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

Phase 1

Completed

Conditions: Neoplasms

Interventions: Drug: TSR-033
Drug: Dostarlimab
Drug: FOLFIRI
Drug: mFOLFOX6
Drug: Bevacizumab

Registration Number: NCT03250832

Lead Sponsor: Tesaro, Inc.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 111

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6	TSR-033	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.
Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI	FOLFIRI	Part 2 Cohort B2 will evaluate the preliminary activity of TSR-033 in combination with FOLFIRI and bevacizumab (SOC) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFOX, with or without biologics.
Part 1c: TSR-033+dostarlimab combination dose escalation	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.
Part 2 Cohort A: TSR-033+dostarlimab combination	TSR-033	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.
Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6	mFOLFOX6	Part 2 Cohort B1 will evaluate the preliminary activity of TSR-033 administered every 2 weeks (Q2W) in combination with dostarlimab administered every 6 weeks (Q6W) along with mFOLFOX6 and bevacizumab (standard of care \[SOC\]) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFIRI, with or without biologics.
Part 1b: TSR-033 monotherapy PK/PDy characterization	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.
Part 1a: TSR-033 monotherapy dose escalation	TSR-033	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.
Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI	TSR-033	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.
Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI	Dostarlimab	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.
Part 2 Cohort B2: TSR-033+dostarlimab with FOLFIRI	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.
Part 1c: TSR-033+dostarlimab combination dose escalation	Dostarlimab	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.
Part 2 Cohort A: TSR-033+dostarlimab combination	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.
Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6	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.
Part 2 Cohort B1: TSR-033+dostarlimab with mFOLFOX6	Bevacizumab	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.

Primary Outcome Measures

Name	Time	Method
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 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 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 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 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 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 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 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 Outcome Measures

Name	Time	Method
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 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.
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: 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 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 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 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 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 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 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 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 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 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 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.