Neoplasms
Conditions
Keywords
Advanced solid tumors, Dostarlimab, Ovarian cancer, Colorectal cancer, Lung cancer, Dose escalation, Dose expansion
Brief summary
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.
Interventions
DRUGTSR-033
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
DRUGDostarlimab
Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.
DRUGmFOLFOX6
mFOLFOX6 is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) which acts as systemic cytotoxic agent.
DRUGFOLFIRI
FOLFIRI is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and irinotecan (IRI) which acts as systemic cytotoxic agent.
DRUGBevacizumab
Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.
Sponsors
GlaxoSmithKline
Tesaro, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) | Up to 28 days | 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. |
| Part 1C: Number of Participants Experiencing DLT | Up to 42 days | 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. |
| Part 2B: Number of Participants Experiencing DLT | Up to 30 days | 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. |
| Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | Up to approximately 51 months | 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. |
| Part 2B: Number of Participants With SAEs, TEAEs and irAEs | Up to approximately 29 months | 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. |
| Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Up to 51 months | 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. |
| Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Up to 29 months | 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. |
| Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Up to 51 months | 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. |
| Part 2B: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Up to 29 months | 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. |
| Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Up to 51 months | 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. |
| Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Up to 29 months | 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. |
| Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Up to 51 months | 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. |
| Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | Up to 29 months | 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. |
| Part 2A: Objective Response Rate (ORR) | Up to 30 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1ab: Number of Participants With Anti-TSR-033 Antibodies | Up to 51 months | Serum samples will be collected and tested for the presence of antibodies to TSR-033. |
| Part 1c: Number of Participants With Anti-TSR-033 Antibodies | Up to 29 months | Serum samples will be collected and tested for the presence of antibodies to TSR-033. |
| Part 2A: Number of Participants With Anti-TSR-033 Antibodies | Up to 29 months | Serum samples will be collected and tested for the presence of antibodies to TSR-033. |
| Part 2B: Number of Participants With Anti-TSR-033 Antibodies | Up to 29 months | Serum samples will be collected and tested for the presence of antibodies to TSR-033. |
| Part 1ab: Objective Response Rate (ORR) | Up to 51 months | 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. |
| Part 1ab: Area Under the Concentration-time Curve From Time Zero to Last Measurable Concentration (AUC [0-last]) of TSR-033 | Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour | 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. |
| Part 2B: Objective Response Rate (ORR) | Up to 29 months | 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. |
| Part 2A: Duration of Response (DOR) | Up to 29 months | 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. |
| Part 2B: Duration of Response (DOR) | Up to 29 months | 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. |
| Part 2A: Disease Control Rate (DCR) | Up to 29 months | 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. |
| Part 2B: Disease Control Rate (DCR) | Up to 29 months | 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. |
| Part 1c: Objective Response Rate (ORR) | Up to 29 months | 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. |
| Part 1c: AUC (0-last) of TSR-033 and Dostarlimab | Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour | 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. |
| Part 1ab: AUC Extrapolated From Time Zero to Infinity (AUC [0-inf]) of TSR-033 | Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour | Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods. |
| Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab | Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour | 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. |
| Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033 | Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour | Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods. |
| Part 1c: AUCtau of TSR-033 and Dostarlimab | Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour | 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. |
| Part 1ab: Maximum Concentration (Cmax) of TSR-033 | Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour | Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods. |
| Part 1c: Cmax of TSR-033 and Dostarlimab | Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour | 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. |
| Part 1ab: Clearance (CL) of TSR-033 | Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour | Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods. |
| Part 1c: CL of TSR-033 and Dostarlimab | Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour | 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. |
| Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033 | Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour | Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods. |
| Part 1c: Vss of TSR-033 and Dostarlimab | Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour | 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. |
| Part 1ab: Terminal Half-life (t1/2) of TSR-033 | Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour | Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods. |
| Part 1c: t1/2 of TSR-033 and Dostarlimab | Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour | 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. |
Countries
France, United States
Participant flow
Recruitment details
The study was comprised of two parts. Part 1 was a dose escalation phase and consisted of two cohorts 1AB and 1C. Part 2 was Colorectal Cancer dose expansion phase and consisted of 3 cohorts 2A, 2B1 and 2B2.
Participants by arm
| Arm | Count |
|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] In part 1a, participants with advanced or metastatic solid tumors received 20 mg TSR-033 via 30-minute intravenous (IV) infusion once every 2 weeks (Q2W). | 3 |
| Part 1AB - TSR-033 (80 mg) In part 1a, participants with advanced or metastatic solid tumors received 80 mg TSR-033 via 30-minute IV infusion once Q2W. In part 1b, additional participants enrolled in this dose level to characterize the PK profile of TSR-033 and assess PDy data followed by treatment with TSR-033 dosed on day 1, and then once Q2W. | 10 |
| Part 1AB - TSR-033 (240 mg) In part 1a, participants with advanced or metastatic solid tumors received 240 mg TSR-033 via 30-minute IV infusion once Q2W. In part 1b, additional participants enrolled in this dose level to characterize the PK profile of TSR-033 and assess PDy data followed by treatment with TSR-033 dosed on day 1, and then once Q2W. | 11 |
| Part 1AB - TSR-033 (720 mg) In part 1a, participants with advanced or metastatic solid tumors received 720 mg TSR-033 via 30-minute IV infusion once Q2W. In part 1b, additional participants enrolled in this dose level to characterize the PK profile of TSR-033 and assess PDy data followed by treatment with TSR-033 dosed on day 1, and then once Q2W. | 10 |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) Participants with advanced or metastatic solid tumors received 80 mg TSR-033 via 30-minute IV infusion in combination with 500 mg dostarlimab on day 1, and then once every 3 weeks (Q3W). | 5 |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) Participants with advanced or metastatic solid tumors received 240 mg TSR-033 via 30-minute IV infusion in combination with 500 mg dostarlimab on day 1, and then once Q3W. | 7 |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) Participants with advanced or metastatic solid tumors received 720 mg TSR-033 via 30-minute IV infusion in combination with 500 mg dostarlimab on day 1, and then once Q3W. | 6 |
| Part 2A - TSR-033 (720 mg) + Dostarlimab (1000 mg) Anti-programmed cell death-1 receptor (PD-1) naive participants with advanced or metastatic microsatellite stable colorectal cancer (MSS-CRC) that progressed following 2 or 3 prior lines of therapy received IV infusion of 720 mg TSR-033 once Q2W in combination with 1000 mg dostarlimab once every 6 weeks (Q6W). | 34 |
| Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 Anti-PD-1-naive participants with advanced or metastatic MSS-CRC following progression on frontline treatment with FOLFIRI (or variant), with or without biologics received IV infusion of 720 mg TSR-033 once (on day 3 of each cycle) Q2W in combination with 1000 mg dostarlimab once (on day 3 of each cycle) Q6W and mFOLFOX6 (on day 1 of each cycle) Q6W and 30-minute IV infusion of bevacizumab (bev) once (on day 1 of each cycle) Q6W. As a part of mFOLFOX6 regimen combination of 2-hour infusion of oxaliplatin with leucovorin and 2-4 minutes infusion of 5-Fluorouracil on day 1 along with continuous 46-hours infusion of 5-Fluorouracil on day 1 to day 3 were administered. | 4 |
| Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI Anti-PD-1-naive participants with advanced or metastatic MSS-CRC following progression on frontline treatment with FOLFOX (or variant), with or without biologics received IV infusion of 720 mg TSR-033 once (on day 3 of each cycle) Q2W in combination with 1000 mg dostarlimab once (on day 3 of each cycle) Q6W and FOLFIRI (on day 1 of each cycle) Q6W and 30-minute IV infusion of bevacizumab (bev) once (on day 1 of each cycle) Q6W. As a part of FOLFIRI regimen combination of 90 minutes infusion of Irinotecan with leucovorin with 2-4 minutes infusion of 5-Fluorouracil on day 1 and continuous 46-hours infusion of 5-Fluorouracil on day 1 to day 3 were administered. | 21 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PACT Phase (up to Approximately 36weeks) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 1 (Up to Approximately 51 Months) | Death | 1 | 6 | 5 | 5 | 3 | 6 | 3 | 0 | 0 | 0 | 0 | 0 |
| Part 1 (Up to Approximately 51 Months) | Sponsor Decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 (Up to Approximately 51 Months) | Withdrawal by Subject | 2 | 4 | 5 | 5 | 2 | 1 | 3 | 0 | 0 | 0 | 0 | 0 |
| Part 2A (Up to Approximately 30 Months) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 18 | 0 | 0 | 0 | 0 |
| Part 2A (Up to Approximately 30 Months) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
| Part 2A (Up to Approximately 30 Months) | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 2A (Up to Approximately 30 Months) | Sponsor Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
| Part 2A (Up to Approximately 30 Months) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 8 | 0 | 0 | 0 | 0 |
| Part 2B (Up to Approximately 29 Months) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 7 | 0 | 0 |
| Part 2B (Up to Approximately 29 Months) | Sponsor Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 |
| Part 2B (Up to Approximately 29 Months) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 7 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB - TSR-033 (720 mg) | Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 2A - TSR-033 (720 mg) + Dostarlimab (1000 mg) | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 19 - 64 years | 1 Participants | 5 Participants | 6 Participants | 6 Participants | 4 Participants | 4 Participants | 5 Participants | 25 Participants | 3 Participants | 17 Participants | 76 Participants |
| Age, Customized >=65 years | 2 Participants | 5 Participants | 5 Participants | 4 Participants | 1 Participants | 3 Participants | 1 Participants | 9 Participants | 1 Participants | 4 Participants | 35 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 8 Participants | 7 Participants | 7 Participants | 3 Participants | 4 Participants | 5 Participants | 28 Participants | 3 Participants | 15 Participants | 83 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 5 Participants | 4 Participants | 2 Participants | 3 Participants | 5 Participants | 18 Participants | 0 Participants | 5 Participants | 51 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 6 Participants | 6 Participants | 3 Participants | 4 Participants | 1 Participants | 16 Participants | 4 Participants | 16 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 6 / 10 | 5 / 11 | 5 / 10 | 3 / 5 | 6 / 7 | 3 / 6 | 18 / 34 | 1 / 4 | 7 / 21 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 10 / 10 | 11 / 11 | 10 / 10 | 5 / 5 | 7 / 7 | 6 / 6 | 31 / 34 | 4 / 4 | 21 / 21 | 0 / 1 | 0 / 1 |
| serious Total, serious adverse events | 1 / 3 | 5 / 10 | 2 / 11 | 1 / 10 | 1 / 5 | 3 / 7 | 4 / 6 | 8 / 34 | 4 / 4 | 7 / 21 | 0 / 1 | 0 / 1 |
Outcome results
Primary
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.
Time frame: Up to 28 days
Population: DLT evaluable population included only those participants who completed the DLT observation period throughout the course of 2 TSR-033 administrations (Day 1 and Day 15 in the first 28 days of study treatment) for Part 1A unless the participant discontinued TSR-033 (Part 1A) due to a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) | 1 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) | 0 Participants |
Primary
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.
Time frame: Up to 42 days
Population: DLT evaluable population included the assessment of DLTs in Part 1C included only those participants who completed the DLT observation period throughout the course of 2 TSR-033 + dostarlimab administrations (Day 1 and Day 21 in the first 42 days of study treatment), for Part 1C unless the participant discontinued TSR-033 + dostarlimab (Part 1C) due to a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1C: Number of Participants Experiencing DLT | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1C: Number of Participants Experiencing DLT | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1C: Number of Participants Experiencing DLT | 0 Participants |
Primary
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.
Time frame: Up to 51 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Creatinine | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Bilirubin | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Alkaline phosphatase | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Bilirubin | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Alkaline phosphatase | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Creatinine | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Creatinine | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Alkaline phosphatase | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Bilirubin | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Bilirubin | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Alkaline phosphatase | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Creatinine | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Bilirubin | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Alkaline phosphatase | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Creatinine | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Alkaline phosphatase | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Creatinine | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Bilirubin | 1 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Creatinine | 1 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Bilirubin | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase | Alkaline phosphatase | 1 Participants |
Primary
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.
Time frame: Up to 51 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hyperkalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypomagnesemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypokalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypoalbuminemia, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hyperkalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypomagnesemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypoalbuminemia, Grade 2 to Grade 3 | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypokalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypomagnesemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hyperkalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypoalbuminemia, Grade 2 to Grade 3 | 1 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypokalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypoalbuminemia, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypomagnesemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hyperkalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypokalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypokalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypoalbuminemia, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypomagnesemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hyperkalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hyperkalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypoalbuminemia, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypokalemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypomagnesemia, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypoalbuminemia, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hyperkalemia, Grade 0 to Grade 3 | 1 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypomagnesemia, Grade 0 to Grade 3 | 1 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypokalemia, Grade 0 to Grade 3 | 1 Participants |
Primary
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.
Time frame: Up to 51 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 1 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 3 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 2 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 1 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 3 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 3 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 1 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 1 to Grade 3 | 1 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 1 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 3 to Grade 3 | 1 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 1 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 3 to Grade 3 | 2 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 1 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 1 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 3 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 1 to Grade 3 | 1 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 3 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 1 to Grade 3 | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 2 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 1 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 1 Participants |
Primary
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.
Time frame: Up to 51 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QRS | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcF | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | PR Interval | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcB | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Heart Rate | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | PR Interval | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Heart Rate | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QRS | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcB | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcF | 2 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | PR Interval | 1 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QRS | 2 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Heart Rate | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcF | 1 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcB | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QRS | 1 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcF | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcB | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Heart Rate | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | PR Interval | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcF | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | PR Interval | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QRS | 0 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Heart Rate | 1 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcB | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcF | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | PR Interval | 0 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Heart Rate | 1 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcB | 1 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QRS | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | Heart Rate | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcB | 1 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QRS | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | QTcF | 0 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results | PR Interval | 0 Participants |
Primary
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.
Time frame: Up to approximately 51 months
Population: Safety population included all participants who receive any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | irAEs | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | TEAEs | 3 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | SAEs | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | TEAEs | 10 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | SAEs | 5 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | irAEs | 4 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | irAEs | 2 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | SAEs | 2 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | TEAEs | 10 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | TEAEs | 10 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | SAEs | 1 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | irAEs | 2 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | TEAEs | 5 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | SAEs | 1 Participants |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | irAEs | 2 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | SAEs | 3 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | irAEs | 3 Participants |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | TEAEs | 7 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | irAEs | 4 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | TEAEs | 6 Participants |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) | SAEs | 4 Participants |
Primary
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.
Time frame: Up to 30 months
Population: Efficacy population included all participants who received any amount of TSR-033.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2A: Objective Response Rate (ORR) | 2.9 Percentage of participants |
Primary
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.
Time frame: Up to 30 days
Population: DLT evaluable population included the assessment of DLTs in Part 2B included only those participants completing the DLT observation period throughout the course of 2 TSR-033 + dostarlimab administrations (Day 3 and Day 17 in the first 30 days of study treatment), for Part 2B unless the participant discontinued TSR-033 + dostarlimab (Part 2B) due to a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants Experiencing DLT | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants Experiencing DLT | 0 Participants |
Primary
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.
Time frame: Up to 29 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Alanine aminotransferase | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Aspartate aminotransferase | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Bilirubin | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Creatinine | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Creatinine | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Alanine aminotransferase | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Bilirubin | 2 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin | Aspartate aminotransferase | 1 Participants |
Primary
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.
Time frame: Up to 29 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypercalcemia, Grade 0 to Grade 4 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypocalcemia, Grade 0 to Grade 4 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypercalcemia, Grade 0 to Grade 4 | 2 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters | Hypocalcemia, Grade 0 to Grade 4 | 2 Participants |
Primary
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.
Time frame: Up to 29 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 4 | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Platelets, Grade 0 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 4 | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | WBC (Leukopenia), Grade 0 to Grade 3 | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | WBC (Leukopenia), Grade 0 to Grade 4 | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | WBC (Leukopenia), Grade 0 to Grade 4 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Hemoglobin, Grade 2 to Grade 3 | 2 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 3 | 2 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 0 to Grade 4 | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Lymphocytes, Grade 2 to Grade 3 | 4 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 3 | 8 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Neutrophils, Grade 0 to Grade 4 | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | Platelets, Grade 0 to Grade 3 | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters | WBC (Leukopenia), Grade 0 to Grade 3 | 4 Participants |
Primary
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.
Time frame: Up to 29 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | QTcB | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | Heart Rate | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | QRS | 1 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | PR Interval | 0 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | QTcF | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | PR Interval | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | QTcF | 2 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | QTcB | 5 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | QRS | 2 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Post Baseline Abnormal ECG Results | Heart Rate | 2 Participants |
Primary
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.
Time frame: Up to approximately 29 months
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With SAEs, TEAEs and irAEs | SAEs | 4 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With SAEs, TEAEs and irAEs | TEAEs | 4 Participants |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With SAEs, TEAEs and irAEs | irAEs | 3 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With SAEs, TEAEs and irAEs | SAEs | 7 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With SAEs, TEAEs and irAEs | TEAEs | 21 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With SAEs, TEAEs and irAEs | irAEs | 11 Participants |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Population: Pharmacokinetic (PK) population included all partiocipants who received any amount of TSR 033 and/or dostarlimab and have ≥1 measurable drug concentration. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: Area Under the Concentration-time Curve From Time Zero to Last Measurable Concentration (AUC [0-last]) of TSR-033 | 606.4256 Hour*microgram/millilitre (h*ug/mL) | Geometric Coefficient of Variation 32.65 |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: Area Under the Concentration-time Curve From Time Zero to Last Measurable Concentration (AUC [0-last]) of TSR-033 | 2601.731 Hour*microgram/millilitre (h*ug/mL) | Geometric Coefficient of Variation 70.3423 |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: Area Under the Concentration-time Curve From Time Zero to Last Measurable Concentration (AUC [0-last]) of TSR-033 | 8176.4963 Hour*microgram/millilitre (h*ug/mL) | Geometric Coefficient of Variation 29.4644 |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: Area Under the Concentration-time Curve From Time Zero to Last Measurable Concentration (AUC [0-last]) of TSR-033 | 23763.7645 Hour*microgram/millilitre (h*ug/mL) | Geometric Coefficient of Variation 48.7606 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: AUC Extrapolated From Time Zero to Infinity (AUC [0-inf]) of TSR-033 | 858.3739 h*ug/mL | Geometric Coefficient of Variation 39.3306 |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: AUC Extrapolated From Time Zero to Infinity (AUC [0-inf]) of TSR-033 | 2783.4404 h*ug/mL | Geometric Coefficient of Variation 112.7081 |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: AUC Extrapolated From Time Zero to Infinity (AUC [0-inf]) of TSR-033 | 12517.0356 h*ug/mL | Geometric Coefficient of Variation 37.2816 |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: AUC Extrapolated From Time Zero to Infinity (AUC [0-inf]) of TSR-033 | 44300.8914 h*ug/mL | Geometric Coefficient of Variation 32.4781 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033 | 816.9529 h*ug/mL | Geometric Coefficient of Variation 32.427 |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033 | 3171.9548 h*ug/mL | Geometric Coefficient of Variation 52.272 |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033 | 9432.5708 h*ug/mL | Geometric Coefficient of Variation 23.5407 |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033 | 27125.0835 h*ug/mL | Geometric Coefficient of Variation 27.0846 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: Clearance (CL) of TSR-033 | 0.0233 Litre/ hour (L/h) | Geometric Coefficient of Variation 39.3306 |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: Clearance (CL) of TSR-033 | 0.0287 Litre/ hour (L/h) | Geometric Coefficient of Variation 112.7081 |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: Clearance (CL) of TSR-033 | 0.0192 Litre/ hour (L/h) | Geometric Coefficient of Variation 37.2816 |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: Clearance (CL) of TSR-033 | 0.0163 Litre/ hour (L/h) | Geometric Coefficient of Variation 32.4781 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: Maximum Concentration (Cmax) of TSR-033 | 7.489 ug/mL | Geometric Coefficient of Variation 30.807 |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: Maximum Concentration (Cmax) of TSR-033 | 22.81 ug/mL | Geometric Coefficient of Variation 29.88 |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: Maximum Concentration (Cmax) of TSR-033 | 74.13 ug/mL | Geometric Coefficient of Variation 21.35 |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: Maximum Concentration (Cmax) of TSR-033 | 217.1 ug/mL | Geometric Coefficient of Variation 34.8 |
Secondary
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.
Time frame: Up to 51 months
Population: Immunogenicity (ADA) population included all participants who received at least 1 dose of TSR-033 and who have at least 1 ADA sample with a result. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
Secondary
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.
Time frame: Up to 51 months
Population: Efficacy population included all participants who received any amount of TSR-033.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: Objective Response Rate (ORR) | 0 Percentage of participants |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: Objective Response Rate (ORR) | 0 Percentage of participants |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: Objective Response Rate (ORR) | 0 Percentage of participants |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: Objective Response Rate (ORR) | 0 Percentage of participants |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: Terminal Half-life (t1/2) of TSR-033 | 119.7937 Hour | Geometric Coefficient of Variation 19.1377 |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: Terminal Half-life (t1/2) of TSR-033 | 240.5387 Hour | Geometric Coefficient of Variation 72.7919 |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: Terminal Half-life (t1/2) of TSR-033 | 198.8801 Hour | Geometric Coefficient of Variation 39.3322 |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: Terminal Half-life (t1/2) of TSR-033 | 214.2533 Hour | Geometric Coefficient of Variation 32.6387 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1.5, 3, 24, 48, 96 and 168 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033 | 3.4821 Litre | Geometric Coefficient of Variation 36.6086 |
| Part 1AB - TSR-033 (80 mg) | Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033 | 5.0563 Litre | Geometric Coefficient of Variation 33.1027 |
| Part 1AB - TSR-033 (240 mg) | Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033 | 4.8329 Litre | Geometric Coefficient of Variation 21.6021 |
| Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) | Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033 | 5.2564 Litre | Geometric Coefficient of Variation 31.2434 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab | TSR-033 | 3201.6715 h*ug/mL | Geometric Coefficient of Variation 35.5887 |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab | Dostarlimab | 30692.5087 h*ug/mL | Geometric Coefficient of Variation 26.1453 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab | TSR-033 | 12336.2784 h*ug/mL | Geometric Coefficient of Variation 26.1779 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab | Dostarlimab | 34298.0046 h*ug/mL | — |
| Part 1AB - TSR-033 (240 mg) | Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab | TSR-033 | 52144.2561 h*ug/mL | Geometric Coefficient of Variation 15.6182 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab | Dostarlimab | 37944.78 h*ug/mL | Geometric Coefficient of Variation 25.3851 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: AUC (0-last) of TSR-033 and Dostarlimab | TSR-033 | 2615.4485 h*ug/mL | Geometric Coefficient of Variation 33.8335 |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: AUC (0-last) of TSR-033 and Dostarlimab | Dostarlimab | 24303.8328 h*ug/mL | Geometric Coefficient of Variation 31.4148 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: AUC (0-last) of TSR-033 and Dostarlimab | TSR-033 | 9317.8306 h*ug/mL | Geometric Coefficient of Variation 21.9902 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: AUC (0-last) of TSR-033 and Dostarlimab | Dostarlimab | 25301.7468 h*ug/mL | Geometric Coefficient of Variation 17.9326 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: AUC (0-last) of TSR-033 and Dostarlimab | TSR-033 | 30750.7484 h*ug/mL | Geometric Coefficient of Variation 28.6869 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: AUC (0-last) of TSR-033 and Dostarlimab | Dostarlimab | 26326.0589 h*ug/mL | Geometric Coefficient of Variation 26.9526 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: AUCtau of TSR-033 and Dostarlimab | TSR-033 | 2929.7274 h*ug/mL | Geometric Coefficient of Variation 34.6086 |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: AUCtau of TSR-033 and Dostarlimab | Dostarlimab | 29866.3126 h*ug/mL | Geometric Coefficient of Variation 33.313 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: AUCtau of TSR-033 and Dostarlimab | TSR-033 | 11351.945 h*ug/mL | Geometric Coefficient of Variation 26.8461 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: AUCtau of TSR-033 and Dostarlimab | Dostarlimab | 32396.6385 h*ug/mL | Geometric Coefficient of Variation 19.5917 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: AUCtau of TSR-033 and Dostarlimab | TSR-033 | 39920.9217 h*ug/mL | Geometric Coefficient of Variation 19.2402 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: AUCtau of TSR-033 and Dostarlimab | Dostarlimab | 32702.9638 h*ug/mL | Geometric Coefficient of Variation 31.1208 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: CL of TSR-033 and Dostarlimab | TSR-033 | 0.025 L/h | Geometric Coefficient of Variation 35.5887 |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: CL of TSR-033 and Dostarlimab | Dostarlimab | 0.0163 L/h | Geometric Coefficient of Variation 26.1453 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: CL of TSR-033 and Dostarlimab | TSR-033 | 0.0195 L/h | Geometric Coefficient of Variation 26.1779 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: CL of TSR-033 and Dostarlimab | Dostarlimab | 0.0146 L/h | — |
| Part 1AB - TSR-033 (240 mg) | Part 1c: CL of TSR-033 and Dostarlimab | TSR-033 | 0.0138 L/h | Geometric Coefficient of Variation 15.6182 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: CL of TSR-033 and Dostarlimab | Dostarlimab | 0.0132 L/h | Geometric Coefficient of Variation 25.3851 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: Cmax of TSR-033 and Dostarlimab | TSR-033 | 23.04 ug/mL | Geometric Coefficient of Variation 29.09 |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: Cmax of TSR-033 and Dostarlimab | Dostarlimab | 171.6 ug/mL | Geometric Coefficient of Variation 34.5 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: Cmax of TSR-033 and Dostarlimab | TSR-033 | 73.5 ug/mL | Geometric Coefficient of Variation 13.8 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: Cmax of TSR-033 and Dostarlimab | Dostarlimab | 163 ug/mL | Geometric Coefficient of Variation 17.2 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: Cmax of TSR-033 and Dostarlimab | TSR-033 | 312.8 ug/mL | Geometric Coefficient of Variation 79.4 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: Cmax of TSR-033 and Dostarlimab | Dostarlimab | 170.8 ug/mL | Geometric Coefficient of Variation 27 |
Secondary
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.
Time frame: Up to 29 months
Population: Immunogenicity (ADA) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: Number of Participants With Anti-TSR-033 Antibodies | 1 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 1c: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
| Part 1AB - TSR-033 (240 mg) | Part 1c: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
Secondary
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.
Time frame: Up to 29 months
Population: Efficacy population included all participants who received any amount of TSR-033.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: Objective Response Rate (ORR) | 0 Percentage of participants |
| Part 1AB - TSR-033 (80 mg) | Part 1c: Objective Response Rate (ORR) | 0 Percentage of participants |
| Part 1AB - TSR-033 (240 mg) | Part 1c: Objective Response Rate (ORR) | 0 Percentage of participants |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: t1/2 of TSR-033 and Dostarlimab | TSR-033 | 140.4589 Hour | Geometric Coefficient of Variation 18.3381 |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: t1/2 of TSR-033 and Dostarlimab | Dostarlimab | 259.3884 Hour | Geometric Coefficient of Variation 33.9148 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: t1/2 of TSR-033 and Dostarlimab | TSR-033 | 241.0348 Hour | Geometric Coefficient of Variation 25.7829 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: t1/2 of TSR-033 and Dostarlimab | Dostarlimab | 318.7548 Hour | Geometric Coefficient of Variation 18.7546 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: t1/2 of TSR-033 and Dostarlimab | TSR-033 | 226.5019 Hour | Geometric Coefficient of Variation 26.7142 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: t1/2 of TSR-033 and Dostarlimab | Dostarlimab | 286.253 Hour | Geometric Coefficient of Variation 23.726 |
Secondary
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.
Time frame: Pre-dose and post-dose 15 minute, 30 minute, 1, 1.5, 3, 24, 48, 96, 168, 336 and 504 hour
Population: Pharmacokinetic (PK) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: Vss of TSR-033 and Dostarlimab | TSR-033 | 4.8162 Litre | Geometric Coefficient of Variation 36.8613 |
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1c: Vss of TSR-033 and Dostarlimab | Dostarlimab | 4.4915 Litre | Geometric Coefficient of Variation 36.0302 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: Vss of TSR-033 and Dostarlimab | TSR-033 | 5.3978 Litre | Geometric Coefficient of Variation 17.3282 |
| Part 1AB - TSR-033 (80 mg) | Part 1c: Vss of TSR-033 and Dostarlimab | Dostarlimab | 4.6431 Litre | Geometric Coefficient of Variation 13.0127 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: Vss of TSR-033 and Dostarlimab | TSR-033 | 4.3845 Litre | Geometric Coefficient of Variation 32.7955 |
| Part 1AB - TSR-033 (240 mg) | Part 1c: Vss of TSR-033 and Dostarlimab | Dostarlimab | 4.3544 Litre | Geometric Coefficient of Variation 34.1792 |
Secondary
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.
Time frame: Up to 29 months
Population: Efficacy population. Only responders by investigator assessment were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2A: Disease Control Rate (DCR) | 8.8 Percentage of participants |
Secondary
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.
Time frame: Up to 29 months
Population: Efficacy population. Only responders by investigator assessment were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2A: Duration of Response (DOR) | 23.3 Months |
Secondary
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.
Time frame: Up to 29 months
Population: Immunogenicity (ADA) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2A: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
Secondary
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.
Time frame: Up to 29 months
Population: Efficacy population. Only responders by investigator assessment were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Disease Control Rate (DCR) | 50 Percentage of participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Disease Control Rate (DCR) | 80 Percentage of participants |
Secondary
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.
Time frame: Up to 29 months
Population: Efficacy population. Only responders by investigator assessment were included in this analysis. There were no responders in the arm Part 2B1, hence the participants analysed in 0.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1AB - TSR-033 (80 mg) | Part 2B: Duration of Response (DOR) | 14.1 Months |
Secondary
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.
Time frame: Up to 29 months
Population: Immunogenicity (ADA) population. Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Number of Participants With Anti-TSR-033 Antibodies | 0 Participants |
Secondary
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.
Time frame: Up to 29 months
Population: Efficacy population included all participants who received any amount of TSR-033.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 2B: Objective Response Rate (ORR) | 0 Percentage of participants |
| Part 1AB - TSR-033 (80 mg) | Part 2B: Objective Response Rate (ORR) | 20 Percentage of participants |