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

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

INTRODUCTION

  • Org Study ID: 4040-01-001
  • Secondary ID: N/A
  • NTC ID: NCT03250832
  • Sponsor: Tesaro, Inc.

BRIEF SUMMARY


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.


  • Overall Status
    Recruiting
  • Start Date
    August 1, 2017
  • Phase
    Phase 1
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Number of Participants With Treatment-Emergent Adverse Events as Assessed by CTCAE v4.0

Primary Outcome 1 - Timeframe: Part 1: Dose Escalation cohorts - 2 years

Primary Outcome 2 - Measure: Number of Participants with Solid Tumors With Complete or Partial Response to the Anti-Tumor Activity of TSR-033 in Combination with dostarlimab

Primary Outcome 2 - Timeframe: Part 2: Dose Expansion Cohorts - 2 years

CONDITION

  • Advanced Solid Tumors
  • Antibodies
  • Immunotherapy
  • Colorectal Cancer

ELIGIBILITY


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.

Gender: All

Minimum Age: N/A

Maximum Age: 18 Years

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Ying Wang, M.D., Ph.D

Role: Study Director

Affiliation: Tesaro, Inc.

Overall Contact

Name: Ying Wang, M.D., Ph.D

Phone: 877-379-3718

Email: GSKClinicalSupportHD@gsk.com

LOCATION

Facility Status Contact
Facility: Innovative Clinical Research Institute (ICRI)
Whittier, California 90606
United States 		Status: Recruiting Contact:
Merrill Shum, M.D.
Facility: Denver Health One
Denver, Colorado 80218
United States 		Status: Recruiting Contact:
Shiraj Sen, M.D.
Facility: Florida Cancer Specialists
Sarasota, Florida 34232
United States 		Status: Recruiting Contact:
Judy Wang, M.D.
Facility: Moffitt Cancer Center
Tampa, Florida 33612
United States 		Status: Recruiting Contact: N/A
Facility: Dana Farber Cancer Institute
Boston, Massachusetts 02115
United States 		Status: Recruiting Contact: N/A
Facility: Stephenson Cancer Center
Oklahoma City, Oklahoma 73117
United States 		Status: Recruiting Contact: N/A
Facility: START
San Antonio, Texas 78229
United States 		Status: Recruiting Contact: N/A

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