<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03250832</url>
  </required_header>
  <id_info>
    <org_study_id>213349</org_study_id>
    <secondary_id>4040-01-001</secondary_id>
    <nct_id>NCT03250832</nct_id>
  </id_info>
  <brief_title>Study of TSR-033 With an Anti-programmed Cell Death-1 Receptor (PD-1) in Participants With Advanced Solid Tumors</brief_title>
  <acronym>CITRINO</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tesaro, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Tesaro, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multicenter, open-label, first-in-human Phase 1 study evaluating the&#xD;
      anti-lymphocyte activation gene-3 (LAG-3) antibody TSR-033 alone, in combination with the&#xD;
      anti-PD-1 antibody dostarlimab, and in combination with dostarlimab, modified folinic acid&#xD;
      (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) (mFOLFOX6) or FOL/leucovorin,&#xD;
      5-fluorouracil and irinotecan (IRI) (FOLFIRI), and bevacizumab in participants with advanced&#xD;
      solid tumors in a broad range of solid tumors. Participants with disease types selected for&#xD;
      evaluation in this study are expected to derive clinical benefit with addition of an&#xD;
      anti-PD-1. The study will be conducted in two parts with Part 1 consisting of dose escalation&#xD;
      to determine the recommended phase 2 dose (RP2D) of TSR-033 as a single agent (Part 1a) and&#xD;
      in combination with dostarlimab (Part 1c). RP2D decisions will be based on the occurrence of&#xD;
      dose-limiting toxicities (DLTs), pharmacokinetics (PK), as well as pharmacodynamics (PDy)&#xD;
      data. Part 2A of the study will investigate the anti-tumor activity of TSR-033 and&#xD;
      dostarlimab in combination in participants with advanced or metastatic microsatellite stable&#xD;
      colorectal cancer (MSS-CRC). Part 2B of the study will investigate the safety and anti-tumor&#xD;
      activity of TSR-033 and dostarlimab in combination with chemotherapy (Cohort B1: mFOLFOX6 and&#xD;
      Cohort B2: FOLFIRI) and bevacizumab in participants with advanced or metastatic MSS-CRC.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 8, 2017</start_date>
  <completion_date type="Actual">February 13, 2023</completion_date>
  <primary_completion_date type="Actual">June 2, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part 1a, Part 1c and 2B: Number of participants experiencing DLT</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>All DLTs mentioned in the protocol will be assessed. Toxicities will be assessed according to Common terminology criteria for adverse events (CTCAE) v5.0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1: Number of participants with serious adverse events (SAEs), treatment-emergent AEs (TEAEs) and immune-related AEs (irAEs)</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2B: Number of participants with SAEs, TEAEs and irAEs</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1: Number of participants with abnormality in hematology parameters</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2B: Number of participants with abnormality in hematology parameters</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1: Number of participants with abnormality in clinical chemistry parameters</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2B: Number of participants with abnormality in clinical chemistry parameters</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1: Number of participants with abnormality in electrocardiogram (ECG) parameters</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2B: Number of participants with abnormality in ECG parameters</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2A: Objective response rate (ORR)</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part 1a: Area under the concentration-time curve from time zero to last measurable concentration (AUC [0-last]) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1b: AUC (0-last) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1c: AUC (0-last) of TSR-033 and dostarlimab</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1a: AUC extrapolated from time zero to infinity (AUC[0-inf]) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1b: AUC (0-inf) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1c: AUC (0-inf) of TSR-033 and dostarlimab</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1a: AUC over a dosing interval at steady state (AUCtau) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1b: AUCtau of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1c: AUCtau of TSR-033 and dostarlimab</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1a: Maximum concentration (Cmax) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1b: Cmax of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1c: Cmax of TSR-033 and dostarlimab</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1a: Clearance (CL) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1b: CL of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1c: CL of TSR-033 and dostarlimab</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1a: Volume of distribution at steady state (Vss) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1b: Vss of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1c: Vss of TSR-033 and dostarlimab</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1a: Terminal half-life (t1/2) of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1b: t1/2 of TSR-033</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1c: t1/2 of TSR-033 and dostarlimab</measure>
    <time_frame>Pre-dose, 0.25, 0.5, 1.0, 1.5, 3, 24, 48, 96, 168 and 336 hours</time_frame>
    <description>Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1: Number of participants with anti-TSR-033 antibodies</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>Serum samples for the determination of anti-TSR-033 antibodies will be the same samples collected as for PK.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Number of participants with anti-TSR-033 antibodies</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>Serum samples for the determination of anti-TSR-033 antibodies will be the same samples collected as for PK.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1: ORR</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>ORR is defined as the proportion of participants achieving CR or PR as assessed by the investigator per RECIST v1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Duration of response (DOR)</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Disease control rate (DCR)</measure>
    <time_frame>Up to 3 years and 6 months</time_frame>
    <description>DCR is defined as defined as the percentage of participants achieving CR, PR, or SD as assessed by the investigator per RECIST v1.1.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">111</enrollment>
  <condition>Neoplasms</condition>
  <arm_group>
    <arm_group_label>Part 1a: TSR-033 monotherapy dose escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1b: TSR-033 monotherapy PK/PDy characterization</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1c: TSR-033+dostarlimab combination dose escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Cohort A: TSR-033+dostarlimab combination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TSR-033</intervention_name>
    <description>TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.</description>
    <arm_group_label>Part 1a: TSR-033 monotherapy dose escalation</arm_group_label>
    <arm_group_label>Part 1b: TSR-033 monotherapy PK/PDy characterization</arm_group_label>
    <arm_group_label>Part 1c: TSR-033+dostarlimab combination dose escalation</arm_group_label>
    <arm_group_label>Part 2 Cohort A: TSR-033+dostarlimab combination</arm_group_label>
    <arm_group_label>Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6</arm_group_label>
    <arm_group_label>Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI</arm_group_label>
    <other_name>LAG-3</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dostarlimab</intervention_name>
    <description>Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.</description>
    <arm_group_label>Part 1c: TSR-033+dostarlimab combination dose escalation</arm_group_label>
    <arm_group_label>Part 2 Cohort A: TSR-033+dostarlimab combination</arm_group_label>
    <arm_group_label>Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6</arm_group_label>
    <arm_group_label>Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mFOLFOX6</intervention_name>
    <description>mFOLFOX6 is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) which acts as systemic cytotoxic agent.</description>
    <arm_group_label>Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>FOLFIRI</intervention_name>
    <description>FOLFIRI is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and irinotecan (IRI) which acts as systemic cytotoxic agent.</description>
    <arm_group_label>Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.</description>
    <arm_group_label>Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6</arm_group_label>
    <arm_group_label>Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for participants in Part 1:&#xD;
&#xD;
          -  The participant is &gt;=18 years of age.&#xD;
&#xD;
          -  The participant has any histologically or cytologically confirmed advanced&#xD;
             (unresectable) or metastatic solid tumor and has PD after treatment with available&#xD;
             therapies that are known to confer clinical benefit or who are intolerant to&#xD;
             treatment.&#xD;
&#xD;
          -  The participant must have an archival tumor tissue sample that is formalin-fixed and&#xD;
             paraffin-embedded (FFPE) (blocks preferred over slides) and requested and confirmed&#xD;
             available from offsite locations prior to dosing. The quality and quantity of the&#xD;
             sample must be confirmed sufficient as per the Study Laboratory Manual. Participants&#xD;
             who do not have archival tissue must agree to a new biopsy to obtain fresh tumor&#xD;
             tissue prior to dosing.&#xD;
&#xD;
          -  Part 1b (PK/PDy cohort): The participant must have lesions amenable for biopsy and&#xD;
             agree to undergo biopsies for fresh tumor tissue prior to treatment, approximately 4&#xD;
             to 6 weeks after treatment, and, whenever possible, at the time of PD and /or end of&#xD;
             treatment (EOT). Serial biopsies are optional for participants in Part 1a and 1c.&#xD;
&#xD;
          -  Female participants must have a negative serum or urine pregnancy test within 72 hours&#xD;
             prior to the date of the first dose of study medication if of childbearing potential&#xD;
             or be of non-childbearing potential. Non-childbearing potential is defined as:&#xD;
&#xD;
               -  Participants &gt;=45 years of age and has not had menses for &gt;1 year.&#xD;
&#xD;
               -  Amenorrheic for &lt;2 years without a hysterectomy and oophorectomy and a&#xD;
                  follicle-stimulating hormone value in the postmenopausal range upon pre-study&#xD;
                  (screening) evaluation.&#xD;
&#xD;
               -  Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented&#xD;
                  hysterectomy or oophorectomy must be confirmed with medical records of the actual&#xD;
                  procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with&#xD;
                  medical records of the actual procedure.&#xD;
&#xD;
          -  Female participants of childbearing potential (that is [ie], those who do not meet&#xD;
             above criteria) must agree to use 2 highly effective forms of contraception with their&#xD;
             partners, starting with the screening visit through 150 days after the last dose of&#xD;
             study therapy.&#xD;
&#xD;
          -  The participant must have an ECOG PS of &lt;=1.&#xD;
&#xD;
          -  The participant has adequate hematologic and organ function, defined as:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt;=1500 per microliter (/μL).&#xD;
&#xD;
               -  Platelets &gt;=100,000/μL.&#xD;
&#xD;
               -  Hemoglobin (Hb) &gt;=9 grams per deciliter (g/dL) or &gt;=5.6 millimoles per liter&#xD;
                  (mmol/L).&#xD;
&#xD;
               -  Serum creatinine &lt;=1.5 times upper limit of normal (× ULN) or calculated&#xD;
                  creatinine clearance (CrCL) &gt;=50 milliliters per minute (mL/min) using&#xD;
                  Cockcroft-Gault equation for participants with creatinine levels &gt;1.5 ×&#xD;
                  institutional ULN&#xD;
&#xD;
               -  Total bilirubin &lt;=1.5 × ULN and direct bilirubin &lt;=1× ULN (in the event that the&#xD;
                  total bilirubin result exceeds the upper institutional limits of normal, direct&#xD;
                  bilirubin will be obtained to determine eligibility).&#xD;
&#xD;
               -  AST and ALT &lt;=2.5 × ULN unless liver metastases are present, in which case they&#xD;
                  must be &lt;=5 × ULN.&#xD;
&#xD;
               -  INR of PT &lt;=1.5 × ULN, unless participant is receiving anticoagulant therapy,&#xD;
                  then PT or partial thromboplastin time (PTT) is within therapeutic range of&#xD;
                  intended use of anticoagulants; aPTT) &lt;= 1.5 × ULN unless participant is&#xD;
                  receiving anticoagulant therapy, then PT or PTT is within therapeutic range of&#xD;
                  intended use of anticoagulants.&#xD;
&#xD;
        Inclusion criteria for participants in Part 2:&#xD;
&#xD;
          -  The participant is &gt;= 18 years of age.&#xD;
&#xD;
          -  The participant has any histologically or cytologically confirmed CRC that is&#xD;
             metastatic or not amenable to potentially curative resection (advanced), in the&#xD;
             opinion of the Investigator.&#xD;
&#xD;
          -  The participant has a primary and/or metastatic tumor(s) that is known to be MSS, as&#xD;
             determined locally.&#xD;
&#xD;
          -  The participant must have lesions amenable for biopsy and agree to undergo biopsies&#xD;
             for fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after, and,&#xD;
             whenever possible, at EOT and/or the time of PD. If the participant has had a biopsy&#xD;
             prior to entering the 28-day screening period, and within approximately 12 weeks of&#xD;
             study treatment, that biopsy sample may be accepted as the Baseline fresh biopsy.&#xD;
             Additionally, submission of sufficient high-quality archival tumor tissue is&#xD;
             recommended, if available, to enable a longitudinal analysis of tumor biomarkers.&#xD;
&#xD;
          -  The participant has measurable disease by RECIST v1.1.&#xD;
&#xD;
          -  The participant has resolution to Grade &lt;=1, per CTCAE v5.0, of all clinically&#xD;
             significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal&#xD;
             therapy, with the exception of peripheral neuropathy, which must have resolved to&#xD;
             Grade &lt;=2, and except where otherwise noted in the eligibility criteria.&#xD;
&#xD;
          -  Female participants must have a negative serum or urine pregnancy test within 72 hours&#xD;
             prior to the date of the first dose of study medication if of childbearing potential&#xD;
             or be of non-childbearing potential. Non-childbearing potential is defined as:&#xD;
&#xD;
               -  Participants &gt;=45 years of age and has not had menses for &gt;1 year.&#xD;
&#xD;
               -  Amenorrheic for &lt;2 years without a hysterectomy and oophorectomy and a&#xD;
                  follicle-stimulating hormone value in the postmenopausal range upon pre-study&#xD;
                  (screening) evaluation.&#xD;
&#xD;
               -  Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented&#xD;
                  hysterectomy or oophorectomy must be confirmed with medical records of the actual&#xD;
                  procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with&#xD;
                  medical records of the actual procedure.&#xD;
&#xD;
          -  Female participants of childbearing potential (ie, those who do not meet above&#xD;
             criteria) must agree to use 2 highly effective forms of contraception with their&#xD;
             partners, starting with the screening visit through 150 days after the last dose of&#xD;
             study therapy.&#xD;
&#xD;
          -  The participant has an ECOG PS of &lt;=1.&#xD;
&#xD;
          -  The participant has adequate hematologic and organ function, defined as:&#xD;
&#xD;
               -  ANC &gt;=1500/μL.&#xD;
&#xD;
               -  Platelets &gt;=100,000/μL.&#xD;
&#xD;
               -  Hb &gt;=9 g/dL or &gt;=5.6 mmol/L.&#xD;
&#xD;
               -  Serum creatinine &lt;=1.5 × ULN or calculated CrCL &gt;=50 mL/min using Cockcroft-Gault&#xD;
                  equation for participants with creatinine levels &gt;1.5 × institutional ULN&#xD;
&#xD;
               -  Total bilirubin &lt;=1.5 × ULN and direct bilirubin &lt;=1× ULN (in the event that the&#xD;
                  total bilirubin result exceeds the upper institutional limits of normal, direct&#xD;
                  bilirubin will be obtained to determine eligibility).&#xD;
&#xD;
               -  AST and ALT &lt;=2.5 × ULN unless liver metastases are present, in which case they&#xD;
                  must be &lt;=5 × ULN.&#xD;
&#xD;
               -  INR of PT &lt;=1.5 × ULN, unless participant is receiving anticoagulant therapy,&#xD;
                  then PT or PTT is within therapeutic range of intended use of anticoagulants;&#xD;
                  aPTT) &lt;= 1.5 × ULN unless participant is receiving anticoagulant therapy, then PT&#xD;
                  or PTT is within therapeutic range of intended use of anticoagulants.&#xD;
&#xD;
               -  Urinary protein is &lt;=1+ on dipstick for routine urinalysis; if urine protein&#xD;
                  &gt;=2+, a 24-hour urine sample must be collected and must demonstrate &lt;1000 mg of&#xD;
                  protein in 24 hours to allow participation in the study.&#xD;
&#xD;
               -  Baseline albumin &gt;=3.0 g/dL.&#xD;
&#xD;
        Inclusion Criteria for participants in Part 2A:&#xD;
&#xD;
          -  The participant must have had at least 2, but no more than 3, prior lines of therapy&#xD;
             in the advanced or metastatic setting. Adjuvant chemotherapy with radiographic&#xD;
             progression &gt;12 months after the last dose will not be considered a line of therapy.&#xD;
&#xD;
          -  The participant has progressed on standard therapies or withdrawn from standard&#xD;
             treatment due to unacceptable toxicity. Previous standard treatment must include all&#xD;
             of the following:&#xD;
&#xD;
               -  Fluoropyrimidine.&#xD;
&#xD;
               -  Oxaliplatin: Participants treated with oxaliplatin in adjuvant setting should&#xD;
                  have progressed after 12 months of completion of adjuvant therapy or they must&#xD;
                  have been treated with oxaliplatin for metastatic disease.&#xD;
&#xD;
               -  Irinotecan.&#xD;
&#xD;
               -  Participants whose disease is known to be RAS-wild-type must have been treated&#xD;
                  with cetuximab, panitumumab, or other epidermal growth factor receptor (EGFR)&#xD;
                  inhibitor for metastatic disease.&#xD;
&#xD;
               -  Bevacizumab and/or another anti-angiogenic agent.&#xD;
&#xD;
               -  Previous treatment with regorafenib and/or TAS-102 are allowed in the absence of&#xD;
                  contraindications and if these agents are available to the participant according&#xD;
                  to local standards.&#xD;
&#xD;
          -  The time between a participants's last chemotherapy and enrollment must be &lt;=8 weeks.&#xD;
&#xD;
        Inclusion Criteria for participants in Part 2B:&#xD;
&#xD;
          -  The participant has received &lt;=2 prior systemic chemotherapy regimens in any setting&#xD;
             (only 1 prior regimen for metastatic disease is permitted).&#xD;
&#xD;
        Inclusion Criteria for participants in Part 2 Cohort B1:&#xD;
&#xD;
          -  The participant has received first-line combination therapy consisting of bevacizumab&#xD;
             or anti-EGFR antibodies with FOLFIRI and has experienced radiographic progression&#xD;
             during or after first-line therapy. Radiographic progression &gt;12 months after the last&#xD;
             dose of adjuvant therapy will not be considered a line of therapy.&#xD;
&#xD;
          -  mFOLFOX6 therapy with bevacizumab is appropriate for the participant and is&#xD;
             recommended by the investigator.&#xD;
&#xD;
        Inclusion Criteria for participants in Part 2 Cohort B2:&#xD;
&#xD;
          -  The participant has received first-line combination therapy consisting of bevacizumab&#xD;
             or anti-EGFR antibodies with FOLFOX (or variant) and has experienced radiographic&#xD;
             progression during or after first-line therapy. Radiographic progression &gt;12 months&#xD;
             after the last dose of adjuvant therapy will not be considered a line of therapy.&#xD;
&#xD;
          -  FOLFIIRI therapy with bevacizumab is appropriate for the participant and is&#xD;
             recommended by the investigator.&#xD;
&#xD;
        Exclusion Criteria for all participants:&#xD;
&#xD;
          -  The participant has previously been treated with an anti-LAG-3 antibody.&#xD;
&#xD;
          -  The participant has known uncontrolled central nervous system (CNS) metastases and/or&#xD;
             carcinomatous meningitis.&#xD;
&#xD;
          -  The participant has a known concurrent, serious, uncontrolled medical disorder,&#xD;
             nonmalignant systemic disease, or active infection requiring systemic therapy,&#xD;
             including human immunodeficiency virus (HIV), known active hepatitis B or hepatitis C,&#xD;
             active infection, or active autoimmune disease.&#xD;
&#xD;
          -  The participant is pregnant or breastfeeding, or expecting to conceive children within&#xD;
             the projected duration of the study.&#xD;
&#xD;
          -  The participant has a history of interstitial lung disease.&#xD;
&#xD;
          -  The participant has not recovered (ie, to Grade &lt;=1 or to Baseline) from radiation-&#xD;
             and chemotherapy-induced AEs, has received transfusion of blood products (including&#xD;
             platelets or red blood cells), or has received administration of colony stimulating&#xD;
             factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte&#xD;
             macrophage colony-stimulating factor, or recombinant erythropoietin) within 3 weeks&#xD;
             prior to the first dose of study drug.&#xD;
&#xD;
          -  The participant is currently participating in an investigational study (therapy or&#xD;
             device) or has participated in an investigational study within 4 weeks prior to the&#xD;
             first dose of study drug.&#xD;
&#xD;
          -  The participant has received prior anticancer therapy (chemotherapy, targeted&#xD;
             therapies, radiotherapy, or immunotherapy) within 21 days or less than 5 times the&#xD;
             half-life of the most recent therapy prior to the first dose of the drug, whichever is&#xD;
             shorter.&#xD;
&#xD;
          -  The participant has received wide-field (full-dose pelvic) radiotherapy within 28 days&#xD;
             prior to the first dose of study drug.&#xD;
&#xD;
          -  The participant has a history of uncontrolled hereditary or acquired bleeding or&#xD;
             thrombotic disorders.&#xD;
&#xD;
          -  The participant has experienced any arterial thrombotic or arterial thromboembolic&#xD;
             events, including, but not limited to myocardial infarction, transient ischemic&#xD;
             attack, or cerebrovascular accident, within 12 months prior to first dose of study&#xD;
             drug.&#xD;
&#xD;
          -  The participant has received a prior autologous or allogeneic organ or&#xD;
             transplantation.&#xD;
&#xD;
          -  The participant has undergone major surgery within 28 days or subcutaneous venous&#xD;
             access device placement within 7 days prior to the first dose of study drug.&#xD;
&#xD;
          -  The participant has had a serious non-healing wound, ulcer, or bone fracture within 28&#xD;
             days prior to first dose of study drug.&#xD;
&#xD;
          -  The participant has an elective or planned major surgery to be performed during the&#xD;
             course of the trial.&#xD;
&#xD;
          -  The participant has a history of inflammatory bowel disease or Crohn's disease&#xD;
             requiring medical intervention (immunomodulatory or immunosuppressive medications or&#xD;
             surgery) in the 12 months prior to the first dose of study drug.&#xD;
&#xD;
          -  The participant has an acute or subacute bowel obstruction, abdominal fistula, or&#xD;
             history of chronic diarrhea which is considered clinically significant, in the opinion&#xD;
             of the investigator.&#xD;
&#xD;
          -  The participant has experienced a Grade &gt;=3 bleeding event within 3 months prior to&#xD;
             the first dose of study drug.&#xD;
&#xD;
          -  The participant has either peptic ulcer disease associated with a bleeding event or&#xD;
             known active diverticulitis.&#xD;
&#xD;
          -  The participant has not recovered (Grade &gt;=1) from AEs and/or complications from any&#xD;
             major surgery prior to the first dose of study drug.&#xD;
&#xD;
          -  The participant has received a vaccine within 7 days of the first dose of study drug.&#xD;
&#xD;
          -  The participant has known hypersensitivity to TSR-033, dostarlimab (Part 1c and Part&#xD;
             2), or associated excipients.&#xD;
&#xD;
        Exclusion Criteria for participants in Part 1:&#xD;
&#xD;
          -  The participant's prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or&#xD;
             anti-LAG-3 agent that resulted in permanent discontinuation due to an AE.&#xD;
&#xD;
        Exclusion Criteria for participants in Part 2:&#xD;
&#xD;
          -  The participant has been previously treated with an anti-PD-1 or anti-PD-L1 antibody.&#xD;
&#xD;
        Exclusion Criteria for participants in Part 2B:&#xD;
&#xD;
          -  The participant has known dihydropyrimidine dehydrogenase deficiency.&#xD;
&#xD;
          -  The participant experienced an arterial thrombotic/thromboembolic event, Grade 4&#xD;
             hypertension, Grade 4 proteinuria, a Grade 3-4 bleeding event, or bowel perforation&#xD;
             during first-line therapy with a bevacizumab-containing regimen.&#xD;
&#xD;
          -  The participant has known hypersensitivity to bevacizumab, mFOLFOLX6 (Cohort B1) or&#xD;
             FOLFIRI (Cohort B2), or associated excipients.&#xD;
&#xD;
          -  The participant experienced PD within 12 months of last dose of adjuvant therapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>GSK Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>GlaxoSmithKline</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Whittier</city>
        <state>California</state>
        <zip>90603</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Sarasota</city>
        <state>Florida</state>
        <zip>34232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Greenville</city>
        <state>South Carolina</state>
        <zip>29605</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Villejuif cedex</city>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 16, 2017</study_first_posted>
  <last_update_submitted>May 3, 2023</last_update_submitted>
  <last_update_submitted_qc>May 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Advanced solid tumors</keyword>
  <keyword>Dostarlimab</keyword>
  <keyword>Ovarian cancer</keyword>
  <keyword>Colorectal cancer</keyword>
  <keyword>Lung cancer</keyword>
  <keyword>Dose escalation</keyword>
  <keyword>Dose expansion</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Dostarlimab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>May 31, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03250832
org study id: 213349
secondary id: 4040-01-001
nct id: NCT03250832
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Part 1a, Part 1c and 2B: Number of participants experiencing DLT
time frame: Up to 3 years and 6 months
description: All DLTs mentioned in the protocol will be assessed. Toxicities will be assessed according to Common terminology criteria for adverse events (CTCAE) v5.0.
measure: 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
description: 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.
measure: Part 2B: Number of participants with SAEs, TEAEs and irAEs
time frame: Up to 3 years and 6 months
description: 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.
measure: Part 1: Number of participants with abnormality in hematology parameters
time frame: Up to 3 years and 6 months
description: 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).
measure: Part 2B: Number of participants with abnormality in hematology parameters
time frame: Up to 3 years and 6 months
description: 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.
measure: Part 1: Number of participants with abnormality in clinical chemistry parameters
time frame: Up to 3 years and 6 months
description: 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.
measure: Part 2B: Number of participants with abnormality in clinical chemistry parameters
time frame: Up to 3 years and 6 months
description: 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.
measure: Part 1: Number of participants with abnormality in electrocardiogram (ECG) parameters
time frame: Up to 3 years and 6 months
description: 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.
measure: Part 2B: Number of participants with abnormality in ECG parameters
time frame: Up to 3 years and 6 months
description: 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.
measure: Part 2A: Objective response rate (ORR)
time frame: Up to 3 years and 6 months
description: 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.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: Part 1a: AUC over a dosing interval at steady state (AUCtau) of TSR-033
time frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: Part 1b: AUCtau of TSR-033
time frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: Part 1c: AUCtau 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
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: Part 1a: Clearance (CL) of TSR-033
time frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected
measure: 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
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: Part 1a: Volume of distribution at steady state (Vss) of TSR-033
time frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96 and 168 hours
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: Part 1b: Vss of TSR-033
time frame: Pre-dose, 0.25, 0.5, 1.5, 3, 24, 48, 96, 168, 336 and 504 hours
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: Part 1c: Vss 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
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 will be collected.
measure: 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
description: Blood samples for determination of serum levels of TSR-033 and dostarlimab will be collected.
measure: Part 1: Number of participants with anti-TSR-033 antibodies
time frame: Up to 3 years and 6 months
description: Serum samples for the determination of anti-TSR-033 antibodies will be the same samples collected as for PK.
measure: Part 2: Number of participants with anti-TSR-033 antibodies
time frame: Up to 3 years and 6 months
description: Serum samples for the determination of anti-TSR-033 antibodies will be the same samples collected as for PK.
measure: Part 1: ORR
time frame: Up to 3 years and 6 months
description: ORR is defined as the proportion of participants achieving CR or PR as assessed by the investigator per RECIST v1.1.
measure: Part 2: Duration of response (DOR)
time frame: Up to 3 years and 6 months
description: 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.
measure: Part 2: Disease control rate (DCR)
time frame: Up to 3 years and 6 months
description: DCR is defined as defined as the percentage of participants achieving CR, PR, or SD as assessed by the investigator per RECIST v1.1.
arm group label: Part 1a: TSR-033 monotherapy dose escalation
arm group type: Experimental
description: 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.
arm group label: Part 1b: TSR-033 monotherapy PK/PDy characterization
arm group type: Experimental
description: 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.
arm group label: Part 1c: TSR-033+dostarlimab combination dose escalation
arm group type: Experimental
description: 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.
arm group label: Part 2 Cohort A: TSR-033+dostarlimab combination
arm group type: Experimental
description: 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.
arm group label: Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6
arm group type: Experimental
description: 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.
arm group label: Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: TSR-033
description: TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
arm group label: Part 1a: TSR-033 monotherapy dose escalation
arm group label: Part 1b: TSR-033 monotherapy PK/PDy characterization
arm group label: Part 1c: TSR-033+dostarlimab combination dose escalation
arm group label: Part 2 Cohort A: TSR-033+dostarlimab combination
arm group label: Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6
arm group label: Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI
other name: LAG-3
intervention type: Drug
intervention name: Dostarlimab
description: Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.
arm group label: Part 1c: TSR-033+dostarlimab combination dose escalation
arm group label: Part 2 Cohort A: TSR-033+dostarlimab combination
arm group label: Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6
arm group label: Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI
intervention type: Drug
intervention name: mFOLFOX6
description: mFOLFOX6 is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) which acts as systemic cytotoxic agent.
arm group label: Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6
intervention type: Drug
intervention name: FOLFIRI
description: FOLFIRI is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and irinotecan (IRI) which acts as systemic cytotoxic agent.
arm group label: Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI
intervention type: Drug
intervention name: Bevacizumab
description: Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.
arm group label: Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6
arm group label: Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: GSK Clinical Trials
role: Study Director
affiliation: GlaxoSmithKline
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country: France
country: United States
responsible party type: Sponsor
mesh term: Bevacizumab
mesh term: Dostarlimab
sharing ipd: No
submitted: May 31, 2023