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A Study of TSR-022 in Participants With Advanced Solid Tumors (AMBER)

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: NCT02817633
Recruitment Status : Recruiting
First Posted : June 29, 2016
Last Update Posted : September 15, 2020
Sponsor:
Information provided by (Responsible Party):
Tesaro, Inc.

Tracking Information
First Submitted Date  ICMJE June 22, 2016
First Posted Date  ICMJE June 29, 2016
Last Update Posted Date September 15, 2020
Actual Study Start Date  ICMJE July 6, 2016
Estimated Primary Completion Date July 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
  • Part 1: Number of participants achieving dose limiting toxicity (DLTs) [ Time Frame: Up to 2 years ]
    Number of participants achieving DLTs will be assessed.
  • Part 1: Number of participants with Serious adverse events (SAEs) [ Time Frame: Up to 2 years ]
    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.
  • Part 1: Number of participants with treatment-emergent adverse event (TEAE) [ Time Frame: Up to 2 years ]
    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.
  • Part 1: Number of participants with TEAEs leading to death [ Time Frame: Up to 2 years ]
    Number of participants with TEAEs leading to death will be assessed.
  • Part 1: Number of participants with AEs leading to discontinuation [ Time Frame: Up to 2 years ]
    Number of participants with AEs leading to discontinuation will be assessed.
  • Part 1: Number of participants with immune-related adverse events (irAEs) [ Time Frame: Up to 2 years ]
    Number of participants with irAEs will be assessed.
  • 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).
  • 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), bicarbonate, amylase, bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, lactate dehydrogenase and lipase.
  • 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).
  • 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, bilirubin, protein, glucose, ketones and urobilinogen.
  • 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.
  • Part 1: Number of participants with abnormal electrocardiogram (ECG) findings [ 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.
  • Part 1: Number of participants with abnormal physical examination [ Time Frame: Up to 2 years ]
    Physical examinations including weight will be assessed.
  • Part 1: Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status scores [ Time Frame: Up to 2 years ]
    Performance status will be assessed using the ECOG scale.
  • Part 1: Number of participants receiving concomitant medications [ Time Frame: Up to 2 years ]
    Concomitant medications will be recorded.
  • Part 2: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 24, 2016)
  • Safety and tolerability of TSR-022 using Common Terminology Criteria for Adverse Events (CTCAE v.4.03) in patients with advanced solid tumors [ Time Frame: Part 1 Dose Escalation - Approximately 2 years ]
  • Anti-tumor activity of TSR-022 in patients with solid tumors, in terms of objective response rate (ORR) as assessed by the Investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 [ Time Frame: Part 2 Expansion - Approximately 2 years ]
  • Recommended Phase 2 dose (RP2D) and schedule as monotherapy and in combination with an anti-PD-1 antibody [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
  • Number of participants with anti-TSR-022 antibodies [ Time Frame: Up to 2 years ]
    Serum samples will be collected for the determination of anti-TSR-022 antibodies.
  • Number of participants with anti-TSR-042 antibodies [ Time Frame: Up to 2 years ]
    Serum samples will be collected for the determination of anti-TSR-042 antibodies.
  • Number of participants with anti-TSR-033 antibodies [ Time Frame: Up to 2 years ]
    Serum samples will be collected for the determination of anti-TSR-033 antibodies.
  • Part 1: ORR by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    The proportion of participants achieving complete response (CR) or partial response (PR) as assessed by investigatory per RECIST version 1.1 will be evaluated.
  • Part 1: ORR by immune-related RECIST (irRECIST) [ Time Frame: Up to 2 years ]
    ORR by (irRECIST) will be evaluated.
  • Part 1: Duration of response (DOR) by 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 disease progression per RECIST version 1.1
  • Part 2: Duration of response (DOR) by 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 disease progression per RECIST version 1.1.
  • Part 1: Disease control rate (DCR) by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    DCR is defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessed by the Investigator per RECIST version 1.1.
  • Part 1: Disease control rate (DCR) by irRECIST [ Time Frame: Up to 2 years ]
    DCR is defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessed by the Investigator per irRECIST will be evaluated.
  • Part 2: Disease control rate (DCR) by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    DCR is defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessed by the Investigator per RECIST version 1.1.
  • Part 2: Disease control rate (DCR) by irRECIST [ Time Frame: Up to 2 years ]
    DCR is defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessed by the Investigator per irRECIST will be evaluated.
  • Part 1: Progression-free survival (PFS) by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    PFS is defined as 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 the time of first documentation of disease progression per RECIST version 1.1.
  • Part 1: Progression-free survival (PFS) by irRECIST [ Time Frame: Up to 2 years ]
    PFS is defined as 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 the time of first documentation of disease progression per irRECIST will be evaluated.
  • Part 2: Progression-free survival (PFS) by RECIST version 1.1 [ Time Frame: Up to 2 years ]
    PFS is defined as 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 the time of first documentation of disease progression per RECIST version 1.1.
  • Part 2: Progression-free survival (PFS) by irRECIST [ Time Frame: Up to 2 years ]
    PFS is defined as 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 the time of first documentation of disease progression per irRECIST will be evaluated.
  • Part 1: Overall survival (OS) [ Time Frame: Up to 2 years ]
    OS is defined as the time from date of first dose of study treatment to the date of death by any cause.
  • Part 2: Overall survival (OS) [ Time Frame: Up to 2 years ]
    OS is defined as the time from date of first dose of study treatment to the date of death by any cause.
  • Part 1a: Maximum plasma concentration (Cmax) of TSR-022 when administered as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose. ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: Cmax of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: Cmax of TSR-022 when administered in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: Cmax of TSR-022 when administered in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e: Cmax of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: Cmax of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: Cmax of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Minimum plasma concentration (Cmin) of TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: Cmin of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: Cmin of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose. ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: Cmin of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e: Cmin of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy. [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: Cmin of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: Cmin of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Area under the concentration × time curve from time 0 to infinity AUC (0-inf) of TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: AUC (0-inf) of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: AUC (0-inf) of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: AUC (0-inf) of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e: AUC (0-inf) of in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: AUC (0-inf) of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: AUC (0-inf) of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Area under the concentration × time curve at steady state (AUCss) of TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: AUCss of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: AUCss of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: AUCss of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e: AUCss of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: AUCss of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: AUCss of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Maximum plasma concentration at steady state (Cmax,ss) of TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: Cmax,ss of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: Cmax,ss of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: Cmax,ss of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e : Cmax,ss of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f : Cmax,ss of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: Cmax,ss of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Minimum plasma concentration at steady state (Cmin,ss) of TSR-022 022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: Cmin,ss of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: Cmin,ss of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples for determination of serum levels of TSR-022 in combination with TSR-042.
  • Part 1d: Cmin,ss of of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e: Cmin,ss of of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: Cmin,ss of of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: Cmin,ss of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Area under the concentration time curve from time 0 to last assessment (AUC 0-last) of TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: AUC 0-last of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: AUC 0-last of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: AUC 0-last of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e: AUC 0-last of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: AUC 0-last of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: AUC 0-last of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Clearance (CL) of TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: CL of TSR-022 in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: CL of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: CL of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e : CL of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: CL of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: CL of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Volume of distribution (Vz) of TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: Vz of TSR-022 and in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: Vz of TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: Vz of TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e : Vz of TSR-022 in combination with TSR-042 in participants not previously treated with anti-PD-(L)1 therapy [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: Vz of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: Vz of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1a: Terminal half life (t½) TSR-022 as monotherapy [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1b: t½ of TSR-022 and in combination with nivolumab [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1c: t½ TSR-022 in combination with TSR-042 [ Time Frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1d: t½ TSR-022 in combination with TSR-042 and TSR-033 [ Time Frame: Pre-dose, 0.5, 1.0, 1.5, 2.5, 3, 24, 48, 96, 168,336 hours post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1e: t½ TSR-022 in combination with TSR-042 in participants not previously treated with PD-(L)1 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 1f: t½ of TSR-022 in combination with TSR-042 and docetaxel [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
  • Part 2: t½ of TSR-022 [ Time Frame: Predose, 0.25, 0.5 hour post dose ]
    Blood samples will be collected for pharmacokinetic analysis.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2016)
  • Safety and tolerability of TSR-022 using CTCAE v.4.03 [ Time Frame: Part 2 - Approximately 2 years ]
    Incidence of treatment-emergent AEs (TEAEs), SAEs, immune-related AEs (irAEs), TEAEs leading to death, and AEs leading to discontinuation occurring while patients are on treatment or up to 90 days after the last dose of study drug as assessed by CTCAE v4.03
  • Overall Response Rate (ORR) by RECIST v. 1.1 (Part 1) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • ORR by immune-related RECIST (irRECIST) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • Duration of response (DOR) by RECIST v 1.1 [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • Disease control rate (DCR) by RECIST v 1.1 and by irRECIST [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • Progression-free survival (PFS) by RECIST v 1.1 and by irRECIST [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • Overall survival (OS) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: AUC, 0-last assessment [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: AUC, 0 to infinity [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: AUC at steady state [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: Minimum Concentration (Cmin) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: Maximum Concentration (Cmax) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: Clearance (CL) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: Cmin at steady state (Cmin,ss) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: Cmax at steady state (Cmax, ss) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: Volume of Distribution (Vz) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • PK Parameter: terminal half-life (t1/2) [ Time Frame: Part 1 and Part 2 - Approximately 4 years ]
  • Pharmacodynamic profile as assessed by receptor occupancy [ Time Frame: Part 1 and 2 - Approximately 4 years ]
  • Immunogenicity as assessed by the presence of anti-drug antibodies [ Time Frame: Part 1 and 2 -Approximately 4 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of TSR-022 in Participants With Advanced Solid Tumors (AMBER)
Official Title  ICMJE A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors (AMBER)
Brief Summary This is a multicenter, open-label, first-in-human Phase 1 study evaluating the anti-T cell immunoglobulin and mucin containing protein-3 (TIM-3) antibody TSR-022. The study will be conducted in 2 parts: with Part 1 consisting of dose escalation and Part 2 dose expansion. Part 1 will determine the recommended Phase 2 dose (RP2D) of TSR-022 as a single agent (Part 1a); in combination with anti-programmed cell death protein-1 (PD-1) antibody, nivolumab (Part 1b); in combination with anti-PD-1 antibody, TSR-042 (Part 1c); in combination with TSR-042 and anti-lymphocyte-activation gene 3 (LAG-3) antibody, TSR-033 (Part 1d); in combination with TSR-042 in participants not previously treated with programmed death-ligand 1 [PD-(L)1] (Part 1e) and in combination with docetaxel (Part 1f). Part 2 of the study will evaluate the antitumor activity of TSR-022, both as monotherapy and in combination with TSR-042 in participants with pre-specified tumor types.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • Drug: TSR-022
    TSR-022 is a humanized immunoglobulin 4 (IgG4) mAb.
  • Drug: Nivolumab
    Nivolumab is a humanized IgG4 monoclonal antibody.
  • Drug: TSR-042
    TSR-042 is a humanized IgG4 monoclonal.
  • Drug: TSR-033
    TSR-033 is a humanized IgG4 monoclonal antibody.
  • Drug: Docetaxel
    Docetaxel is a commercially available chemotherapeutic agent.
Study Arms  ICMJE
  • Experimental: Part 1a: TSR-022 monotherapy
    Part 1a (monotherapy dose escalation) will evaluate TSR-022 at ascending weight-based doses. TSR-022 will be administered intravenously (IV).
    Intervention: Drug: TSR-022
  • Experimental: Part 1b: TSR-022 in combination with nivolumab
    Participants in Part 1b will receive nivolumab at the standard dose in combination with ascending doses of TSR-022. The starting dose of TSR-022 will be the Part 1a dose at which less than or equal to (<=)1 of 6 participants experienced dose-limiting toxicity (DLTs).
    Interventions:
    • Drug: TSR-022
    • Drug: Nivolumab
  • Experimental: Part 1c: TSR-022 in combination with TSR-042
    Participants in Part 1c will receive escalating doses of TSR-022 in combination with TSR-042.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
  • Experimental: Part 1d: TSR-022 in combination with TSR-042 and TSR-033
    Part 1d will initially evaluate TSR-022 and TSR-033, at ascending doses in combination with TSR-042 at a constant dose. At each dose escalation step, only 1 drug will be escalated, either TSR-022 or TSR-033.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
    • Drug: TSR-033
  • Experimental: Part 1e: TSR-022 in combination with TSR-042
    Part 1e will evaluate TSR-022 in combination with TSR-042 in participants with select cancer types who have not received prior treatment with anti-PD-L1.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
  • Experimental: Part 1f: TSR-022 in combination with TSR-042 and Docetaxel
    Part 1f will evaluate the triple combination therapy of TSR-022, TSR-042 , and docetaxel, Q3W, for safety. The starting dose of docetaxel will be 75 mg/m^2.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
    • Drug: Docetaxel
  • Experimental: Part 2: Cohort A (Melanoma) (TSR-022 as monotherapy)
    Participants with advanced or metastatic melanoma will be enrolled in Cohort A and will receive treatment with TSR-022 at RP2D as monotherapy.
    Intervention: Drug: TSR-022
  • Experimental: Part 2: Cohort A (Melanoma) (TSR-022 with TSR-042)
    Participants with advanced or metastatic melanoma will be enrolled in Cohort A and will receive treatment with TSR-022 at RP2D in combination with TSR-042.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
  • Experimental: Part2:CohortB Non-small cell lung cancer (TSR-022-monotherapy)
    Participants with advanced or metastatic Non-small cell lung cancer (NSCLC) will be enrolled in Cohort B and will receive treatment with TSR-022 at RP2D as monotherapy.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
  • Experimental: Part2:CohortB Non-small cell lung cancer(TSR-022 with TSR-042)
    Participants with advanced or metastatic NSCLC will be enrolled in Cohort B and will receive treatment with TSR-022 at RP2D in combination with TSR-042.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
  • Experimental: Part2:CohortC Colorectal cancer (TSR-022 as monotherapy)
    Participants with advanced/metastatic Colorectal cancer (CRC) will be enrolled in this arm and will receive treatment with TSR-022 at RP2D as monotherapy.
    Intervention: Drug: TSR-022
  • Experimental: Part2:CohortC Colorectal cancer (TSR-022 with TSR-042)
    Participants with advanced/metastatic CRC will be enrolled in Cohort C and will receive treatment with TSR-022 at RP2D in combination with TSR-042.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
  • Experimental: Part 2: Cohort D (TIM-3 selected NSCLC)
    Participants with advanced or metastatic NSCLC having a positive TIM-3 expression will be enrolled in Cohort D. Participants will be administered TSR-022 at RP2D in combination with TSR-042.
    Interventions:
    • Drug: TSR-022
    • Drug: TSR-042
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 7, 2020)		 369
Original Estimated Enrollment  ICMJE
 (submitted: June 24, 2016)		 402
Estimated Study Completion Date  ICMJE July 24, 2023
Estimated Primary Completion Date July 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Participant is at least 18 years of age.
  • Female participants of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the date of the first dose of study medication or be of non-childbearing potential.
  • Participant has adequate organ function.

Inclusion Criteria for Participants in Part 1 and Part 2 Cohorts A, B, and C:

  • Participant with advanced or metastatic solid tumor who meets the requirements for the part of the study/cohort he/she will participate in, as follows:
  • Part 1: Participant with advanced or metastatic solid tumor and has disease progression after treatment with available therapies that are known to confer clinical benefit or who is intolerant to treatment (except for Part 1e, where special interest tumor types will be specified by the Sponsor).
  • Part 1e:
  • Advanced or metastatic melanoma participants who have not been previously treated with anti-PD-1, anti-PD-L1, or anti cytotoxic T lymphocyte-associated protein-(CTLA-4) therapies. Participant may be treatment naïve.
  • Advanced or metastatic NSCLC participants who have not received anti-PD-1 or anti-PD-L1 therapies and have received <=2 prior lines of treatment.
  • Part 2: Histologically proven advanced (unresectable) or metastatic solid tumor that is measurable by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST version 1.1 criteria and meets 1 of the following disease types:
  • Cohort A (melanoma) - Participants with advanced or metastatic melanoma who have progressed following treatment with an anti-PD-1 or anti-PD-L1 antibody.
  • Cohort B (NSCLC) - Participants with advanced or metastatic NSCLC who have progressed following:
  • Treatment with an anti-PD-1 or anti-PD-L1 antibody.
  • Cohort C (CRC) - Participants with advanced/metastatic CRC who have progressed following standard treatment which must include fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated. Participants should have received no more than 3 prior lines of therapy (including adjuvant therapy).
  • Biopsies
  • Part 1: Participants must have archival tumor tissue available that is formalin-fixed and paraffin-embedded. Tumor tissue must be requested from off-site locations and confirmed available prior to dosing.
  • For participants in Part 1 who do not have archival tissue, a new biopsy must be performed to obtain tumor tissue.
  • Part 2 Cohorts A, B, and C: All participants enrolled in Part 2 Cohorts A to C are required to have fresh tumor tissue biopsy prior to dosing. Archival tissue should also be provided (if available) to enable a longitudinal analysis of tumor biomarkers.
  • If a participants has had a biopsy prior to entering the 21-day screening period and within approximately 12 weeks of study treatment, that biopsy may be accepted as the Baseline fresh biopsy.
  • All participants are also required to have lesions amenable to biopsy and to agree to tumor biopsies prior to the initiation of treatment (as noted above) approximately 4 to 6 weeks after initiating treatment, and, if possible, upon treatment discontinuation (for participant with PD).
  • Inclusion Criteria for Participants in Part 2 Cohort D
  • Participants with advanced or metastatic NSCLC that is measurable by CT or MRI per RECIST version 1.1 criteria and meet the following criteria:
  • NSCLC histology includes squamous or non-squamous cell carcinoma.
  • Participants have received no more than 2 prior lines of therapy, which must include a platinum-based chemotherapy (eg, cisplatin, carboplatin) and an anti-PD-(L)1 antibody.
  • Participants must have documented radiographic progression by RECIST version 1.1 criteria on prior anti-PD-1 or anti-PD-L1 therapy.
  • Biopsies
  • If a participant has had a biopsy prior to entering the 35-day screening period and within approximately 12 weeks of study treatment, that biopsy may be accepted as the Baseline fresh biopsy.

Exclusion Criteria

  • History of Grade >=3 immune-related AE with prior immunotherapy, with the exception of non-clinically significant lab abnormalities.
  • Participant has 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. Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the Medical Monitor.
  • Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active infection requiring systemic therapy.
  • 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) infection or HIV 1/2 antibodies.
  • Participant has 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 (ie, with use of disease-modifying agents, corticosteroids or immunosuppressive drugs).
  • Participant has a history of pneumonitis.
  • 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 [GM-CSF], or recombinant erythropoietin) within 3 weeks prior to the first dose of study drug.
  • Participant is currently participating and receiving study therapy or has participated in a study of an investigational agent and received investigational therapy or used an investigational device within 4 weeks prior to the first dose of study drug.
  • 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 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 vaccine within 7 days of planned start of study therapy.
  • Participant has a known hypersensitivity to TSR-022 components or excipients, or, if applicable, nivolumab, TSR-042, or TSR-033 components or excipients.

Exclusion Criteria for Participants in Part 1 and Part 2 Cohorts A, B, and C

  • Participant received prior therapy as defined below:
  • Part 1a: Anti-CTLA-4, anti-PD-1, anti-PD-1-ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD-L2) agent within 3 weeks (that is, 21 days) prior to initiation of study treatment.
  • Part 1b, Part 1c, Part 1d, and Part1f: Anti-CTLA-4 within 3 weeks (that is, 21 days) prior to initiation of study treatment and/or prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-TIM-3, or anti-LAG-3, or docetaxel agent that resulted in permanent discontinuation due to an AE.
  • Part 1e: Prior treatment with with an anti-PD-(L)1, anti-LAG-3 or anti-TIM-3.
  • NSCLC participants with known EGFR mutations, ALK translocations, or ROS1 mutations.
  • Participants with uveal melanoma.
  • Part 1f: History of severe hypersensitivity reaction to docetaxel, paclitaxel, or other drugs formulated with polysorbate 80.
  • Part 2 Cohorts A, B, and C combination arms (TSR-022 + TSR-042):
  • Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent that resulted in permanent discontinuation due to an AE.
  • Prior treatment with an anti-LAG-3 or anti-TIM-3.

Exclusion Criteria for Participants in Part 2 Cohort D

  • A participant with negative (as determined by Central Testing Lab) or unevaluable TIM-3 expression from tissue obtained prior to study entry will not be eligible for the study.
  • Participant has received prior therapy as defined below:
  • Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent that resulted in permanent discontinuation due to an AE.
  • Prior treatment with an anti-LAG-3 or anti-TIM-3.
  • Radiologic or clinical progression <= 8 weeks after initiation of prior anti-PD-1 or anti-PD-L1 antibody.
  • Participants with known EGFR mutation, ALK translocation, or ROS1 mutation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: US GSK Clinical Trials Call Cente 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com
Listed Location Countries  ICMJE Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02817633
Other Study ID Numbers  ICMJE 213348
4020-01-001 ( Other Identifier: Tesaro )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Tesaro, Inc.
Study Sponsor  ICMJE Tesaro, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account Tesaro, Inc.
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP