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

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

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)

Study Overview

• Status: Completed
• Conditions: Hematologic Neoplasms
• Intervention / Treatment: Biological: BMS-986016; Biological: BMS-936558

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Local Institution - 0011
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution - 0012
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Local Institution - 0007
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0004
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Local Institution - 0010
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
  • Oregon
    • Portland, Oregon, United States, 97239
      • Local Institution - 0002
  • Texas
    • Houston, Texas, United States, 77030
      • Local Institution - 0006
  • Washington
    • Seattle, Washington, United States, 98109
      • Local Institution - 0001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• El Halabi L, Adam J, Gravelle P, Marty V, Danu A, Lazarovici J, Ribrag V, Bosq J, Camara-Clayette V, Laurent C, Ghez D. Expression of the Immune Checkpoint Regulators LAG-3 and TIM-3 in Classical Hodgkin Lymphoma. Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):257-266.e3. doi: 10.1016/j.clml.2020.11.009. Epub 2020 Nov 12.

Helpful Links

• BMS Clinical Trial Information
• FDA Safety Alerts and Recalls
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2014
• Primary Completion (Actual): February 16, 2022
• Study Completion (Actual): February 16, 2022

Study Registration Dates

• First Submitted: February 12, 2014
• First Submitted That Met QC Criteria: February 12, 2014
• First Posted (Estimate): February 13, 2014

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 20, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: non-Hodgkin lymphoma; relapsed; refractory; Hodgkin lymphoma; chronic lymphocytic leukemia; indolent lymphoma; diffused large B-cell lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: CA224-022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No