Nivolumab, BMS-936558 in Combination with Relatlimab, BMS-986016 in Patients with Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting

A Phase II Study of Anti-PD1 Monoclonal Antibody (Nivolumab, BMS-936558) Administered in Combination with Anti-LAG3 Monoclonal Antibody (Relatlimab, BMS-986016) in Patients with Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting

The main goal of this study is to evaluate the antitumor activity of relatlimab and nivolumab in combination in subjects with unresectable or metastatic melanoma who have not received prior treatment with immunotherapy.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: Relatlimab; Drug: Nivolumab; Drug: Relatlimab + Nivolumab

Detailed Description

This study will evaluate the antitumor activity of anti-LAG3 monoclonal antibody relatlimab and the anti-PD1 monoclonal antibody nivolumab in combination in subjects with unresectable or metastatic melanoma who have not received prior treatment with immunotherapy. The trial is designed with a lead-in phase of 2 cycles (4 week) treatment of either nivolumab, relatlimab, or the combination of nivolumab/relatlimab, followed by a combination phase of nivolumab/relatlimab treatment in all subjects. This lead-in design with accompanying tumor biopsies and peripheral blood analyses will enable mechanistic analyses of the effect of LAG3 and PD1 blockade alone and in combination to enhance understanding of mechanisms of response and resistance. Duration of response, progression free survival, and safety will be assessed as secondary objectives.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Men or women 18 years of age or older meeting AJCC 8th edition criteria for unresectable stage IIIB, stage IIIC, stage IIID, or stage IV melanoma who have not received treatment with immunotherapy in the metastatic setting

Exclusion Criteria:

• Known or suspected CNS metastases, with the following exceptions:

  • Subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following radiation and/or surgical treatment at the time of consent. Subjects must be off steroids for at least 2 weeks prior to randomization.
  • Subjects with signs or symptoms of brain metastases are not eligible unless brain metastases are ruled out by computed tomography or magnetic resonance imaging.
• Active autoimmune disease requiring treatment, with the exception of type 1 diabetes mellitus, vitiligo, resolved childhood asthma/atopy, controlled hyper/hypothyroidism, hypoadrenalism or hypopituitarism.
• Prior systemic treatment in the metastatic setting, including anti-PD1, anti-PDL1, anti-PDL2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways; or chemotherapy.
• Prior adjuvant treatment with anti-PD1, anti-PDL1, and/or anti-LAG3 antibody. Note that prior adjuvant treatment with targeted therapy (e.g. BRAF/MEK inhibition), anti-CTLA4, or treatment not otherwise specified above would be permitted.
• Ocular melanoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Relatlimab; Cycle 1: Relatlimab (BMS-986016) is supplied as a sterile 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV for the first 4 weeks (cycle 1). Cycle 2+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV once every 4 weeks.	Drug: Relatlimab; Relatlimab (BMS-986016) - 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV.; Other Names: BMS-986016
Experimental: Nivolumab; Cycle 1: Nivolumab (BMS-936558) is supplied as a sterile 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV for the first 4 weeks. Cycle 2+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV once every 4 weeks.	Drug: Nivolumab; Nivolumab (BMS-936558) - 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV.; Other Names: BMS-936558
Experimental: Relatlimab + Nivolumab; Cycle 1+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV for the first 4 weeks (Cycle 1), then once every 4 weeks afterwards.	Drug: Relatlimab + Nivolumab; Combination (Relatlimab + Nivolumab) therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV.; Other Names: BMS-986016 and BMS-936558

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in LAG3 Expression	LAG3 (cell surface molecule expressed on activated T cells) expression is either positive (present) or not detectable if absent after completion of lead-in phase.	At baseline and at 4 weeks
Change in PD1 expression	PD1 (programmed cell death protein 1) expression is either positive (present) or not detectable if absent after completion of lead-in phase	At baseline and at 4 weeks
Change in Tumor Size	Tumor size will be assessed per Response Evaluation Criteria in Solid Tumors. Per RECIST 1.1, Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of: 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II on imaging guidance).; 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable).; 20 mm by chest X-ray.	At baseline and at 4 weeks
Overall Response Rate (ORR)	Number of participants experiencing Complete Response (CR) + Number of participants experiencing Partial Response (PR)/total patients assessed. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on 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. (Note: the appearance of one or more new lesions is also considered progression). SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	Beginning at 12 weeks post initial treatment, up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Rate	Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) / total patients assessed per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	12 weeks post initial treatment, up to 4 years
Duration of Response	Time from first documented Complete Response (CR) or Partial Response (PR) until the first date that progressive disease is objectively documented. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	12 weeks post initial treatment, up to 4 years
Progression-free Survival (PFS)	Progression-free survival is defined as the time between the date of randomization and the first date of documented progression or death due to any cause, whichever occurs first. Per RECIST v1.1, Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on 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.	Up to 4 years
Overall Survival (OS)	Overall survival is defined as the time between the date of randomization and the date of death due to any cause.	Up to 4 years
LAG3 Expression	LAG3 (cell surface molecule expressed on activated T cells) expression (positive (present) or not detectable if absent) in tumor and peripheral blood of treated participants who experience a complete response, partial response, or stable disease, prior to ultimately experiencing disease progression.	At week 16 (2 weeks post combination treatment (3 cycles))
PD-1 Expression	PD-1 (programmed cell death protein 1) expression (positive (present) or not detectable if absent) in tumor and peripheral blood of treated participants who experience a complete response, partial response, or stable disease, prior to ultimately experiencing disease progression.	At week 16 (12 weeks post combination treatment (3 cycles))
Change in CD4+ tumor infiltrating lymphocytes	Percentage and number of CD4+ tumor infiltrating lymphocytes present	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Change in CD8+ tumor infiltrating lymphocytes	Percentage and number of CD8+ tumor infiltrating lymphocytes present	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Change in granzyme B serum levels	Level of granzyme B (a serine protease secreted cells to mediate apoptosis in target cells) in serum.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Change in cell effector/memory status	Measure of cells that have previously encountered and responded to their cognate antigen.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Change in activation and maturation of dendritic cells	Measure of expression of activation and maturation of dendritic cells	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Change in T cell count	Number of T cells present in blood and tumor	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Change in T cell count	Number of T cells present in blood and tumor in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	At the time of disease progression - up to 4 years
Change in soluble LAG3 levels	Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood and tumor tissue.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Soluble LAG3 levels	Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood and tumor tissue in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	At the time of disease progression - up to 4 years
Change in Regulatory T cell (Treg) marker level	Amount of Regulatory T cell (Treg) markers present in blood and tumor tissue.	At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
Regulatory T cell (Treg) marker levels	Amount of Regulatory T cell (Treg) markers present in blood and tumor tissue.in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	At the time of disease progression - up to 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Single cell RNA sequencing	The presence and quantity of RNA in in blood and tumor tissue.	2 weeks
Single cell RNA sequencing	The presence and quantity of RNA in in blood and tumor tissue.	At 4 weeks post Cycle 1
Single cell RNA sequencing	The presence and quantity of RNA in in blood and tumor tissue.	At week 16 (12 weeks post combination treatment (3 cycles)
Single cell RNA sequencing	The presence and quantity of RNA in in blood and tumor tissue in patients that had previously demonstrated complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	At the time of disease progression - up to 4 years

Collaborators and Investigators

• Sponsor: John Kirkwood
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: John Kirkwood, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2019
• Primary Completion (Actual): July 3, 2024
• Study Completion (Actual): July 3, 2024

Study Registration Dates

• First Submitted: October 18, 2018
• First Submitted That Met QC Criteria: November 15, 2018
• First Posted (Actual): November 16, 2018

Study Record Updates

• Last Update Posted (Actual): September 25, 2024
• Last Update Submitted That Met QC Criteria: September 23, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: immunotherapy; Stage IV; Stage IIIB; Stage IIIC; Stage IIID; immune checkpoint blockade (ICB); Lymphocyte activation gene-3 (LAG3; CD223)
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Relatlimab
• Other Study ID Numbers: 18-071

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No