A Phase 1 interventional study of TSR-033 and Dostarlimab in Neoplasms, sponsored by Tesaro, Inc.. Completed at 12 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-04-11.
Sponsored by Tesaro, Inc. (part of GlaxoSmithKline) · Phase 1, Interventional, and Treatment
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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.
10,824 studies on the registry are indexed under Neoplasms; 2,325 are open to participants now.
This study's enrollment of 111 is above the median of 60 across 7,706 interventional studies indexed under Neoplasms.
Browse Neoplasms studies →Tesaro, Inc. is the lead sponsor of 33 studies on the registry; none are open to participants now.
Of its 12 completed or terminated interventional studies of FDA-regulated products, 12 (100%) have results posted.
First submitted before Tesaro, Inc. became part of GlaxoSmithKline.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria for participants in Part 1:
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 or be of non-childbearing potential. Non-childbearing potential is defined as:
The participant has adequate hematologic and organ function, defined as:
Inclusion criteria for participants in Part 2:
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:
The participant has adequate hematologic and organ function, defined as:
Inclusion Criteria for participants in Part 2A:
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:
Inclusion Criteria for participants in Part 2B:
Inclusion Criteria for participants in Part 2 Cohort B1:
Inclusion Criteria for participants in Part 2 Cohort B2:
Exclusion Criteria for all participants:
Exclusion Criteria for participants in Part 1:
Exclusion Criteria for participants in Part 2:
Exclusion Criteria for participants in Part 2B:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
The standard rules for measuring tumours on CT or MRI scans, to tell whether a cancer is shrinking, stable or growing during treatment.
“Measurable disease per RECIST 1.1” usually means at least one tumour 10 mm or more at its longest on a CT scan, or a lymph node 15 mm or more across its short axis.
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
A “mini-stroke”: temporary stroke-like symptoms caused by reduced blood flow to part of the brain, spinal cord or eye, without signs of a new stroke on a scan.
Stroke symptoms need emergency care at once, even if they go away.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
PD-1, PD-L1 and CTLA-4 are proteins that act as brakes on the immune system. Checkpoint inhibitors, such as pembrolizumab or nivolumab, block them so the immune system can attack a cancer.
PD-L1 can also be measured in a tumour sample. Some scores count stained tumour cells only (TPS); others also count certain immune cells (CPS). The study names the score and the minimum it uses.
Histologically or cytologically confirmed
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
INR, PT and aPTT (clotting tests)
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Measurable disease
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
RECIST
The standard rules for measuring tumours on CT or MRI scans, to tell whether a cancer is shrinking, stable or growing during treatment.
“Measurable disease per RECIST 1.1” usually means at least one tumour 10 mm or more at its longest on a CT scan, or a lymph node 15 mm or more across its short axis.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CTCAE grade
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Line of therapy
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Adjuvant and neoadjuvant
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Autoimmune disease
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
TIA (transient ischaemic attack)
A “mini-stroke”: temporary stroke-like symptoms caused by reduced blood flow to part of the brain, spinal cord or eye, without signs of a new stroke on a scan.
Stroke symptoms need emergency care at once, even if they go away.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
PD-1, PD-L1 and checkpoint inhibitors
PD-1, PD-L1 and CTLA-4 are proteins that act as brakes on the immune system. Checkpoint inhibitors, such as pembrolizumab or nivolumab, block them so the immune system can attack a cancer.
PD-L1 can also be measured in a tumour sample. Some scores count stained tumour cells only (TPS); others also count certain immune cells (CPS). The study names the score and the minimum it uses.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Part 1a will evaluate TSR-033 at ascending doses (20 milligrams \[mg\], 80 mg and 240 mg) every 2 weeks. Cohorts will be enrolled sequentially and will initially follow a 3+3 design at a starting dose of 20 mg.
Drug: TSR-033
Part 1b will evaluate the PK profile and assess PDy data from blood and tumor tissue samples following TSR-033 treatment. The participants will begin treatment with TSR-033 on Day 1 followed by 28 days observation for collection of blood sampling for PK/PDy. Participants will receive their second dose of TSR-033 on Day 29 and every 14 days thereafter.
Drug: TSR-033
Participants will be administered ascending doses of TSR-033 in combination with dostarlimab 500 mg every 3 weeks. Planned dose levels of TSR-033 include 80 and 240 mg.
Drug: TSR-033 · Drug: Dostarlimab
Part 2 Cohort A will evaluate the preliminary activity of TSR-033 in combination with dostarlimab in anti-PD-1 naive participants with third and fourth line MSS-CRC. TSR-033 will be administered every 2 weeks and dostarlimab every 6 weeks.
Drug: TSR-033 · Drug: Dostarlimab
Part 2 Cohort B1 will evaluate the preliminary activity of TSR-033 administered every 2 weeks (Q2W) in combination with dostarlimab administered every 6 weeks (Q6W) along with mFOLFOX6 and bevacizumab (standard of care \[SOC\]) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFIRI, with or without biologics.
Drug: TSR-033 · Drug: Dostarlimab · Drug: mFOLFOX6 · Drug: Bevacizumab
Part 2 Cohort B2 will evaluate the preliminary activity of TSR-033 in combination with FOLFIRI and bevacizumab (SOC) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFOX, with or without biologics.
Drug: TSR-033 · Drug: Dostarlimab · Drug: FOLFIRI · Drug: Bevacizumab
TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4.
Also known as: LAG-3
Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody.
mFOLFOX6 is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) which acts as systemic cytotoxic agent.
FOLFIRI is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and irinotecan (IRI) which acts as systemic cytotoxic agent.
Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
| Milestone | 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 | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 3 | 10 | 11 | 10 | 5 | 7 | 6 | 0 | 0 | 0 | 0 | 0 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 3 | 10 | 11 | 10 | 5 | 7 | 6 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Death | 1 | 6 | 5 | 5 | 3 | 6 | 3 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 2 | 4 | 5 | 5 | 2 | 1 | 3 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Sponsor decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Milestone | 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 | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 34 | 0 | 0 | 0 | 0 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 33 | 0 | 0 | 0 | 0 |
| Withdrew: Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 18 | 0 | 0 | 0 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 8 | 0 | 0 | 0 | 0 |
| Withdrew: Sponsor decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
| Withdrew: Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Milestone | 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 | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 21 | 0 | 0 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 20 | 0 | 0 |
| Withdrew: Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 7 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 7 | 0 | 0 |
| Withdrew: Sponsor decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 |
| Milestone | 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 | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
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.
| Hour*microgram/millilitre (h*ug/mL) | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | 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 | 606.4256 ± 32.65 | 2601.731 ± 70.3423 | 8176.4963 ± 29.4644 | 23763.7645 ± 48.7606 |
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.
| h*ug/mL | 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) |
|---|---|---|---|
| TSR-033 | 2615.4485 ± 33.8335 | 9317.8306 ± 21.9902 | 30750.7484 ± 28.6869 |
| Dostarlimab | 24303.8328 ± 31.4148 | 25301.7468 ± 17.9326 | 26326.0589 ± 26.9526 |
Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.
| h*ug/mL | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | 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 | 858.3739 ± 39.3306 | 2783.4404 ± 112.7081 | 12517.0356 ± 37.2816 | 44300.8914 ± 32.4781 |
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.
| h*ug/mL | 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) |
|---|---|---|---|
| TSR-033 | 3201.6715 ± 35.5887 | 12336.2784 ± 26.1779 | 52144.2561 ± 15.6182 |
| Dostarlimab | 30692.5087 ± 26.1453 | 34298.0046 ± NA | 37944.78 ± 25.3851 |
Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.
| h*ug/mL | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033 | 816.9529 ± 32.427 | 3171.9548 ± 52.272 | 9432.5708 ± 23.5407 | 27125.0835 ± 27.0846 |
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.
| h*ug/mL | 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) |
|---|---|---|---|
| TSR-033 | 2929.7274 ± 34.6086 | 11351.945 ± 26.8461 | 39920.9217 ± 19.2402 |
| Dostarlimab | 29866.3126 ± 33.313 | 32396.6385 ± 19.5917 | 32702.9638 ± 31.1208 |
Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.
| ug/mL | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1ab: Maximum Concentration (Cmax) of TSR-033 | 7.489 ± 30.807 | 22.81 ± 29.88 | 74.13 ± 21.35 | 217.1 ± 34.8 |
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.
| ug/mL | 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) |
|---|---|---|---|
| TSR-033 | 23.04 ± 29.09 | 73.5 ± 13.8 | 312.8 ± 79.4 |
| Dostarlimab | 171.6 ± 34.5 | 163 ± 17.2 | 170.8 ± 27 |
Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.
| Litre/ hour (L/h) | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1ab: Clearance (CL) of TSR-033 | 0.0233 ± 39.3306 | 0.0287 ± 112.7081 | 0.0192 ± 37.2816 | 0.0163 ± 32.4781 |
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.
| L/h | 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) |
|---|---|---|---|
| TSR-033 | 0.025 ± 35.5887 | 0.0195 ± 26.1779 | 0.0138 ± 15.6182 |
| Dostarlimab | 0.0163 ± 26.1453 | 0.0146 ± NA | 0.0132 ± 25.3851 |
Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.
| Litre | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033 | 3.4821 ± 36.6086 | 5.0563 ± 33.1027 | 4.8329 ± 21.6021 | 5.2564 ± 31.2434 |
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.
| Litre | 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) |
|---|---|---|---|
| TSR-033 | 4.8162 ± 36.8613 | 5.3978 ± 17.3282 | 4.3845 ± 32.7955 |
| Dostarlimab | 4.4915 ± 36.0302 | 4.6431 ± 13.0127 | 4.3544 ± 34.1792 |
Blood samples were collected for PK analysis of TSR-033 when administered intravenously as monotherapy. PK parameter was determined using standard non-compartmental methods.
| Hour | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1ab: Terminal Half-life (t1/2) of TSR-033 | 119.7937 ± 19.1377 | 240.5387 ± 72.7919 | 198.8801 ± 39.3322 | 214.2533 ± 32.6387 |
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.
| Hour | 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) |
|---|---|---|---|
| TSR-033 | 140.4589 ± 18.3381 | 241.0348 ± 25.7829 | 226.5019 ± 26.7142 |
| Dostarlimab | 259.3884 ± 33.9148 | 318.7548 ± 18.7546 | 286.253 ± 23.726 |
Serum samples will be collected and tested for the presence of antibodies to TSR-033.
| Participants | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1ab: Number of Participants With Anti-TSR-033 Antibodies | 0 | 0 | 0 | 0 |
Serum samples will be collected and tested for the presence of antibodies to TSR-033.
| Participants | 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 1c: Number of Participants With Anti-TSR-033 Antibodies | 1 | 0 | 0 |
Serum samples will be collected and tested for the presence of antibodies to TSR-033.
| Participants | Part 2A - TSR-033 (720 mg) + Dostarlimab (1000 mg) |
|---|---|
| Part 2A: Number of Participants With Anti-TSR-033 Antibodies | 0 |
Serum samples will be collected and tested for the presence of antibodies to TSR-033.
| Participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Part 2B: Number of Participants With Anti-TSR-033 Antibodies | 0 | 0 |
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.
| Percentage of participants | Part 1AB - TSR-033 [20 Milligrams (mg)] | Part 1AB - TSR-033 (80 mg) | Part 1AB - TSR-033 (240 mg) | Part 1AB: TSR-033:Part 1AB - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1ab: Objective Response Rate (ORR) | 0 (0 to 70.8) | 0 (0 to 30.8) | 0 (0 to 28.5) | 0 (0 to 30.8) |
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.
| Percentage of participants | 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 1c: Objective Response Rate (ORR) | 0 (0 to 52.2) | 0 (0 to 41) | 0 (0 to 45.9) |
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.
| Percentage of participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Part 2B: Objective Response Rate (ORR) | 0 (0 to 60.2) | 20 (5.7 to 43.7) |
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.
| Months | Part 2A - TSR-033 (720 mg) + Dostarlimab (1000 mg) |
|---|---|
| Part 2A: Duration of Response (DOR) | 23.3 (23.3 to 23.3) |
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.
| Months | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Part 2B: Duration of Response (DOR) | — | 14.1 (6.7 to 19.2) |
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.
| Percentage of participants | Part 2A - TSR-033 (720 mg) + Dostarlimab (1000 mg) |
|---|---|
| Part 2A: Disease Control Rate (DCR) | 8.8 (1.9 to 23.7) |
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.
| Percentage of participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Part 2B: Disease Control Rate (DCR) | 50 (6.8 to 93.2) | 80 (56.3 to 94.3) |
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.
| Participants | Part 1A - TSR-033 [20 Milligrams (mg)] | Part 1A - TSR-033 (80 mg) | Part 1A - TSR-033 (240 mg) | Part 1A - TSR-033 (720 mg) |
|---|---|---|---|---|
| Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) | 0 | 1 | 0 | 0 |
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.
| Participants | 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 1C: Number of Participants Experiencing DLT | 0 | 0 | 0 |
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.
| Participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Part 2B: Number of Participants Experiencing DLT | 0 | 0 |
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.
| Participants | 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) |
|---|---|---|---|---|---|---|---|
| SAEs | 1 | 5 | 2 | 1 | 1 | 3 | 4 |
| TEAEs | 3 | 10 | 10 | 10 | 5 | 7 | 6 |
| irAEs | 0 | 4 | 2 | 2 | 2 | 3 | 4 |
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.
| Participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| SAEs | 4 | 7 |
| TEAEs | 4 | 21 |
| irAEs | 3 | 11 |
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.
| Participants | 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) |
|---|---|---|---|---|---|---|---|
| Hemoglobin, Grade 1 to Grade 3 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Hemoglobin, Grade 2 to Grade 3 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Lymphocytes, Grade 0 to Grade 3 | 0 | 2 | 0 | 0 | 1 | 1 | 1 |
| Lymphocytes, Grade 2 to Grade 3 | 0 | 0 | 0 | 1 | 0 | 0 | 2 |
| Lymphocytes, Grade 3 to Grade 3 | 0 | 0 | 0 | 1 | 2 | 0 | 0 |
| Neutrophils, Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
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.
| Participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Hemoglobin, Grade 2 to Grade 3 | 0 | 2 |
| Lymphocytes, Grade 0 to Grade 3 | 1 | 2 |
| Lymphocytes, Grade 0 to Grade 4 | 1 | 0 |
| Lymphocytes, Grade 2 to Grade 3 | 0 | 4 |
| Neutrophils, Grade 0 to Grade 3 | 1 | 8 |
| Neutrophils, Grade 0 to Grade 4 | 1 | 1 |
| Platelets, Grade 0 to Grade 3 | 0 | 1 |
| WBC (Leukopenia), Grade 0 to Grade 3 | 1 | 4 |
| WBC (Leukopenia), Grade 0 to Grade 4 | 1 | 0 |
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.
| Participants | 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) |
|---|---|---|---|---|---|---|---|
| Hyperkalemia, Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Hypoalbuminemia, Grade 2 to Grade 3 | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Hypokalemia, Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Hypomagnesemia, Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
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.
| Participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Hypercalcemia, Grade 0 to Grade 4 | 0 | 2 |
| Hypocalcemia, Grade 0 to Grade 4 | 0 | 2 |
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.
| Participants | 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) |
|---|---|---|---|---|---|---|---|
| Alkaline phosphatase | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Bilirubin | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Creatinine | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
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.
| Participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| Alanine aminotransferase | 1 | 0 |
| Aspartate aminotransferase | 1 | 1 |
| Bilirubin | 1 | 2 |
| Creatinine | 0 | 1 |
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.
| Participants | 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) |
|---|---|---|---|---|---|---|---|
| QTcF | 1 | 2 | 1 | 0 | 0 | 0 | 0 |
| QTcB | 1 | 1 | 0 | 0 | 0 | 1 | 1 |
| QRS | 0 | 0 | 2 | 1 | 0 | 0 | 0 |
| Heart Rate | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| PR Interval | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
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.
| Participants | Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|
| QTcF | 1 | 2 |
| QTcB | 1 | 5 |
| QRS | 1 | 2 |
| Heart Rate | 0 | 2 |
| PR Interval | 0 | 1 |
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.
| Percentage of participants | Part 2A - TSR-033 (720 mg) + Dostarlimab (1000 mg) |
|---|---|
| Part 2A: Objective Response Rate (ORR) | 2.9 (0.1 to 15.3) |
Collected over All cause mortality, non-serious adverse events (Non-SAEs) and serious adverse events (SAEs) were collected maximum up to 51 months for Part 1 and up to approximately 29 months for Part 2A and up to 29 months for Part 2B and and from month 51 to week 36 for PACT phase.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part 1AB - TSR-033 [20 Milligrams (mg)] | 1/3 (33.3%) | 1/3 (33.3%) | 3/3 (100%) |
| Part 1AB - TSR-033 (80 mg) | 6/10 (60%) | 5/10 (50%) | 10/10 (100%) |
| Part 1AB - TSR-033 (240 mg) | 5/11 (45.5%) | 2/11 (18.2%) | 11/11 (100%) |
| Part 1AB - TSR-033 (720 mg) | 5/10 (50%) | 1/10 (10%) | 10/10 (100%) |
| Part 1C - TSR-033 (80 mg) + Dostarlimab (500 mg) | 3/5 (60%) | 1/5 (20%) | 5/5 (100%) |
| Part 1C - TSR-033 (240 mg) + Dostarlimab (500 mg) | 6/7 (85.7%) | 3/7 (42.9%) | 7/7 (100%) |
| Part 1C - TSR-033 (720 mg) + Dostarlimab (500 mg) | 3/6 (50%) | 4/6 (66.7%) | 6/6 (100%) |
| Part 2A - TSR-033 (720 mg) + Dostarlimab (1000 mg) | 18/34 (52.9%) | 8/34 (23.5%) | 31/34 (91.2%) |
| Part 2B1 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev + mFOLFOX6 | 1/4 (25%) | 4/4 (100%) | 4/4 (100%) |
| Part 2B2 - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI | 7/21 (33.3%) | 7/21 (33.3%) | 21/21 (100%) |
| PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| Event | 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 | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 1/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 0/6 | 0/34 | 0/4 | 0/21 | 0/1 | 0/1 |
| CholecystitisHepatobiliary disorders | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 0/6 | 0/34 | 1/4 | 0/21 | 0/1 | 0/1 |
| Neutropenic sepsisInfections and infestations | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 0/6 | 0/34 | 1/4 | 0/21 | 0/1 | 0/1 |
| PyelonephritisInfections and infestations | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 0/6 | 0/34 | 1/4 | 0/21 | 0/1 | 0/1 |
| Infusion related reactionInjury, poisoning and procedural complications | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 0/6 | 0/34 | 1/4 | 0/21 | 0/1 | 0/1 |
| PneumothoraxRespiratory, thoracic and mediastinal disorders | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 0/6 | 0/34 | 1/4 | 0/21 | 0/1 | 0/1 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 0/3 | 0/10 | 0/11 | 0/10 | 1/5 | 0/7 | 0/6 | 0/34 | 0/4 | 1/21 | 0/1 | 0/1 |
| AnaemiaBlood and lymphatic system disorders | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 1/6 | 0/34 | 0/4 | 0/21 | 0/1 | 0/1 |
| Pericardial effusionCardiac disorders | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 1/6 | 0/34 | 0/4 | 0/21 | 0/1 | 0/1 |
| EnteritisGastrointestinal disorders | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 1/6 | 0/34 | 0/4 | 0/21 | 0/1 | 0/1 |
| Event | 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 | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) | PACT Phase - TSR-033 (720 mg) + Dostarlimab (1000 mg) + Bev +FOLFIRI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DiarrhoeaGastrointestinal disorders | 0/3 | 0/10 | 1/11 | 1/10 | 0/5 | 1/7 | 2/6 | 2/34 | 3/4 | 10/21 | 0/1 | 0/1 |
| FatigueGeneral disorders | 1/3 | 1/10 | 0/11 | 2/10 | 2/5 | 3/7 | 3/6 | 10/34 | 3/4 | 10/21 | 0/1 | 0/1 |
| NauseaGastrointestinal disorders | 0/3 | 3/10 | 2/11 | 1/10 | 2/5 | 0/7 | 4/6 | 7/34 | 2/4 | 11/21 | 0/1 | 0/1 |
| Decreased appetiteMetabolism and nutrition disorders | 0/3 | 4/10 | 1/11 | 2/10 | 1/5 | 1/7 | 4/6 | 6/34 | 1/4 | 4/21 | 0/1 | 0/1 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 2/3 | 1/10 | 3/11 | 3/10 | 1/5 | 2/7 | 2/6 | 5/34 | 1/4 | 3/21 | 0/1 | 0/1 |
| VomitingGastrointestinal disorders | 0/3 | 2/10 | 1/11 | 2/10 | 3/5 | 1/7 | 2/6 | 5/34 | 2/4 | 5/21 | 0/1 | 0/1 |
| Blood alkaline phosphatase increasedInvestigations | 0/3 | 0/10 | 0/11 | 1/10 | 1/5 | 0/7 | 3/6 | 3/34 | 0/4 | 0/21 | 0/1 | 0/1 |
| Neutrophil count decreasedInvestigations | 0/3 | 0/10 | 0/11 | 0/10 | 0/5 | 0/7 | 0/6 | 0/34 | 2/4 | 7/21 | 0/1 | 0/1 |
| Tumour painNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/3 | 1/10 | 1/11 | 0/10 | 1/5 | 0/7 | 3/6 | 2/34 | 0/4 | 0/21 | 0/1 | 0/1 |
| DizzinessNervous system disorders | 0/3 | 0/10 | 2/11 | 1/10 | 0/5 | 0/7 | 0/6 | 0/34 | 2/4 | 5/21 | 0/1 | 0/1 |
| Age, Customized(Participants) | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 19 - 64 years | 1 | 5 | 6 | 6 | 4 | 4 | 5 | 25 | 3 | 17 | 76 |
| >=65 years | 2 | 5 | 5 | 4 | 1 | 3 | 1 | 9 | 1 | 4 | 35 |
| Sex: Female, Male(Participants) | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | 2 | 7 | 5 | 4 | 2 | 3 | 5 | 18 | 0 | 5 | 51 |
| Male | 1 | 3 | 6 | 6 | 3 | 4 | 1 | 16 | 4 | 16 | 60 |
| Race/Ethnicity, Customized(Participants) | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| White | 3 | 8 | 7 | 7 | 3 | 4 | 5 | 28 | 3 | 15 | 83 |
| Black | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 4 | 0 | 3 | 9 |
| Asian | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 4 |
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 3 |
| Other | 0 | 1 | 4 | 1 | 0 | 3 | 1 | 1 | 0 | 1 | 12 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Aug 2017 to primary completion in Jun 2022, 57 months.
Results were first posted in Feb 2024, 1 year 8 months after primary completion.
Of 677 industry-sponsored phase 1 interventional studies under Neoplasms, half reached primary completion within 38 months of starting (the median), counting those still running; a quarter within 22 and three quarters within 61. This study's 57 months is above that.
Counting every sponsor, half of 904 studies reached it within 40 months; a quarter within 23 and three quarters within 64.
Neoplasms covers many different conditions, not one, so the studies compared here vary widely. Read these figures as a rough guide.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Mar 2024. You cannot join it, but the record below documents what was studied.
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