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Completed

NCT Number: NCT03743766

Nivolumab, BMS-936558 in Combination With 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.

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Key information

Conditions

Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Relatlimab

Drug

Relatlimab (BMS-986016) - 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV.

Other names: BMS-986016

Nivolumab

Drug

Nivolumab (BMS-936558) - 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV.

Other names: BMS-936558

Relatlimab + Nivolumab

Drug

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

Primary outcomes

  1. LAG3 Gene Expression From scRNAseq

    Time frame: At Baseline

    Percent Lymphocyte-activation gene 3 (LAG3) level (cell surface molecule expressed on activated T cells) expression from scRNAseq

  2. LAG3 Gene Expression From scRNAseq

    Time frame: At Week 4

    Percent Lymphocyte-activation gene 3 (LAG3) level (cell surface molecule expressed on activated T cells) expression from scRNAseq

  3. PD1 Expression

    Time frame: At baseline (Week 0)

    Percent PD1 (programmed cell death protein 1) expression after completion of lead-in phase.

  4. PD1 Expression

    Time frame: At Week 4

    Percent PD1 (programmed cell death protein 1) expression after completion of lead-in phase.

  5. Change in Tumor Size

    Time frame: At baseline and at 4 weeks

    Percentage change in tumor size assessed per Response Evaluation Criteria in Solid Tumors. Per RECIST 1.1, Tumor 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.

  6. Overall Response Rate (ORR)

    Time frame: Beginning at 12 weeks post initial treatment, up to 4 years

    Percent 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.

  7. Overall Response Rate (ORR) - ITT (Intent-to-treat) Population

    Time frame: Beginning at 12 weeks post initial treatment, up to 4 years

    Percent 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.

Secondary outcomes

  1. Secondary Outcome: Clinical Benefit Rate

    Time frame: 12 weeks post initial treatment, up to 4 years

    Percent of patients with 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.

  2. Clinical Benefit Rate - ITT (Intent-to-treat) Population

    Time frame: 12 weeks post initial treatment, up to 4 years

    Percent of patients with 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.

  3. Duration of Response

    Time frame: 12 weeks post initial treatment, up to 4 years

    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.

  4. Progression-free Survival (PFS)

    Time frame: Up to 4 years

    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.

  5. Progression-free Survival (PFS) by Lead-in Arm

    Time frame: Up to 4 years

    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.

  6. Overall Survival (OS)

    Time frame: Up to 4 years

    Overall survival is defined as the time between the date of randomization and the date of death due to any cause.

  7. CD8+ Tumor Infiltrating Lymphocytes

    Time frame: At Baseline

    Number of CD8+ tumor infiltrating lymphocytes present.

  8. CD8+ Tumor Infiltrating Lymphocytes

    Time frame: At Week 4

    Number of CD8+ tumor infiltrating lymphocytes present.

  9. CD4+ Tumor Infiltrating Lymphocytes

    Time frame: At Week 4

    Number of CD4+ tumor infiltrating lymphocytes present.

  10. CD4+ Tumor Infiltrating Lymphocytes

    Time frame: At Baseline

    Number of CD4+ tumor infiltrating lymphocytes present.

  11. LAG3 Levels - PBMC

    Time frame: At Baseline

    To determine the amount of LAG3 expressed on activated T cells in the blood through single-cell RNA sequencing. The LAG3 expression is reported as the natural log (ln) of the number of LAG3 transcripts divided by the number of total mapped reads plus 1.

  12. LAG3 Levels - PBMC

    Time frame: At Week 4

    To determine the amount of LAG3 expressed on activated T cells in the blood through single-cell RNA sequencing. The LAG3 expression is reported as the natural log (ln) of the number of LAG3 transcripts divided by the number of total mapped reads plus 1.

  13. LAG3 Levels - TIL

    Time frame: At Baseline

    To determine the amount of LAG3 expressed on activated tumor infiltrating lymphocytes (TIL) through single-cell RNA sequencing. The LAG3 expression is reported as the natural log (ln) of the number of LAG3 transcripts divided by the number of total mapped reads plus 1.

  14. LAG3 Levels - PBMC

    Time frame: At Week 16

    To determine the amount of LAG3 expressed on activated T cells in the blood through single-cell RNA sequencing. The LAG3 expression is reported as the natural log (ln) of the number of LAG3 transcripts divided by the number of total mapped reads plus 1.

  15. LAG3 Levels - TIL

    Time frame: At Week 4

    To determine the amount of LAG3 expressed on activated tumor infiltrating lymphocytes (TIL) through single-cell RNA sequencing. The LAG3 expression is reported as the natural log (ln) of the number of LAG3 transcripts divided by the number of total mapped reads plus 1.

  16. PD-1 Expression in PBMC

    Time frame: At Baseline

    To determine the amount of PD-1 (programmed cell death protein 1) expressed on PBMCs through single-cell RNA sequencing in treated patients. The PD-1 expression is reported as the natural log (ln) of the number of PD-1 transcripts divided by the number of total mapped reads plus 1.

  17. PD-1 Expression in PBMC

    Time frame: At Week 4

    To determine the amount of PD-1 (programmed cell death protein 1) expressed on PBMCs through single-cell RNA sequencing in treated patients. The PD-1 expression is reported as the natural log (ln) of the number of PD-1 transcripts divided by the number of total mapped reads plus 1.

  18. PD-1 Expression in PBMC

    Time frame: At Week 16

    To determine the amount of PD-1 (programmed cell death protein 1) expressed on PBMCs through single-cell RNA sequencing in treated patients. The PD-1 expression is reported as the natural log (ln) of the number of PD-1 transcripts divided by the number of total mapped reads plus 1.

  19. PD-1 Expression in TIL

    Time frame: At Baseline

    To determine the amount of PD-1 (programmed cell death protein 1) expressed on TILs through single-cell RNA sequencing in treated patients. The PD-1 expression is reported as the natural log (ln) of the number of PD-1 transcripts divided by the number of total mapped reads plus 1.

  20. PD-1 Expression in TIL

    Time frame: At Week 4

    To determine the amount of PD-1 (programmed cell death protein 1) expressed on TILs through single-cell RNA sequencing in treated patients. The PD-1 expression is reported as the natural log (ln) of the number of PD-1 transcripts divided by the number of total mapped reads plus 1.

  21. Cell Effector/Memory Status - TIL

    Time frame: At Baseline

    Measure of cells that have previously encountered and responded to their cognate antigen in TIL.

  22. Cell Effector/Memory Status - TIL

    Time frame: At Week 4

    Measure of cells that have previously encountered and responded to their cognate antigen in TIL.

  23. Cell Effector/Memory Status - PBMCs

    Time frame: At Baseline

    Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs.

  24. Cell Effector/Memory Status - PBMC

    Time frame: At Week 4

    Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs.

  25. Cell Effector/Memory Status - PBMC

    Time frame: At Week 16

    Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs.

  26. Regulatory T Cell (Treg) Marker Levels - PMBCs

    Time frame: At Baseline

    Amount of Regulatory T cell (Treg) markers present in PBMCs in treated patients.

  27. Regulatory T Cell (Treg) Marker Levels - PMBCs

    Time frame: At Week 4

    Amount of Regulatory T cell (Treg) markers present in PBMCs in treated patients.

  28. Regulatory T Cell (Treg) Marker Levels - PMBCs

    Time frame: At Week 16

    Amount of Regulatory T cell (Treg) markers present in PBMCs in treated patients.

  29. Regulatory T Cell (Treg) Marker Levels - TIL

    Time frame: At Baseline

    Amount of Regulatory T cell (Treg) markers present in TILs in treated patients.

  30. Regulatory T Cell (Treg) Marker Levels - TIL

    Time frame: At Week 4

    Amount of Regulatory T cell (Treg) markers present in TILs in treated patients.

  31. Activation and Maturation of Dendritic Cells - PBMC

    Time frame: At Baseline

    Measure of expression of activation and maturation of dendritic cells in PBMCs.

  32. Activation and Maturation of Dendritic Cells - PBMC

    Time frame: At Week 4

    Measure of expression of activation and maturation of dendritic cells in PBMCs.

  33. Activation and Maturation of Dendritic Cells - PBMC

    Time frame: At Week 16

    Measure of expression of activation and maturation of dendritic cells in PBMCs.

  34. Activation and Maturation of Dendritic Cells - TIL

    Time frame: At Baseline

    Measure of expression of activation and maturation of dendritic cells in tumor (TIL).

  35. Activation and Maturation of Dendritic Cells - TIL

    Time frame: At Week 4

    Measure of expression of activation and maturation of dendritic cells in tumor (TIL).

  36. Soluble LAG3 Levels - PBMC

    Time frame: At the time of disease progression - up to 4 years

    Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood 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.

  37. Soluble LAG3 Levels - TIL

    Time frame: At the time of disease progression - up to 4 years

    Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in 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.

  38. Granzyme B Serum Levels

    Time frame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks

    Level of granzyme B (a serine protease secreted cells to mediate apoptosis in target cells) in serum.

  39. T Cell Count

    Time frame: At 4 weeks

    Number of T cells present in TIL or PBMC.

  40. T Cell Count

    Time frame: At 12 weeks

    Number of T cells present in TIL or PBMC.

  41. T Cell Count

    Time frame: At the time of disease progression - up to 4 years

    Number of T cells present in TIL or PBMC.

Other outcomes

  1. Single Cell RNA Sequencing

    Time frame: 2 weeks

    The presence and quantity of RNA in in blood and tumor tissue.

  2. Single Cell RNA Sequencing

    Time frame: At 4 weeks post Cycle 1

    The presence and quantity of RNA in in blood and tumor tissue.

  3. Single Cell RNA Sequencing

    Time frame: At week 16 (12 weeks post combination treatment (3 cycles)

    The presence and quantity of RNA in in blood and tumor tissue.

  4. Single Cell RNA Sequencing

    Time frame: At the time of disease progression - up to 4 years

    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.

Sponsors and collaborators

Lead sponsor

John Kirkwood

Other

Collaborators

  • Bristol-Myers Squibb

Registry information

Official study title

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

Important dates

Study start
2019
Primary completion
2024
Study completion
2025
First posted
Nov 16, 2018
Registry last updated
Aug 31, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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