A Study to Evaluate the Safety, Tolerability, and Efficacy of Relatlimab in Relapsed or Refractory B-Cell Malignancies

Study Overview
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Brief Summary
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The primary objective of this study is to characterize the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) of relatlimab administered alone or in combination with nivolumab to subjects with relapsed or refractory B-cell malignancies. Co-primary objective is to investigate the preliminary efficacy of relatlimab in combination with nivolumab in subjects with relapsed or refractory Hodgkin lymphoma (HL), and relapsed or refractory Diffused Large B Cell lymphoma (DLBCL)

Official Title
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A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (Relatlimab, BMS-986016) Administered Alone and in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Relapsed or Refractory B-Cell Malignancies

Conditions
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Hematologic Neoplasms

Intervention / Treatment
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* Biological: BMS-986016
* Biological: BMS-936558


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have histologic or cytologic confirmation of chronic lymphocytic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, or Multiple Myeloma and have relapsed following prior treatment or been refractory to prior treatment Must have progressed or been refractory to, at least one prior standard therapy, including radiation, immunomodulatory agents (eg, lenalidomide), immunotherapy, cytotoxic chemotherapy, and select antibody (anti-CD20, alemtuzumab, or anti-CD30) therapy. Must be more than 100 days post autologous transplant Exclusion Criteria: Known or suspected central nervous system (CNS) metastases or with the CNS as the only site of active disease (controlled CNS metastases are allowed) Known or suspected autoimmune disease History of allergy to anti-PD-1 or anti-PD-L1 antibody therapy or to other monoclonal antibodies or related compounds or to any of their components Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - relatlimab (Dose escalation)<br> | Biological: BMS-986016<br>* Specified Dose on Specified Days<br>* Other names: Anti-LAG-3 (Anti-Lymphocyte Activation Gene-3), relatlimab;|
| Experimental: Part C - relatlimab + nivolumab (Dose escalation)<br> | Biological: BMS-986016<br>* Specified Dose on Specified Days<br>* Other names: Anti-LAG-3 (Anti-Lymphocyte Activation Gene-3), relatlimab;Biological: BMS-936558<br>* Specified Dose on Specified Days<br>* Other names: Anti-PD-1 (Anti-Programmed-Death-1), MDX-1106, nivolumab;|
| Experimental: Part B - relatlimab (Cohort expansion)<br> | Biological: BMS-986016<br>* Specified Dose on Specified Days<br>* Other names: Anti-LAG-3 (Anti-Lymphocyte Activation Gene-3), relatlimab;|
| Experimental: Part D - relatlimab + nivolumab (Cohort expansion)<br> | Biological: BMS-986016<br>* Specified Dose on Specified Days<br>* Other names: Anti-LAG-3 (Anti-Lymphocyte Activation Gene-3), relatlimab;Biological: BMS-936558<br>* Specified Dose on Specified Days<br>* Other names: Anti-PD-1 (Anti-Programmed-Death-1), MDX-1106, nivolumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation | Number of participants with any grade adverse events (AEs), any grade serious adverse events (SAEs) and any grade AEs leading to discontinuation of any drug. The severity of AEs will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. An 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. | From first dose to 100 days post last dose (Up to 51 months) | 
| Number of Participants Who Died | Number of participants who died due to any cause. | From first dose to 135 days post last dose (Up to 52 months) | 
| Number of Participants With On-Treatment Laboratory Abnormalities in Specific Hepatics Tests | Number of participants with laboratory abnormalities in specific hepatic tests based on SI unit convention. The number of participants with the following laboratory abnormalities from on-treatment evaluations will be summarized: ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN Total bilirubin > 2 x ULN ALP > 1.5 x ULN Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN | From first dose to 30 days post last dose (Up to 49 months) | 
| Objective Response Rate (ORR) - Part D | Investigator-assessed ORR per International Working Group (IWG 2007) response criteria for malignant lymphoma is defined as the number of participants with a best overall documented response (BOR) of either a complete response (CR) or partial response (PR). Complete response: Disappearance of all evidence of disease. Partial response: Regression of measurable disease and no new sites. >= 50% decrease in sum of the produce of the diameters of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions). Progressive disease: Any new lesion or increase by >=50% of previously involved sites from nadir. | From first dose date to the date of disease progression per investigator or the date of subsequent therapy, whichever occurs first (Up to approximately 95 months) | 
| Duration of Response (DoR) - Part D | Investigator-assessed DoR per International Working Group (IWG 2007)) response criteria for malignant lymphoma is defined as the time between the date of first documented response (complete response or partial response) to the date of the first objectively documented progression, or death due to any cause, whichever occurs first. Complete response: Disappearance of all evidence of disease. Partial response: Regression of measurable disease and no new sites. >= 50% decrease in sum of the produce of the diameters of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions). Progressive disease: Any new lesion or increase by >=50% of previously involved sites from nadir. | From first dose to the date of the first objectively documented progression, or death due to any cause, whichever occurs first (Up to approximately 95 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMS-986016 Maximum Observed Serum Concentration (Cmax) | BMS-986016 Maximum Observed Serum Concentration (Cmax). Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 = Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Time of Maximum Observed Serum Concentration (Tmax) | BMS-986016 Time of Maximum Observed Serum Concentration (Tmax). Period 0 = treatment period Period 1 = Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Area Under the Concentration-time Curve in One Dosing Interval (AUC(TAU)) | BMS-986016 Area under the concentration-time curve in one dosing interval (AUC(TAU)). Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 = Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Concentration at the End of a Dosing Interval (Ctau) | BMS-986016 Concentration at the end of a dosing interval (Ctau). Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 = Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Effective Elimination Half-life That Explains the Degree of AUC Accumulation Observed (T 1/2eff AUC) | BMS-986016 effective elimination half-life that explains the degree of AUC accumulation observed (t 1/2eff AUC). Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 = Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Total Body Clearance (CL/T) | BMS-986016 total body clearance (CL/T). Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 = Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Cmax Accumulation Index (AI_Cmax) | BMS-986016 cmax accumulation index (AI_Cmax). AI is calculated based on ratio of Cmax at steady state to Cmax after the first dose. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 - Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Accumulation Index (AI_AUC) | BMS-986016 accumulation index (AI_AUC). AI is calculated based on ratio of AUC(TAU) at steady state to AUC(TAU) after the first dose. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 - Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Ctau Accumulation Index (AI_Ctau) | BMS-986016 Ctau accumulation index (AI_Ctau). AI is calculated based on ratio of Ctau at steady state to Ctau after the first dose. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 - Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Average Concentration Over a Dosing Interval ([AUC(TAU)/Tau] (Css,Avg) | BMS-986016 average concentration over a dosing interval ([AUC(TAU)/tau] (Css,avg). Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 - Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 1, Cycle 3 Day 1 | 
| BMS-986016 Trough Observed Serum Concentration (Ctrough) | BMS-986016 trough observed serum concentration (Ctrough). Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. Period 0 = treatment period Period 1 - Re-challenge period | PK assessment include the following timepoints: pre-dose, 1, 4, 24, 48, 96, 144, 192 hours end-of-infusion on cycle 1 Day 15, 29, 43, Cycle 2 Day 1, 15, 29, Cycle 3 Day 1, 15, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, and Cycle 11 Day 1 | 
| Number of Participants With Anti-BMS-986016 Antibodies (ADA) | Number of participants with anti-BMS-986016 antibodies (ADA) with status as baseline ADA positive, ADA positive and ADA negative. Baseline ADA positive participant is defined as a participant with positive seroconversion detected in the last sample before initiation of treatment. ADA-positive participant is a participant with at least one ADA-positive sample relative to baseline after initiation of the treatment. ADA negative participant is defined as a participant with no ADA positive sample after the initiation of treatment. | From first dose to 135 days post last dose (Up to 52 months) | 
| Number of Participants With Anti-Nivolumab Antibodies (ADA) | Number of participants with anti-Nivolumab antibodies (ADA) with status as baseline ADA positive, ADA positive and ADA negative. Baseline ADA positive participant is defined as a participant with positive seroconversion detected in the last sample before initiation of treatment. ADA-positive participant is a participant with at least one ADA-positive sample relative to baseline after initiation of the treatment. ADA negative participant is defined as a participant with no ADA positive sample after the initiation of treatment. | From first dose to 135 days post last dose (Up to 52 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hodgkin lymphoma, non-Hodgkin lymphoma, diffused large B-cell lymphoma, indolent lymphoma, chronic lymphocytic leukemia, relapsed, refractory