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Study of TSR-033 With an Anti-programmed Cell Death-1 Receptor (PD-1) in Participants With Advanced Solid Tumors (CITRINO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03250832
Recruitment Status : Recruiting
First Posted : August 16, 2017
Last Update Posted : September 15, 2020
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Tesaro, Inc.

Brief Summary:
This is a multicenter, open-label, first-in-human Phase 1 study evaluating the anti-lymphocyte activation gene-3 (LAG-3) antibody TSR-033 alone, in combination with the anti-PD-1 antibody dostarlimab, and in combination with dostarlimab, modified folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) (mFOLFOX6) or FOL/leucovorin, 5-fluorouracil and irinotecan (IRI) (FOLFIRI), and bevacizumab in participants with advanced solid tumors in a broad range of solid tumors. Participants with disease types selected for evaluation in this study are expected to derive clinical benefit with addition of an anti-PD-1. The study will be conducted in two parts with Part 1 consisting of dose escalation to determine the recommended phase 2 dose (RP2D) of TSR-033 as a single agent (Part 1a) and in combination with dostarlimab (Part 1c). RP2D decisions will be based on the occurrence of dose-limiting toxicities (DLTs), pharmacokinetics (PK), as well as pharmacodynamics (PDy) data. Part 2A of the study will investigate the anti-tumor activity of TSR-033 and dostarlimab in combination in participants with advanced or metastatic microsatellite stable colorectal cancer (MSS-CRC). Part 2B of the study will investigate the safety and anti-tumor activity of TSR-033 and dostarlimab in combination with chemotherapy (Cohort B1: mFOLFOX6 and Cohort B2: FOLFIRI) and bevacizumab in participants with advanced or metastatic MSS-CRC.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: TSR-033 Drug: Dostarlimab Drug: mFOLFOX6 Drug: FOLFIRI Drug: Bevacizumab Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 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-033, an Anti-LAG-3 Monoclonal Antibody, Alone and in Combination With an Anti-PD-1 in Patients With Advanced Solid Tumors
Actual Study Start Date : August 8, 2017
Estimated Primary Completion Date : October 1, 2021
Estimated Study Completion Date : October 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part 1a: TSR-033 monotherapy dose escalation
Part 1a will evaluate TSR-033 at ascending doses (20 milligrams [mg], 80 mg and 240 mg) every 2 weeks. Cohorts will be enrolled sequentially and will initially follow a 3+3 design at a starting dose of 20 mg.
Drug: TSR-033
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
Other Name: LAG-3

Experimental: Part 1b: TSR-033 monotherapy PK/PDy characterization
Part 1b will evaluate the PK profile and assess PDy data from blood and tumor tissue samples following TSR-033 treatment. The participants will begin treatment with TSR-033 on Day 1 followed by 28 days observation for collection of blood sampling for PK/PDy. Participants will receive their second dose of TSR-033 on Day 29 and every 14 days thereafter.
Drug: TSR-033
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
Other Name: LAG-3

Experimental: Part 1c: TSR-033+dostarlimab combination dose escalation
Participants will be administered ascending doses of TSR-033 in combination with dostarlimab 500 mg every 3 weeks. Planned dose levels of TSR-033 include 80 and 240 mg.
Drug: TSR-033
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
Other Name: LAG-3

Drug: Dostarlimab
Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.

Experimental: Part 2 Cohort A: TSR-033+dostarlimab combination
Part 2 Cohort A will evaluate the preliminary activity of TSR-033 in combination with dostarlimab in anti-PD-1 naive participants with third and fourth line MSS-CRC. TSR-033 will be administered every 2 weeks and dostarlimab every 6 weeks.
Drug: TSR-033
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
Other Name: LAG-3

Drug: Dostarlimab
Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.

Experimental: Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6
Part 2 Cohort B1 will evaluate the preliminary activity of TSR-033 administered every 2 weeks (Q2W) in combination with dostarlimab administered every 6 weeks (Q6W) along with mFOLFOX6 and bevacizumab (standard of care [SOC]) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFIRI, with or without biologics.
Drug: TSR-033
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
Other Name: LAG-3

Drug: Dostarlimab
Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.

Drug: mFOLFOX6
mFOLFOX6 is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) which acts as systemic cytotoxic agent.

Drug: Bevacizumab
Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.

Experimental: Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI
Part 2 Cohort B2 will evaluate the preliminary activity of TSR-033 in combination with FOLFIRI and bevacizumab (SOC) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFOX, with or without biologics.
Drug: TSR-033
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
Other Name: LAG-3

Drug: Dostarlimab
Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.

Drug: FOLFIRI
FOLFIRI is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and irinotecan (IRI) which acts as systemic cytotoxic agent.

Drug: Bevacizumab
Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.




Primary Outcome Measures :
  1. Part 1a, Part 1c and 2B: Number of participants experiencing DLT [ Time Frame: Up to 3 years and 6 months ]
    All DLTs mentioned in the protocol will be assessed. Toxicities will be assessed according to Common terminology criteria for adverse events (CTCAE) v5.0.

  2. Part 1: Number of participants with serious adverse events (SAEs), treatment-emergent AEs (TEAEs) and immune-related AEs (irAEs) [ Time Frame: Up to 3 years and 6 months ]
    An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is an important medical event that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. A TEAE will be defined as any new AE that begins, or any pre-existing condition that worsens in severity, after at least 1 dose of study treatment has been administered. irAEs will be assessed.

  3. Part 2: Number of participants with SAEs, TEAEs and irAEs [ Time Frame: Up to 3 years and 6 months ]
    An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is an important medical event that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. A TEAE will be defined as any new AE that begins, or any pre-existing condition that worsens in severity, after at least 1 dose of study treatment has been administered. irAEs will be assessed.

  4. Part 1: Number of participants with abnormality in hematology parameters [ Time Frame: Up to 3 years and 6 months ]
    Blood samples will be collected to evaluate hemoglobin, mean corpuscular volume (MCV), white blood cell (WBC) count, platelets, 5-part differential white cell count, mean platelet volume and coagulation factors including international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT).

  5. Part 2: Number of participants with abnormality in hematology parameters [ Time Frame: Up to 3 years and 6 months ]
    Blood samples will be collected to evaluate hemoglobin, MCV, WBC count, platelets, 5-part differential white cell count, mean platelet volume and coagulation factors including INR, aPTT and PT.

  6. Part 1: Number of participants with abnormality in clinical chemistry parameters [ Time Frame: Up to 3 years and 6 months ]
    Blood samples will be collected to evaluate sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, urea or blood urea nitrogen (BUN), bicarbonate, amylase, bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, lactate dehydrogenase and lipase.

  7. Part 2: Number of participants with abnormality in clinical chemistry parameters [ Time Frame: Up to 3 years and 6 months ]
    Blood samples will be collected to evaluate sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, urea or BUN, bicarbonate, amylase, bilirubin, alkaline phosphatase, AST, ALT, total protein, albumin, lactate dehydrogenase and lipase.

  8. Part 1: Number of participants with abnormality in thyroid function [ Time Frame: Up to 3 years and 6 months ]
    Blood samples will be collected to evaluate thyroid-stimulating hormone (TSH), Triiodothyronine (T3) or free (F) T3 and free Thyroxine (FT4).

  9. Part 2: Number of participants with abnormality in thyroid function [ Time Frame: Up to 3 years and 6 months ]
    Blood samples will be collected to evaluate TSH, T3 or FT3 and FT4.

  10. Part 1: Number of participants with abnormality in routine urinalysis parameters [ Time Frame: Up to 3 years and 6 months ]
    Urine samples will be collected to evaluate specific gravity, leucocyte esterase, nitrite, blood, bilirubin, protein, glucose, ketones and urobilinogen.

  11. Part 2: Number of participants with abnormality in routine urinalysis parameters [ Time Frame: Up to 3 years and 6 months ]
    Urine samples will be collected to evaluate specific gravity, leucocyte esterase, nitrite, blood, bilirubin, protein, glucose, ketones and urobilinogen.

  12. Part 1: Number of participants with abnormality in vital signs [ Time Frame: Up to 3 years and 6 months ]
    Blood pressure, pulse, respiratory rate, and temperature will be assessed.

  13. Part 2: Number of participants with abnormality in vital signs [ Time Frame: Up to 3 years and 6 months ]
    Blood pressure, pulse, respiratory rate, and temperature will be assessed.

  14. Part 1: Number of participants with abnormality in electrocardiogram (ECG) parameters [ Time Frame: Up to 3 years and 6 months ]
    12-lead ECG will be obtained using an ECG machine. Participants will be in supine or a semi-recumbent position (about 30 degrees of elevation) and rested for approximately 2 minutes before ECGs are recorded.

  15. Part 2: Number of participants with abnormality in ECG parameters [ Time Frame: Up to 3 years and 6 months ]
    12-lead ECG will be obtained using an ECG machine. Participants will be in supine or a semi-recumbent position (about 30 degrees of elevation) and rested for approximately 2 minutes before ECGs are recorded.

  16. Part 1: Number of participants with abnormality in physical examination [ Time Frame: Up to 3 years and 6 months ]
    Physical examination including weight will be assessed.

  17. Part 2: Number of participants with abnormality in physical examination [ Time Frame: Up to 3 years and 6 months ]
    Physical examination including weight will be assessed.

  18. Part 1: Number of participants with abnormality in Eastern cooperative Oncology Group performance status (ECOG PS) [ Time Frame: Up to 3 years and 6 months ]
    PS will be assessed using ECOG scale. The scale consists of 4 grades (from 0 to 4) where 0 implies fully active and 4 implies completely disabled.

  19. Part 2: Number of participants with abnormality in ECOG PS [ Time Frame: Up to 3 years and 6 months ]
    PS will be assessed using ECOG scale. The scale consists of 4 grades (from 0 to 4) where 0 implies fully active and 4 implies completely disabled.

  20. Part 1: Number of participants using concomitant medications [ Time Frame: Up to 3 years and 6 months ]
    Any medication the participant takes during the study other than the study treatment, including herbal and other nontraditional remedies, will be considered a concomitant medication.

  21. Part 2: Number of participants using concomitant medications [ Time Frame: Up to 3 years and 6 months ]
    Any medication the participant takes during the study other than the study treatment, including herbal and other nontraditional remedies, will be considered a concomitant medication.

  22. Part 2: Objective response rate (ORR) [ Time Frame: Up to 3 years and 6 months ]
    ORR is defined as proportion of participants achieving complete response (CR) or partial response (PR) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.


Secondary Outcome Measures :
  1. Part 1a: Area under the concentration-time curve from time zero to last measurable concentration (AUC [0-last]) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  2. Part 1b: AUC (0-last) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  3. Part 1c: AUC (0-last) of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  4. Part 2: AUC (0-last) of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  5. Part 1a: AUC extrapolated from time zero to infinity (AUC[0-inf]) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  6. Part 1b: AUC (0-inf) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  7. Part 1c: AUC (0-inf) of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  8. Part 2: AUC (0-inf) of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction

  9. Part 1a: AUC at steady state (AUCss) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  10. Part 1b: AUCss of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  11. Part 1c: AUCss of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  12. Part 2: AUCss of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  13. Part 1a: Minimum concentration (Cmin) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected

  14. Part 1b: Cmin of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected

  15. Part 1c: Cmin of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  16. Part 2: Cmin of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  17. Part 1a: Minimum concentration at steady state (C[min,ss]) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  18. Part 1b: C(min,ss) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  19. Part 1c: C(min,ss) of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  20. Part 2: C(min,ss) of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  21. Part 1a: Maximum concentration (Cmax) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected

  22. Part 1b: Cmax of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  23. Part 1c: Cmax of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  24. Part 2: Cmax TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  25. Part 1a: Maximum concentration at steady state (C[max,ss]) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  26. Part 1b: (C[max,ss]) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  27. Part 1c:(C[max,ss]) of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  28. Part 2: (C[max,ss]) of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  29. Part 1a: Clearance (CL) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  30. Part 1b: CL of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected

  31. Part 1c: CL of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  32. Part 2: CL of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  33. Part 1a: Volume of distribution (Vz) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  34. Part 1b: Vz of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  35. Part 1c: Vz of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  36. Part 2: Vz of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  37. Part 1a: Terminal half-life (t1/2) of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  38. Part 1b: t1/2 of TSR-033 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours ]
    Blood samples for determination of serum levels of TSR-033 will be collected.

  39. Part 1c: t1/2 of TSR-033 and dostarlimab [ Time Frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.

  40. Part 2: t1/2 of TSR-033 and dostarlimab with chemotherapy and bevacizumab [ Time Frame: Pre-dose and end of infusion ]
    Blood samples for determination of serum levels of TSR-033 and dostarlimab in combination with chemotherapy and bevacizumab will be collected. End of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily stopped due to an infusion reaction.

  41. Part 1: Number of participants with anti-TSR-033 antibodies [ Time Frame: Up to 3 years and 6 months ]
    Serum samples for the determination of anti-TSR-033 antibodies will be the same samples collected as for PK.

  42. Part 2: Number of participants with anti-TSR-033 antibodies [ Time Frame: Up to 3 years and 6 months ]
    Serum samples for the determination of anti-TSR-033 antibodies will be the same samples collected as for PK.

  43. Part 1: Number of participants with anti-dostarlimab antibodies [ Time Frame: Up to 3 years and 6 months ]
    Serum samples for the determination of anti-dostarlimab antibodies will be the same samples collected as for PK.

  44. Part 2: Number of participants with anti-dostarlimab antibodies [ Time Frame: Up to 3 years and 6 months ]
    Serum samples for the determination of anti-dostarlimab antibodies will be the same samples collected as for PK.

  45. Part 1: ORR [ Time Frame: Up to 3 years and 6 months ]
    ORR is defined as the proportion of participants achieving CR or PR as assessed by the investigator per RECIST v1.1.

  46. Part 1: Duration of response (DOR) [ Time Frame: Up to 3 years and 6 months ]
    DOR is defined as the time from first documentation of CR or PR by RECIST v1.1 until the time of first documentation of progressive disease (PD) per RECIST v1.1.

  47. Part 2: DOR [ Time Frame: Up to 3 years and 6 months ]
    DOR is defined as the time from first documentation of CR or PR by RECIST v1.1 until the time of first documentation of PD per RECIST v1.1.

  48. Part 1: Disease control rate (DCR) [ Time Frame: Up to 3 years and 6 months ]
    DCR is defined as defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessed by the Investigator per RECIST v1.1.

  49. Part 2: DCR [ Time Frame: Up to 3 years and 6 months ]
    DCR is defined as defined as the percentage of participants achieving CR, PR, or SD as assessed by the investigator per RECIST v1.1.

  50. Part 1: Progression-free survival (PFS) [ Time Frame: Up to 3 years and 6 months ]
    PFS is defined as the time from date of first study dose to the date of first documentation of progression or death by any cause in the absence of documented progression, whichever occurs first.

  51. Part 2: PFS [ Time Frame: Up to 3 years and 6 months ]
    PFS is defined as the time from date of first study dose to the date of first documentation of progression or death by any cause in the absence of documented progression, whichever occurs first.

  52. Part 1: Overall survival (OS) [ Time Frame: Up to 3 years and 6 months ]
    OS is defined as the time from date of first dose of study treatment to the date of death by any cause.

  53. Part 2: OS [ Time Frame: Up to 3 years and 6 months ]
    OS is defined as the time from date of first dose of study treatment to the date of death by any cause.



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.


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

Inclusion Criteria for participants in Part 1:

  • The participant is >=18 years of age.
  • The participant has any histologically or cytologically confirmed advanced (unresectable) or metastatic solid tumor and has PD after treatment with available therapies that are known to confer clinical benefit or who are intolerant to treatment.
  • The participant must have an archival tumor tissue sample that is formalin-fixed and paraffin-embedded (FFPE) (blocks preferred over slides) and requested and confirmed available from offsite locations prior to dosing. The quality and quantity of the sample must be confirmed sufficient as per the Study Laboratory Manual. Participants who do not have archival tissue must agree to a new biopsy to obtain fresh tumor tissue prior to dosing.
  • Part 1b (PK/PDy cohort): The participant must have lesions amenable for biopsy and agree to undergo biopsies for fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after treatment, and, whenever possible, at the time of PD and /or end of treatment (EOT). Serial biopsies are optional for participants in Part 1a and 1c.
  • Female participants must have a negative serum or urine pregnancy test within 72 hours prior to the date of the first dose of study medication if of childbearing potential or be of non-childbearing potential. Non-childbearing potential is defined as:

    • Participants >=45 years of age and has not had menses for >1 year.
    • Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.
    • 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.
  • Female participants of childbearing potential (that is [ie], those who do not meet above criteria) must agree to use 2 highly effective forms of contraception with their partners, starting with the screening visit through 150 days after the last dose of study therapy.
  • The participant must have an ECOG PS of <=1.
  • The participant has adequate hematologic and organ function, defined as:

    • Absolute neutrophil count (ANC) >=1500 per microliter (/μL).
    • Platelets >=100,000/μL.
    • Hemoglobin (Hb) >=9 grams per deciliter (g/dL) or >=5.6 millimoles per liter (mmol/L).
    • Serum creatinine <=1.5 times upper limit of normal (× ULN) or calculated creatinine clearance (CrCL) >=50 milliliters per minute (mL/min) using Cockcroft-Gault equation for participants with creatinine levels >1.5 × institutional ULN
    • Total bilirubin <=1.5 × ULN and direct bilirubin <=1× ULN (in the event that the total bilirubin result exceeds the upper institutional limits of normal, direct bilirubin will be obtained to determine eligibility).
    • AST and ALT <=2.5 × ULN unless liver metastases are present, in which case they must be <=5 × ULN.
    • INR of PT <=1.5 × ULN, unless participant is receiving anticoagulant therapy, then PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants; aPTT) <= 1.5 × ULN unless participant is receiving anticoagulant therapy, then PT or PTT is within therapeutic range of intended use of anticoagulants.

Inclusion criteria for participants in Part 2:

  • The participant is >= 18 years of age.
  • The participant has any histologically or cytologically confirmed CRC that is metastatic or not amenable to potentially curative resection (advanced), in the opinion of the Investigator.
  • The participant has a primary and/or metastatic tumor(s) that is known to be MSS, as determined locally.
  • The participant must have lesions amenable for biopsy and agree to undergo biopsies for fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after, and, whenever possible, at EOT and/or the time of PD. If the participant has had a biopsy prior to entering the 28-day screening period, and within approximately 12 weeks of study treatment, that biopsy sample may be accepted as the Baseline fresh biopsy. Additionally, submission of sufficient high-quality archival tumor tissue is recommended, if available, to enable a longitudinal analysis of tumor biomarkers.
  • The participant has measurable disease by RECIST v1.1.
  • The participant has resolution to Grade <=1, per CTCAE v5.0, of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy, with the exception of peripheral neuropathy, which must have resolved to Grade <=2, and except where otherwise noted in the eligibility criteria.
  • Female participants must have a negative serum or urine pregnancy test within 72 hours prior to the date of the first dose of study medication if of childbearing potential or be of non-childbearing potential. Non-childbearing potential is defined as:

    • Participants >=45 years of age and has not had menses for >1 year.
    • Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.
    • 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.
  • Female participants of childbearing potential (ie, those who do not meet above criteria) must agree to use 2 highly effective forms of contraception with their partners, starting with the screening visit through 150 days after the last dose of study therapy.
  • The participant has an ECOG PS of <=1.
  • The participant has adequate hematologic and organ function, defined as:

    • ANC >=1500/μL.
    • Platelets >=100,000/μL.
    • Hb >=9 g/dL or >=5.6 mmol/L.
    • Serum creatinine <=1.5 × ULN or calculated CrCL >=50 mL/min using Cockcroft-Gault equation for participants with creatinine levels >1.5 × institutional ULN
    • Total bilirubin <=1.5 × ULN and direct bilirubin <=1× ULN (in the event that the total bilirubin result exceeds the upper institutional limits of normal, direct bilirubin will be obtained to determine eligibility).
    • AST and ALT <=2.5 × ULN unless liver metastases are present, in which case they must be <=5 × ULN.
    • INR of PT <=1.5 × ULN, unless participant is receiving anticoagulant therapy, then PT or PTT is within therapeutic range of intended use of anticoagulants; aPTT) <= 1.5 × ULN unless participant is receiving anticoagulant therapy, then PT or PTT is within therapeutic range of intended use of anticoagulants.
    • Urinary protein is <=1+ on dipstick for routine urinalysis; if urine protein >=2+, a 24-hour urine sample must be collected and must demonstrate <1000 mg of protein in 24 hours to allow participation in the study.
    • Baseline albumin >=3.0 g/dL.

Inclusion Criteria for participants in Part 2A:

  • The participant must have had at least 2, but no more than 3, prior lines of therapy in the advanced or metastatic setting. Adjuvant chemotherapy with radiographic progression >12 months after the last dose will not be considered a line of therapy.
  • The participant has progressed on standard therapies or withdrawn from standard treatment due to unacceptable toxicity. Previous standard treatment must include all of the following:

    • Fluoropyrimidine.
    • Oxaliplatin: Participants treated with oxaliplatin in adjuvant setting should have progressed after 12 months of completion of adjuvant therapy or they must have been treated with oxaliplatin for metastatic disease.
    • Irinotecan.
    • Participants whose disease is known to be RAS-wild-type must have been treated with cetuximab, panitumumab, or other epidermal growth factor receptor (EGFR) inhibitor for metastatic disease.
    • Bevacizumab and/or another anti-angiogenic agent.
    • Previous treatment with regorafenib and/or TAS-102 are allowed in the absence of contraindications and if these agents are available to the participant according to local standards.
  • The time between a participants's last chemotherapy and enrollment must be <=8 weeks.

Inclusion Criteria for participants in Part 2B:

  • The participant has received <=2 prior systemic chemotherapy regimens in any setting (only 1 prior regimen for metastatic disease is permitted).

Inclusion Criteria for participants in Part 2 Cohort B1:

  • The participant has received first-line combination therapy consisting of bevacizumab or anti-EGFR antibodies with FOLFIRI and has experienced radiographic progression during or after first-line therapy. Radiographic progression >12 months after the last dose of adjuvant therapy will not be considered a line of therapy.
  • mFOLFOX6 therapy with bevacizumab is appropriate for the participant and is recommended by the investigator.

Inclusion Criteria for participants in Part 2 Cohort B2:

  • The participant has received first-line combination therapy consisting of bevacizumab or anti-EGFR antibodies with FOLFOX (or variant) and has experienced radiographic progression during or after first-line therapy. Radiographic progression >12 months after the last dose of adjuvant therapy will not be considered a line of therapy.
  • FOLFIIRI therapy with bevacizumab is appropriate for the participant and is recommended by the investigator.

Exclusion Criteria for all participants:

  • The participant has previously been treated with an anti-LAG-3 antibody.
  • The participant has known uncontrolled central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • The participant has a known concurrent, serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection requiring systemic therapy, including human immunodeficiency virus (HIV), known active hepatitis B or hepatitis C, active infection, or active autoimmune disease.
  • The participant is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study.
  • The participant has a history of interstitial lung disease.
  • The participant has not recovered (ie, to Grade <=1 or to Baseline) from radiation- and chemotherapy-induced AEs, has received transfusion of blood products (including platelets or red blood cells), or has received administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 3 weeks prior to the first dose of study drug.
  • The participant is currently participating in an investigational study (therapy or device) or has participated in an investigational study within 4 weeks prior to the first dose of study drug.
  • The participant has received prior anticancer 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 the first dose of the drug, whichever is shorter.
  • The participant has received wide-field (full-dose pelvic) radiotherapy within 28 days prior to the first dose of study drug.
  • The participant has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders.
  • The participant has experienced any arterial thrombotic or arterial thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 12 months prior to first dose of study drug.
  • The participant has received a prior autologous or allogeneic organ or transplantation.
  • The participant has undergone major surgery within 28 days or subcutaneous venous access device placement within 7 days prior to the first dose of study drug.
  • The participant has had a serious non-healing wound, ulcer, or bone fracture within 28 days prior to first dose of study drug.
  • The participant has an elective or planned major surgery to be performed during the course of the trial.
  • The participant has a history of inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) in the 12 months prior to the first dose of study drug.
  • The participant has an acute or subacute bowel obstruction, abdominal fistula, or history of chronic diarrhea which is considered clinically significant, in the opinion of the investigator.
  • The participant has experienced a Grade >=3 bleeding event within 3 months prior to the first dose of study drug.
  • The participant has either peptic ulcer disease associated with a bleeding event or known active diverticulitis.
  • The participant has not recovered (Grade >=1) from AEs and/or complications from any major surgery prior to the first dose of study drug.
  • The participant has received a vaccine within 7 days of the first dose of study drug.
  • The participant has known hypersensitivity to TSR-033, dostarlimab (Part 1c and Part 2), or associated excipients.

Exclusion Criteria for participants in Part 1:

  • The participant's prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-3 agent that resulted in permanent discontinuation due to an AE.

Exclusion Criteria for participants in Part 2:

  • The participant has been previously treated with an anti-PD-1 or anti-PD-L1 antibody.

Exclusion Criteria for participants in Part 2B:

  • The participant has known dihydropyrimidine dehydrogenase deficiency.
  • The participant experienced an arterial thrombotic/thromboembolic event, Grade 4 hypertension, Grade 4 proteinuria, a Grade 3-4 bleeding event, or bowel perforation during first-line therapy with a bevacizumab-containing regimen.
  • The participant has known hypersensitivity to bevacizumab, mFOLFOLX6 (Cohort B1) or FOLFIRI (Cohort B2), or associated excipients.
  • The participant experienced PD within 12 months of last dose of adjuvant therapy.

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): NCT03250832


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
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United States, California
GSK Investigational Site Recruiting
Los Angeles, California, United States, 90095
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Joel Randolph Hecht         
GSK Investigational Site Recruiting
Whittier, California, United States, 90603
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Merrill K Shum         
United States, Colorado
GSK Investigational Site Recruiting
Denver, Colorado, United States, 80218
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Shiraj Sen         
United States, Florida
GSK Investigational Site Recruiting
Sarasota, Florida, United States, 34232
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Judy S Wang         
GSK Investigational Site Recruiting
Tampa, Florida, United States, 33612
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Richard Kim         
United States, Massachusetts
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02115
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: James F Cleary         
United States, Ohio
GSK Investigational Site Recruiting
Cleveland, Ohio, United States, 44106
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: David Bajor         
United States, Oklahoma
GSK Investigational Site Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Susanna V Ulahannan         
United States, Pennsylvania
GSK Investigational Site Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Anuradha Krishnamurthy         
United States, South Carolina
GSK Investigational Site Recruiting
Greenville, South Carolina, United States, 29605
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Ki Chung         
United States, Texas
GSK Investigational Site Recruiting
San Antonio, Texas, United States, 78229
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Amita Patnaik         
GSK Investigational Site Recruiting
Temple, Texas, United States, 76508
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Lucas Wong         
France
GSK Investigational Site Recruiting
Villejuif cedex, France, 94805
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Aurelien Marabelle         
Sponsors and Collaborators
Tesaro, Inc.
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
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Responsible Party: Tesaro, Inc.
ClinicalTrials.gov Identifier: NCT03250832    
Other Study ID Numbers: 213349
4040-01-001 ( Other Identifier: Tesaro )
First Posted: August 16, 2017    Key Record Dates
Last Update Posted: September 15, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Tesaro, Inc.:
Advanced solid tumors
Dostarlimab
Ovarian cancer
Colorectal cancer
Lung cancer
Dose escalation
Dose expansion
Additional relevant MeSH terms:
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Bevacizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors