An Investigational Immuno-therapy Study to Assess the Safety, Tolerability and Effectiveness of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors

Phase 2CompletedNCT01968109

Bristol-Myers Squibb1,482 enrolled

Overview

The purpose of the study is to assess the safety, tolerability and effectiveness of experimental medication BMS-986016 administered alone and in combination with nivolumab in patients with solid tumors that have spread and/or cannot be removed by surgery. The following tumor types are included in this study: Non-Small Cell Lung Cancer (NSCLC), gastric cancer, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, squamous cell carcinoma of the head and neck, and melanoma, that have NOT previously been treated with immunotherapy. NSCLC and melanoma that HAVE previously been treated with immunotherapy.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,482

Conditions

Neoplasms by Site

Interventions

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

Inclusion Criteria: * For Dose escalation: subjects with cervical, ovarian, bladder and colorectal cancer (CRC), head and neck, gastric and hepatocellular cancer naive to immuno-oncology agents; 1st line melanoma and 1st line/2nd line NSCLC; Renal Cell Carcinoma naive to IO; NSCLC progressing while on or after therapy with anti-PD1/anti-PDL-1 and melanoma subjects progressed while-on or after treatment with anti-PD1 or anti-PDL1 with or without anti-CTLA-4. * For Dose Expansion: all of the above in escalation except for cervical, ovarian, and CRC * Progressed, or been intolerant to, at least one standard treatment regimen, except for participants in 1st line cohorts. * ECOG performance status between 0 and 2 * At least 1 lesion with measurable disease at baseline * Availability of an existing tumor biopsy sample (and consent to allow pre-treatment tumor biopsy) Exclusion Criteria: * Primary central nervous system (CNS) tumors or solid tumors with CNS metastases as the only site of active disease * Autoimmune disease * Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent * Uncontrolled CNS metastases Other protocol defined inclusion/exclusion criteria could apply

Locations (54)

Local Institution - 0043

La Jolla, California, United States

Local Institution - 0053

Aurora, Colorado, United States

Local Institution - 0058

Tampa, Florida, United States

Local Institution - 0003

Chicago, Illinois, United States

Local Institution - 0048

Niles, Illinois, United States

Outcomes

Primary Outcomes

Number of Participants With Adverse Events, Deaths and Clinically Relevant Laboratory Abnormalities

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. SAEs is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization; results significant disability; or is a congenital anomaly/birth defect.

Time frame: From first dose and within 135 days after last dose of study therapy (Up to approximately 82 months)

Part C, D1, D2, E - Objective Response Rate Per BICR

ORR is defined as the percentage of participants whose best overall response (BOR) is either CR or PR by blinded independent central review (BICR) per response evaluation criteria in solid tumors (RECIST) v1.1 based on Clopper-Pearson method. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \\\< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From first dose to the date of first objectively documented progression, per RECIST v1.1, or death due to any cause, whichever occurred first (up to approximately 127 months)

Part C, D1, D2, E - Disease Control Rate (DCR) Per BICR

Disease Control Rate (DCR) (as per Recists v1.1) is defined as the percentage of randomized participants who achieve a BOR of confirmed CR, confirmed PR, or stable disease (SD), based on BICR assessments divided by the number of all randomized participants. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \\\< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From first dose to the date of first objectively documented progression, per RECIST v1.1, or death due to any cause, whichever occurred first (up to approximately 127 months)

Part C, D1, D2, E - Duration of Response (DOR) Per BICR

DOR for a participant with a best overall response (BOR) of CR or PR is defined as the time between the date of first response and the date of the first objectively documented tumor progression by blinded independent central review (BICR) per response evaluation criteria in solid tumors (RECIST) v1.1 or death, whichever occurs first. Median computed using Kaplan-Meier method. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \\\< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From first dose to the date of first objectively documented progression, per RECIST v1.1, or death due to any cause, whichever occurred first (up to approximately 127 months)

Part D1: Number of Participants With Adverse Events in the Broad Scope Standardized MedDRA (SMQ) Anaphylactic Reaction Occurring Within 2 Days of Any Doses of Study Therapy

Time frame: From first dose and within 2 days of first dose of study therapy

Part C, D1, D2, E - Objective Response Rate Per BICR

Time frame: From first dose (Day 1) and up to 97 months

Secondary Outcomes

Part C, D1 and D2: Progression-Free Survival (PFS) Rate Per BICR

Progression Free Survival Rates at 12 months is defined as the proportion of participants who achieve PFS at 12 months. PFS for a participant is defined as the time from randomization date to the date of first objectively documented disease progression by blinded independent central review (BICR) per response evaluation criteria in solid tumors (RECIST) v1.1 or death due to any cause, whichever occurs first. Based on Kaplan-Meier Estimates. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Up to 12 months

Part D1 and D2: Overall Survival (OS) at 12 and 24 Months

Overall survival at 1 year, and 2 years is defined as the proportion of participants who are alive at 1 year, and 2 years. Based on Kaplan-Meier Estimates.

Time frame: At 12 and 24 months after first dose

Part C, D1, D2, E - Objective Response Rate Per Investigator

ORR is defined as the percentage of participants whose best overall response (BOR) is either CR or PR by investigator per response evaluation criteria in solid tumors (RECIST) v1.1 based on Clopper-Pearson method. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \\\< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From first dose to the date of first objectively documented progression, per RECIST v1.1, or death due to any cause, whichever occurred first (up to approximately 127 months)

Part C, D1, D2, E - Disease Control Rate (DCR) Per Investigator

Part C, D1, D2, E - Duration of Response (DOR) Per Investigator

DOR for a participant with a best overall response (BOR) of CR or PR is defined as the time between the date of first response and the date of the first objectively documented tumor progression by investigator per response evaluation criteria in solid tumors (RECIST) v1.1 or death, whichever occurs first. Median computed using Kaplan-Meier method. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \\\< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From first dose to the date of first objectively documented progression, per RECIST v1.1, or death due to any cause, whichever occurred first (up to approximately 127 months)

Part C, D1 and D2: Progression-Free Survival (PFS) Rate Per Investigator

Progression Free Survival Rates up to 12 months is defined as the proportion of participants who achieve PFS up to 12 months. PFS for a participant is defined as the time from randomization date to the date of first objectively documented disease progression by investigator per response evaluation criteria in solid tumors (RECIST) v1.1 or death due to any cause, whichever occurs first. Based on Kaplan-Meier Estimates. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Up to 12 months

Number of Participants With Positive Anti Drug Antibodies

Blood samples were collected to assess anti-drug antibodies.

Time frame: predose, and 4-hour post-dose of relatlimab on Cycle 1 Day 1 and Cycle 3 Day 1 (Each cycle consist of 28 days)

Part A, A/A1, and B: Number of Participants With Clinically Relevant QT Prolongation

Abnormal electrocardiogram parameter included QT prolongation.

Time frame: predose, and 4-hour post-dose of relatlimab on Cycle 1 Day 1 and Cycle 3 Day 1 (Each cycle consist of 28 days)

Maximum Observed Concentration (Cmax) of BMS-986016 (Relatlimab)

Blood samples were collected for assessment of pharmacokinetic parameter of BMS-986016 (relatlimab).

Time frame: Day 1 of Cycle 1 and 3

Time to Maximum Observed Concentration (Tmax) of BMS-986016 (Relatlimab)

Blood samples were collected for assessment of pharmacokinetic parameter of BMS-986016 (relatlimab).

Time frame: Day 1 of Cycle 1 and 3 (Each cycle consist of 28 days).

Area Under the Concentration-time Curve in One Dosing Interval (AUCtau) of BMS-986016 (Relatlimab)

Blood samples were collected for assessment of pharmacokinetic parameter of BMS-986016 (relatlimab).

Time frame: Day 1 of Cycle 1 and 3 (Each cycle consist of 28 days).

Part A/A1, B, C, D1, D2 and E: Trough Observed Concentration (Ctrough) of BMS-986016 (Relatlimab)

Blood samples were collected for assessment of pharmacokinetic parameter of BMS-986016 (relatlimab). Ctrough is defined as the lowest concentration of drug in the blood immediately before the next dose is administered. Ctrough was only assessed for arm Part A/A1, B, C, D1, D2 and E as pre-specified.

Time frame: Day 1 of Cycle 3 (Each cycle consist of 28 days)

Part A/A1, B, CTotal Body Clearance (CLT) of BMS-986016 (Relatlimab)

Blood samples were collected for assessment of pharmacokinetic parameter of BMS-986016 (relatlimab). CLT was only assessed for arm Part A/A1, B, C as pre-specified.

Time frame: Day 1 of Cycle 3 (Each cycle consist of 28 days).

Part A/A1, B, C AUC Accumulation Index AI_AUC of BMS-986016 (Relatlimab)

Blood samples were collected for assessment of pharmacokinetic parameter of BMS-986016 (relatlimab). AUC Accumulation Index is a pharmacokinetic metric used to quantify how much a drug accumulates in the body after repeated dosing compared to a single dose. It is ratio of AUC Steady State (AUCss) and AUC1. AUCₛₛ is the area under the plasma concentration-time curve during a dosing interval at steady state (after repeated doses). AUC₁ is the area under the curve after a single dose. Only assessed for arm Part A/A1, B, C as pre-specified.

Time frame: Day 1 of Cycle 3 (Each cycle consist of 28 days)