both will be considered as 1 line of therapy. Treatment with single-agent bevacizumab given as maintenance is not counted as a separate line of therapy. If a therapeutic regimen is modified or changed for a reason other than lack of response or PD (such as allergic reaction, toxicity, or drug availability), this is not counted as a separate line of therapy. The use of single-agent hormonal therapy given for reasons other than PD per RECIST v1.1 (i.e., hormonal therapy given for increasing Cancer antigen [CA]-125 levels) is not counted as a separate line of therapy.
  • Participants must have been previously treated with platinum-based regimen, taxane agent(s), and bevacizumab (bevacizumab could be used as a single agent or in combination with another agent, in frontline therapy, as maintenance, or for treatment of recurrent disease).
  • Part 2B: Participants must have archival tumor tissue available that is formalin-fixed and paraffin-embedded.
  • For participants who do not have archival tissue, a new biopsy must be performed to obtain a tissue sample prior to study treatment initiation. For participants without available archival tissue, the biopsy should be taken from the tumor lesions (either primary or metastatic) that have easy accessibility and low biopsy-associated risks and will exclude biopsies of the liver, brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach or bowel.
  • For Cohort G, participant must provide formalin fixed paraffin embedded (FFPE) tumor tissue block(s) with sufficient tumor content (as confirmed by the Sponsor's designated central laboratory) during screening to enable, for example, measures of homologous recombination pathway defects and PD-L1 status. The use of slides created from paraffin-embedded tissue as opposed to FFPE blocks must be approved by the Sponsor.
  • Female participants must have a negative serum pregnancy test within 72 hours prior to the date of the first dose of study medication: unless they are of non-child bearing potential.
  • Non child bearing potential is defined as: >= 45 years of age and has not had menses for > 1 year; Amenorrheic for < 2 years without a hysterectomy and oophorectomy and have a follicle- stimulating hormone (FSH) value in the postmenopausal range upon pre-study (screening) evaluation. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scan. Tubal ligation must be confirmed with medical records of the actual procedure.
  • Female participants of childbearing potential must agree to use 1 highly effective form of contraception with their partner starting with the screening visit through 150 days after the last dose of study therapy.
  • Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of <= 2 for Part 1 and <= 1 for Part 2.
  • Participant has an adequate organ function.

Exclusion Criteria

  • Participant has received prior therapy with an anti- programmed death receptor 1 (anti-PD-1), anti-PD-1- ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD- L2) agent.
  • Participant has a known uncontrolled central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • Participant has a known additional malignancy that progressed or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell cancer (SqCC) of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
  • Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).
  • Participant is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the Screening Visit through 150 days after the last dose of study treatment.
  • Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
  • Participant has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  • Participant has a known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid (HCV RNA) (qualitative) is detected).
  • Participant has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease- modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Use of inhaled steroids, local injection of steroids, and steroid eye drops are allowed.
  • Participant has as history of interstitial lung disease.
  • Participant has not recovered (i.e., to <= Grade 1 or to Baseline) from radiation- and chemotherapy-induced AEs or received transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 3 weeks prior to the first dose of study drug.
  • Participant has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study drug.
  • Participant has received prior anti-cancer therapy (chemotherapy, targeted therapies, radiotherapy, or immunotherapy) within 21 days, or less than 5 times the half-life of the most recent therapy prior to study Day 1, whichever is shorter.
  • Participant has not recovered adequately (<= Grade 1) from AEs and/or complications from any major surgery prior to starting therapy.
  • Participant has received a live vaccine within 14 days of planned start of study therapy.
  • Participant has a known hypersensitivity to dostarlimab components or excipients.
  • For Cohort G, participants will not be eligible if they meet the following criteria:
  • Participants who experienced disease progression within 3 months (as evidenced by radiographic progression per RECIST) of first-line platinum therapy.
  • Participants with known deleterious or suspicious deleterious mutation in BRCA1 or BRCA2 genes (local testing permitted).
  • Participants has received prior therapy with a poly(adenosine diphosphate-ribose) polymerase (PARP)-1/PARP-2 inhibitor.
  • Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, might interfere with the participant's participation for the full duration of the study treatment, or is not in the best interest of the participant to participate.
  • Participant is immunocompromised. Participants with splenectomy are allowed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02715284


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Locations
Show Show 117 study locations
Sponsors and Collaborators
Tesaro, Inc.
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
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Responsible Party: Tesaro, Inc.
ClinicalTrials.gov Identifier: NCT02715284    
Other Study ID Numbers: 213346
4010-01-001 ( Other Identifier: Tesaro )
First Posted: March 22, 2016    Key Record Dates
Last Update Posted: May 15, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Tesaro, Inc.:
Metastatic solid tumors
Advanced solid tumors
anti-PD-1
TSR-042
Immunotherapy
PD-1
Endometrial
Non-small cell lung cancer, NSCLC
MSI-High
Dostarlimab
dMMR