Clinical Trials /

Study of TSR-033 With an Anti-PD-1 in Patients With Advanced Solid Tumors

NCT03250832

Description:

This is a multicenter, open-label, first-in-human Phase 1 study evaluating TSR-033, an anti-LAG-3 Monoclonal Antibody, alone and in combination with an anti-PD-1 in Patients with Advanced Solid Tumors in a broad range of solid tumors. Patients 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: dose escalation and cohort expansion.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of TSR-033 With an Anti-PD-1 in Patients With Advanced Solid Tumors
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 4040-01-001
  • NCT ID: NCT03250832

Conditions

  • Advanced Solid Tumors
  • Antibodies
  • Immunotherapy
  • Colorectal Cancer

Interventions

DrugSynonymsArms
TSR-033LAG-3Experimental: Part 1 - Dose Escalation
Anti-PD-1PD-1Experimental: Part 1 - Dose Escalation

Purpose

This is a multicenter, open-label, first-in-human Phase 1 study evaluating TSR-033, an anti-LAG-3 Monoclonal Antibody, alone and in combination with an anti-PD-1 in Patients with Advanced Solid Tumors in a broad range of solid tumors. Patients 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: dose escalation and cohort expansion.

Detailed Description

      This is a multi-center, open-label, first-in-human, Phase 1 study evaluating the anti-LAG-3
      antibody of TSR-033 alone and in combination with anti-PD-1. The study will be conducted in 2
      parts, with Part 1 consisting of dose escalation to determine the RP2D of TSR-033 as a single
      agent (Part 1a) and in combination with an anti-PD-1 antibody (Part 1c). RP2D decisions will
      be based on the occurrence of dose-limiting toxicities (DLTs), PK, as well as PDy data. These
      regimens will be evaluated in patients with advanced solid tumors who have limited available
      treatment options as determined by the Investigator.

      Part 2 of the study will evaluate for Cohort A the anti-tumor activity of TSR-033 in
      combination with an anti-PD-1 in patients. The safety and tolerability of TSR-033 and
      dostarlimab added to either mFOLFOX6 and bevacizumab or FOLFIRI and bevacizumab in patients
      with stage IV MSS-CRC will be evaluated for patients in Cohort B.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental: Part 1 - Dose EscalationExperimentalPart 1 will be a dose escalation to determine the RP2D of TSR-033 as a single agent and in combination with an anti-PD-1.
  • TSR-033
  • Anti-PD-1
Experimental: Part 2 - Expansion CohortsExperimentalPart 2 of the study will further explore the safety and tolerability of TSR-033 in combination with dostarlimab as well as in combination with either mFOLFOX6/FOLFIRI and bevacizumab in patients with colorectal cancer.
  • TSR-033
  • Anti-PD-1

Eligibility Criteria

        Main Patient Selection Criteria

          -  Key Inclusion Criteria for Patients in Part 1:

          -  The patient has any histologically or cytologically confirmed advanced (unresectable)
             or metastatic solid tumor and has progressive disease (PD) after treatment with
             available therapies that are known to confer clinical benefit or who are intolerant to
             treatment.

          -  The patient must have an archival tumor tissue sample that is formalin-fixed and
             paraffin-embedded (FFPE) (blocks preferred over slides) and requested and confirmed
             available from offsite locations prior to dosing. The quality and quantity of the
             sample must be confirmed sufficient as per the Study Laboratory Manual. Patients who
             do not have archival tissue must agree to a new biopsy to obtain fresh tumor tissue
             prior to dosing.

          -  Part 1b (PK/PDy cohort): The patient must have lesions amenable for biopsy and agree
             to undergo biopsies for fresh tumor tissue prior to treatment, approximately 4 to 6
             weeks after initiating study treatment, and, whenever possible, at end of treatment
             (EOT) and/or the time of PD. Serial biopsies are optional for patients in Part 1a and
             1c.

          -  Key Inclusion Criteria for Patients in Part 2:

          -  The patient has any histologically or cytologically confirmed CRC that is metastatic
             or not amenable to potentially curative resection (advanced), in the opinion of the
             Investigator.

          -  The patient has a primary and/or metastatic tumor(s) that is known to be MSS, as
             determined locally.

          -  The patient must have lesions amenable for biopsy and agree to undergo biopsies for
             fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after initiating
             study treatment, and, whenever possible, at EOT and/or the time of PD. If the patient
             has had a biopsy prior to entering the 28-day screening period, and within
             approximately 12 weeks of study treatment, that biopsy sample may be accepted as the
             baseline fresh biopsy. Additionally, submission of sufficient high-quality archival
             tissue is recommended, if available, to enable a longitudinal analysis of tumor
             biomarkers.

          -  The patient has measurable disease by RECIST v1.1.

          -  The patient must have a baseline albumin ≥3.0 g/dL.

          -  Key Inclusion Criteria for Patients in Part 2A:

          -  The patient must have had at least 2, but no more than 3, prior lines of therapy in
             the advanced or metastatic setting. Adjuvant chemotherapy with radiographic
             progression >12 months after the last dose will not be considered a line of therapy.

          -  The patient has progressed on standard therapies or withdrawn from standard treatment
             due to unacceptable toxicity. Previous standard treatment must include all of the
             following: a) fluoropyrimidine, b) oxaliplatin (patients treated with oxaliplatin in
             adjuvant setting should have progressed after 12 months of completion of adjuvant
             therapy or they must have been treated with oxaliplatin for metastatic disease), c)
             irinotecan, d) patients whose disease is known to be RAS-wild-type must have been
             treated with cetuximab for metastatic disease, and e) bevacizumab and/or another
             anti-angiogenic agent, and f) previous treatment with regorafenib and/or TAS-102 are
             allowed in the absence of contraindications and if these agents are available to the
             patient according to local standards.

          -  The time between a patient's last chemotherapy and enrollment must be ≤8 weeks.

          -  Key Inclusion Criteria for Patients in Part 2B:

          -  The patient has received ≤2 prior systemic chemotherapy regimens in any setting (only
             1 prior regimen for metastatic disease is permitted).

          -  Key Inclusion Criteria for Patients in Part 2 Cohort B1:

          -  The patient has received first-line combination therapy consisting of bevacizumab or
             anti-EGFR antibodies with FOLFIRI and has experienced radiographic progression during
             or after first-line therapy. Radiographic progression >12 months after the last dose
             of adjuvant therapy will not be considered a line of therapy.

          -  mFOLFOX6 therapy with bevacizumab is appropriate for the patient and is recommended by
             the Investigator.

          -  Key Inclusion Criteria for Patients in Part 2 Cohort B2:

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

          -  FOLIRI therapy with bevacizumab is appropriate for the patient and is recommended by
             the Investigator.

          -  Key Exclusion Criteria for all Patients:

          -  The patient has previously been treated with an anti-LAG-3 antibody.

          -  The patient has known uncontrolled central nervous system (CNS) metastases and/or
             carcinomatous meningitis.

          -  The patient has a known concurrent, serious, uncontrolled medical disorder,
             nonmalignant systemic disease, or active infection requiring systemic therapy,
             including human immunodeficiency virus (HIV), known active hepatitis B or hepatitis C,
             active infection, or active autoimmune disease.

          -  The patient is pregnant or breastfeeding, or expecting to conceive children within the
             projected duration of the study.

          -  The patient has a history of interstitial lung disease.

          -  The patient has not recovered (ie, to Grade ≤1 or to baseline) from radiation- and
             chemotherapy-induced adverse events (AEs), has received transfusion of blood products
             (including platelets or red blood cells), or has received administration of colony
             stimulating factors (including granulocyte colony-stimulating factor [G-CSF],
             granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin)
             within 3 weeks prior to the first dose of study drug.

          -  The patient is currently participating in an investigational study (therapy or device)
             or has participated in an investigational study within 4 weeks prior to the first dose
             of study drug.

          -  The patient has received prior anticancer therapy (chemotherapy, targeted therapies,
             radiotherapy, or immunotherapy) within 21 days or less than 5 times the half-life of
             the most recent therapy prior to the first dose of the drug, whichever is shorter.

          -  The patient has not recovered (Grade ≥1) from AEs and/or complications from any major
             surgery prior to the first dose of study drug.

          -  The patient has received a vaccine within 7 days of the first dose of study drug.

          -  The patient has known hypersensitivity to TSR-033, dostarlimab (Part 1c and Part 2),
             or associated excipients.

          -  Key Exclusion Criteria for Patients in Part 1:

          -  Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-3 agent that
             resulted in permanent discontinuation due to an AE.

          -  Key Exclusion Criteria for Patients in Part 2:

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

          -  Key Exclusion Criteria for Patients in Part 2B:

          -  The patient has known hypersensitivity to bevacizumab, mFOLFOLX6 (Cohort B1) or
             FOLFIRI (Cohort B2), or associated excipients.

          -  The patient experienced PD within 12 months of last dose of adjuvant therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Treatment-Emergent Adverse Events as Assessed by CTCAE v4.0
Time Frame:Part 1: Dose Escalation cohorts - 2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:PK parameter
Time Frame:Approximately 2 years
Safety Issue:
Description:PK: AUC of TSR-033 when given alone and in combination with Anti-PD-1
Measure:- Duration of response (DOR) by RECIST v. 1.1
Time Frame:Part 1 and Part 2 - Approximately 4 years
Safety Issue:
Description:
Measure:- Disease control rate (DCR) by RECIST v. 1.1
Time Frame:Part 1 and Part 2 - Approximately 4 years
Safety Issue:
Description:
Measure:- Progression-free survival (PFS) by RECIST v. 1.1
Time Frame:Part 1 and Part 2 - Approximately 4 years
Safety Issue:
Description:
Measure:- Overall survival (OS)
Time Frame:Part 1 and Part 2 - Approximately 4 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tesaro, Inc.

Trial Keywords

  • advanced solid tumors
  • endometrioid ovarian cancer
  • fallopian tube cancer
  • primary peritoneal cancer
  • breast cancer
  • bladder cancer
  • urothelial carcinoma
  • TNBC
  • triple-negative breast cancer
  • LAG-3
  • colorectal cancer
  • lung cancer

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