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

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

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.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: TSR-033; Drug: Dostarlimab; Drug: mFOLFOX6; Drug: Bevacizumab; Drug: FOLFIRI

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Villejuif cedex, France, 94805
    • GSK Investigational Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • GSK Investigational Site
    • Whittier, California, United States, 90603
      • GSK Investigational Site
  • Florida
    • Sarasota, Florida, United States, 34232
      • GSK Investigational Site
    • Tampa, Florida, United States, 33612
      • GSK Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • GSK Investigational Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • GSK Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • GSK Investigational Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • GSK Investigational Site
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • GSK Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • GSK Investigational Site
    • San Antonio, Texas, United States, 78229
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for participants in Part 1:

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

• Female participants must have a negative serum or urine pregnancy test within 72 hours prior to the date of the first dose of study medication if of childbearing potential or be of non-childbearing potential. Non-childbearing potential is defined as:

  • Participants >=45 years of age and has not had menses for >1 year.
  • Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.
  • Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
• Female participants of childbearing potential (that is [ie], those who do not meet above criteria) must agree to use 2 highly effective forms of contraception with their partners, starting with the screening visit through 150 days after the last dose of study therapy.
• The participant must have an ECOG PS of <=1.

• The participant has adequate hematologic and organ function, defined as:

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

Inclusion criteria for participants in Part 2:

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

• Female participants must have a negative serum or urine pregnancy test within 72 hours prior to the date of the first dose of study medication if of childbearing potential or be of non-childbearing potential. Non-childbearing potential is defined as:

  • Participants >=45 years of age and has not had menses for >1 year.
  • Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.
  • Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
• Female participants of childbearing potential (ie, those who do not meet above criteria) must agree to use 2 highly effective forms of contraception with their partners, starting with the screening visit through 150 days after the last dose of study therapy.
• The participant has an ECOG PS of <=1.

• The participant has adequate hematologic and organ function, defined as:

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

Inclusion Criteria for participants in Part 2A:

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

• The participant has progressed on standard therapies or withdrawn from standard treatment due to unacceptable toxicity. Previous standard treatment must include all of the following:

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

Inclusion Criteria for participants in Part 2B:

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

Inclusion Criteria for participants in Part 2 Cohort B1:

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

Inclusion Criteria for participants in Part 2 Cohort B2:

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

Exclusion Criteria for all participants:

• The participant has previously been treated with an anti-LAG-3 antibody.
• The participant has known uncontrolled central nervous system (CNS) metastases and/or carcinomatous meningitis.
• The participant has a known concurrent, serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection requiring systemic therapy, including human immunodeficiency virus (HIV), known active hepatitis B or hepatitis C, active infection, or active autoimmune disease.
• The participant is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study.
• The participant has a history of interstitial lung disease.
• The participant has not recovered (ie, to Grade <=1 or to Baseline) from radiation- and chemotherapy-induced AEs, has received transfusion of blood products (including platelets or red blood cells), or has received administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 3 weeks prior to the first dose of study drug.
• The participant is currently participating in an investigational study (therapy or device) or has participated in an investigational study within 4 weeks prior to the first dose of study drug.
• The participant has received prior anticancer therapy (chemotherapy, targeted therapies, radiotherapy, or immunotherapy) within 21 days or less than 5 times the half-life of the most recent therapy prior to the first dose of the drug, whichever is shorter.
• The participant has received wide-field (full-dose pelvic) radiotherapy within 28 days prior to the first dose of study drug.
• The participant has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders.
• The participant has experienced any arterial thrombotic or arterial thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 12 months prior to first dose of study drug.
• The participant has received a prior autologous or allogeneic organ or transplantation.
• The participant has undergone major surgery within 28 days or subcutaneous venous access device placement within 7 days prior to the first dose of study drug.
• The participant has had a serious non-healing wound, ulcer, or bone fracture within 28 days prior to first dose of study drug.
• The participant has an elective or planned major surgery to be performed during the course of the trial.
• The participant has a history of inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) in the 12 months prior to the first dose of study drug.
• The participant has an acute or subacute bowel obstruction, abdominal fistula, or history of chronic diarrhea which is considered clinically significant, in the opinion of the investigator.
• The participant has experienced a Grade >=3 bleeding event within 3 months prior to the first dose of study drug.
• The participant has either peptic ulcer disease associated with a bleeding event or known active diverticulitis.
• The participant has not recovered (Grade >=1) from AEs and/or complications from any major surgery prior to the first dose of study drug.
• The participant has received a vaccine within 7 days of the first dose of study drug.
• The participant has known hypersensitivity to TSR-033, dostarlimab (Part 1c and Part 2), or associated excipients.

Exclusion Criteria for participants in Part 1:

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

Exclusion Criteria for participants in Part 2:

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

Exclusion Criteria for participants in Part 2B:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1a: TSR-033 monotherapy dose escalation; Part 1a will evaluate TSR-033 at ascending doses (20 milligrams [mg], 80 mg and 240 mg) every 2 weeks. Cohorts will be enrolled sequentially and will initially follow a 3+3 design at a starting dose of 20 mg.	Drug: TSR-033; TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.; Other Names: LAG-3
Experimental: Part 1b: TSR-033 monotherapy PK/PDy characterization; Part 1b will evaluate the PK profile and assess PDy data from blood and tumor tissue samples following TSR-033 treatment. The participants will begin treatment with TSR-033 on Day 1 followed by 28 days observation for collection of blood sampling for PK/PDy. Participants will receive their second dose of TSR-033 on Day 29 and every 14 days thereafter.	Drug: TSR-033; TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.; Other Names: LAG-3
Experimental: Part 1c: TSR-033+dostarlimab combination dose escalation; Participants will be administered ascending doses of TSR-033 in combination with dostarlimab 500 mg every 3 weeks. Planned dose levels of TSR-033 include 80 and 240 mg.	Drug: TSR-033; TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.; Other Names: LAG-3; Drug: Dostarlimab; Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.
Experimental: Part 2 Cohort A: TSR-033+dostarlimab combination; Part 2 Cohort A will evaluate the preliminary activity of TSR-033 in combination with dostarlimab in anti-PD-1 naive participants with third and fourth line MSS-CRC. TSR-033 will be administered every 2 weeks and dostarlimab every 6 weeks.	Drug: TSR-033; TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.; Other Names: LAG-3; Drug: Dostarlimab; Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.
Experimental: Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6; Part 2 Cohort B1 will evaluate the preliminary activity of TSR-033 administered every 2 weeks (Q2W) in combination with dostarlimab administered every 6 weeks (Q6W) along with mFOLFOX6 and bevacizumab (standard of care [SOC]) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFIRI, with or without biologics.	Drug: TSR-033; TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.; Other Names: LAG-3; Drug: Dostarlimab; Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.; Drug: mFOLFOX6; mFOLFOX6 is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) which acts as systemic cytotoxic agent.; Drug: Bevacizumab; Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.
Experimental: Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI; Part 2 Cohort B2 will evaluate the preliminary activity of TSR-033 in combination with FOLFIRI and bevacizumab (SOC) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFOX, with or without biologics.	Drug: TSR-033; TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.; Other Names: LAG-3; Drug: Dostarlimab; Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.; Drug: Bevacizumab; Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.; Drug: FOLFIRI; FOLFIRI is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and irinotecan (IRI) which acts as systemic cytotoxic agent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT)	DLTs were assessed based on common terminology criteria for adverse events (CTCAE) v5.0 included drug-related AEs like grade>=2 uveitis, eye pain, or blurred vision that does not resolve with topical therapy within 2 weeks, grade ≥2 immune-related endocrine toxicity that required hormone replacement, grade 2 or 3 colitis or diarrhea that persisted without resolution to grade<=1 for >=7days despite adequate immune suppressive therapy, grade 3 or 4 immune-related AEs (irAE) without resolution to grade<=1 or baseline within 8 days despite adequate immune suppressive therapy, any grade clinically significant (CS) irAE requiring treatment discontinuation, other grade>=3 non-hematologic toxicity, any CS grade>=3 non-hematologic laboratory abnormality, any CS hematologic toxicity and any death that is not clearly attributed to the underlying disease or extraneous causes. CTCAE defines Grade 0 as normal, 1 as mild, 2 as moderate, 3 as severe and Grade 4 as life-threatening consequences.	Up to 28 days
Part 1C: Number of Participants Experiencing DLT	DLTs were assessed based on common terminology criteria for adverse events (CTCAE) v5.0 included drug-related AEs like grade>=2 uveitis, eye pain, or blurred vision that does not resolve with topical therapy within 2 weeks, grade ≥2 immune-related endocrine toxicity that required hormone replacement, grade 2 or 3 colitis or diarrhea that persisted without resolution to grade<=1 for >=7days despite adequate immune suppressive therapy, grade 3 or 4 immune-related AEs (irAE) without resolution to grade<=1 or baseline within 8 days despite adequate immune suppressive therapy, any grade clinically significant (CS) irAE requiring treatment discontinuation, other grade>=3 non-hematologic toxicity, any CS grade>=3 non-hematologic laboratory abnormality, any CS hematologic toxicity and any death that is not clearly attributed to the underlying disease or extraneous causes. CTCAE defines Grade 0 as normal, 1 as mild, 2 as moderate, 3 as severe and Grade 4 as life-threatening consequences.	Up to 42 days
Part 2B: Number of Participants Experiencing DLT	DLTs were assessed based on common terminology criteria for adverse events (CTCAE) v5.0 included drug-related AEs like grade>=2 uveitis, eye pain, or blurred vision that does not resolve with topical therapy within 2 weeks, grade ≥2 immune-related endocrine toxicity that required hormone replacement, grade 2 or 3 colitis or diarrhea that persisted without resolution to grade<=1 for >=7days despite adequate immune suppressive therapy, grade 3 or 4 immune-related AEs (irAE) without resolution to grade<=1 or baseline within 8 days despite adequate immune suppressive therapy, any grade clinically significant (CS) irAE requiring treatment discontinuation, other grade>=3 non-hematologic toxicity, any CS grade>=3 non-hematologic laboratory abnormality, any CS hematologic toxicity and any death that is not clearly attributed to the underlying disease or extraneous causes. CTCAE defines Grade 0 as normal, 1 as mild, 2 as moderate, 3 as severe and Grade 4 as life-threatening consequences.	Up to 30 days
Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs)	SAEs are 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. TEAEs are defined as any new AE that begins, or any pre-existing condition that worsens in severity, after at least 1 dose of study treatment administration. Immune-related adverse events of interest (irAEs) are defined as any >= Grade 2 AEs based on a pre-specified list. CTCAE defines Grade 0 as normal, 1 as mild, 2 as moderate, 3 as severe and Grade 4 as life-threatening consequences.	Up to approximately 51 months
Part 2B: Number of Participants With SAEs, TEAEs and irAEs	SAEs are 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. TEAEs are defined as any new AE that begins, or any pre-existing condition that worsens in severity, after at least 1 dose of study treatment administration. Immune-related adverse events of interest (irAEs) are defined as any >= Grade 2 AEs based on a pre-specified list. CTCAE defines Grade 0 as normal, 1 as mild, 2 as moderate, 3 as severe and Grade 4 as life-threatening consequences.	Up to approximately 29 months
Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters	Blood samples were collected for the analysis of hematology parameters and each parameter was graded according to national cancer institute (NCI)-common terminology criteria for adverse events (CTCAE) version 5.0. Grade 0: normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent non-missing measurement prior to the first administration of study drug. Data has been presented for the number of participants with hematology grade shifts from baseline grade to grade 3 and 4 for each parameter.	Up to 51 months
Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters	Blood samples were collected for the analysis of hematology parameters and each parameter was graded according to national cancer institute (NCI)-common terminology criteria for adverse events (CTCAE) version 5.0. Grade 0: normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent non-missing measurement prior to the first administration of study drug. Data have been presented for the number of participants with hematology grade shifts from baseline grade to grade 3 and 4 for each parameter. WBC is white blood cells.	Up to 29 months
Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters	Blood samples were collected for the analysis of clinical chemistry parameters and each parameter was graded according to national cancer institute (NCI)-common terminology criteria for adverse events (CTCAE) version 5.0. Grade 0: normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent non-missing measurement prior to the first administration of study drug. Data have been presented for the number of participants with clinical chemistry grade shifts from baseline grade to grade 3 and 4 for each parameter.	Up to 51 months
Part 2B: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters	Blood samples were collected for the analysis of clinical chemistry parameters and each parameter was graded according to national cancer institute (NCI)-common terminology criteria for adverse events (CTCAE) version 5.0. Grade 0: normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent non-missing measurement prior to the first administration of study drug. Data have been presented for the number of participants with clinical chemistry grade shifts from baseline grade to grade 3 and 4 for each parameter.	Up to 29 months
Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase	Blood samples were collected for the analysis of clinical chemistry parameters and each parameter was graded according to national cancer institute (NCI)-common terminology criteria for adverse events (CTCAE) version 5.0. Grade 0: normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Data have been presented for the number of participants with clinical chemistry grade3 and 4 toxicities each parameter.	Up to 51 months
Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin	Blood samples were collected for the analysis of clinical chemistry parameters and each parameter was graded according to national cancer institute (NCI)-common terminology criteria for adverse events (CTCAE) version 5.0. Grade 0: normal, Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the most recent non-missing measurement prior to the first administration of study drug. Data have been presented for the number of participants with clinical chemistry grade 3 and 4 toxicities each parameter.	Up to 29 months
Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results	12-lead ECG were obtained using an ECG machine. Participants were in supine or a semi-recumbent position (about 30 degrees of elevation) and rested for approximately 2 minutes before ECGs are recorded. ECG results included QT interval corrected for heart rate according to Bazett's formula (QTcB), QT interval corrected for heart rate according to Fridericia's formula (QTcF), QRS interval, PR Interval and Heart rate.	Up to 51 months
Part 2B: Number of Participants With Post Baseline Abnormal ECG Results	12-lead ECG were obtained using an ECG machine. Participants were in supine or a semi-recumbent position (about 30 degrees of elevation) and rested for approximately 2 minutes before ECGs are recorded. ECG results included QT interval corrected for heart rate according to Bazett's formula (QTcB), QT interval corrected for heart rate according to Fridericia's formula (QTcF), QRS interval, PR Interval and Heart rate.	Up to 29 months
Part 2A: Objective Response Rate (ORR)	ORR is defined as percentage 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. CR defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Up to 30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1ab: Area Under the Concentration-time Curve From Time Zero to Last Measurable Concentration (AUC [0-last]) of TSR-033	Blood samples were collected for pharmacokinetic (PK) analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Part 1c: AUC (0-last) of TSR-033 and Dostarlimab	Blood samples were collected for PK analysis of TSR-033 when administered intravenously in combination with dostarlimab. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Part 1ab: AUC Extrapolated From Time Zero to Infinity (AUC [0-inf]) of TSR-033	Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab	Blood samples were collected for PK analysis of TSR-033 when administered intravenously in combination with dostarlimab. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033	Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Part 1c: AUCtau of TSR-033 and Dostarlimab	Blood samples were collected for PK analysis of TSR-033 when administered intravenously in combination with dostarlimab. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Part 1ab: Maximum Concentration (Cmax) of TSR-033	Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Part 1c: Cmax of TSR-033 and Dostarlimab	Blood samples were collected for PK analysis of TSR-033 when administered intravenously in combination with dostarlimab. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Part 1ab: Clearance (CL) of TSR-033	Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Part 1c: CL of TSR-033 and Dostarlimab	Blood samples were collected for PK analysis of TSR-033 when administered intravenously in combination with dostarlimab. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033	Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Part 1c: Vss of TSR-033 and Dostarlimab	Blood samples were collected for PK analysis of TSR-033 when administered intravenously in combination with dostarlimab. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Part 1ab: Terminal Half-life (t1/2) of TSR-033	Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Part 1c: t1/2 of TSR-033 and Dostarlimab	Blood samples were collected for PK analysis of TSR-033 when administered intravenously in combination with dostarlimab. PK parameter was determined using standard non-compartmental methods.	Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Part 1ab: Number of Participants With Anti-TSR-033 Antibodies	Serum samples will be collected and tested for the presence of antibodies to TSR-033.	Up to 51 months
Part 1c: Number of Participants With Anti-TSR-033 Antibodies	Serum samples will be collected and tested for the presence of antibodies to TSR-033.	Up to 29 months
Part 2A: Number of Participants With Anti-TSR-033 Antibodies	Serum samples will be collected and tested for the presence of antibodies to TSR-033.	Up to 29 months
Part 2B: Number of Participants With Anti-TSR-033 Antibodies	Serum samples will be collected and tested for the presence of antibodies to TSR-033.	Up to 29 months
Part 1ab: Objective Response Rate (ORR)	ORR is defined as percentage 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. CR defined as disappearance of all target & non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Up to 51 months
Part 1c: Objective Response Rate (ORR)	ORR is defined as percentage 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. CR defined as disappearance of all target & non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Up to 29 months
Part 2B: Objective Response Rate (ORR)	ORR is defined as percentage 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. CR defined as disappearance of all target & non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Up to 29 months
Part 2A: Duration of Response (DOR)	DOR was defined as the time from first documentation of CR or PR by RECIST v1.1 until the time offirst documentation of PD per RECIST v1.1. CR defined as disappearance of all target & non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Up to 29 months
Part 2B: Duration of Response (DOR)	DOR was defined as the time from first documentation of CR or PR by RECIST v1.1 until the time offirst documentation of PD per RECIST v1.1. CR defined as disappearance of all target & non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Up to 29 months
Part 2A: Disease Control Rate (DCR)	DCR is defined as defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessedby the investigator per RECIST v1.1. CR defined as disappearance of all target & non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.	Up to 29 months
Part 2B: Disease Control Rate (DCR)	DCR is defined as defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessedby the investigator per RECIST v1.1. CR defined as disappearance of all target & non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter. PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.	Up to 29 months

Collaborators and Investigators

• Sponsor: Tesaro, Inc.
• Collaborators: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2017
• Primary Completion (Actual): June 2, 2022
• Study Completion (Actual): February 13, 2023

Study Registration Dates

• First Submitted: June 22, 2017
• First Submitted That Met QC Criteria: August 11, 2017
• First Posted (Actual): August 16, 2017

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Colorectal cancer; Ovarian cancer; Lung cancer; Dose escalation; Advanced solid tumors; Dose expansion; Dostarlimab
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Dostarlimab
• Other Study ID Numbers: 213349; 4040-01-001 (Other Identifier: Tesaro)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No