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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
43
Relatlimab (BMS-986016) - 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV.
Nivolumab (BMS-936558) - 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV.
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.
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
LAG3 Gene Expression From scRNAseq
Percent Lymphocyte-activation gene 3 (LAG3) level (cell surface molecule expressed on activated T cells) expression from scRNAseq
Time frame: At Baseline
LAG3 Gene Expression From scRNAseq
Percent Lymphocyte-activation gene 3 (LAG3) level (cell surface molecule expressed on activated T cells) expression from scRNAseq
Time frame: At Week 4
PD1 Expression
Percent PD1 (programmed cell death protein 1) expression after completion of lead-in phase.
Time frame: At baseline (Week 0)
PD1 Expression
Percent PD1 (programmed cell death protein 1) expression after completion of lead-in phase.
Time frame: At Week 4
Change in Tumor Size
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.
Time frame: At baseline and at 4 weeks
Overall Response Rate (ORR)
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.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: Beginning at 12 weeks post initial treatment, up to 4 years
Overall Response Rate (ORR) - ITT (Intent-to-treat) Population
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.
Time frame: Beginning at 12 weeks post initial treatment, up to 4 years
Secondary Outcome: Clinical Benefit Rate
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.
Time frame: 12 weeks post initial treatment, up to 4 years
Clinical Benefit Rate - ITT (Intent-to-treat) Population
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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 4 years
Progression-free Survival (PFS) by Lead-in Arm
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.
Time frame: 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.
Time frame: Up to 4 years
CD8+ Tumor Infiltrating Lymphocytes
Number of CD8+ tumor infiltrating lymphocytes present.
Time frame: At Baseline
CD8+ Tumor Infiltrating Lymphocytes
Number of CD8+ tumor infiltrating lymphocytes present.
Time frame: At Week 4
CD4+ Tumor Infiltrating Lymphocytes
Number of CD4+ tumor infiltrating lymphocytes present.
Time frame: At Week 4
CD4+ Tumor Infiltrating Lymphocytes
Number of CD4+ tumor infiltrating lymphocytes present.
Time frame: At Baseline
LAG3 Levels - PBMC
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.
Time frame: At Baseline
LAG3 Levels - PBMC
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.
Time frame: At Week 4
LAG3 Levels - TIL
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.
Time frame: At Baseline
LAG3 Levels - PBMC
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.
Time frame: At Week 16
LAG3 Levels - TIL
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.
Time frame: At Week 4
PD-1 Expression in PBMC
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.
Time frame: At Baseline
PD-1 Expression in PBMC
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.
Time frame: At Week 4
PD-1 Expression in PBMC
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.
Time frame: At Week 16
PD-1 Expression in TIL
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.
Time frame: At Baseline
PD-1 Expression in TIL
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.
Time frame: At Week 4
Cell Effector/Memory Status - TIL
Measure of cells that have previously encountered and responded to their cognate antigen in TIL.
Time frame: At Baseline
Cell Effector/Memory Status - TIL
Measure of cells that have previously encountered and responded to their cognate antigen in TIL.
Time frame: At Week 4
Cell Effector/Memory Status - PBMCs
Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs.
Time frame: At Baseline
Cell Effector/Memory Status - PBMC
Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs.
Time frame: At Week 4
Cell Effector/Memory Status - PBMC
Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs.
Time frame: At Week 16
Regulatory T Cell (Treg) Marker Levels - PMBCs
Amount of Regulatory T cell (Treg) markers present in PBMCs in treated patients.
Time frame: At Baseline
Regulatory T Cell (Treg) Marker Levels - PMBCs
Amount of Regulatory T cell (Treg) markers present in PBMCs in treated patients.
Time frame: At Week 4
Regulatory T Cell (Treg) Marker Levels - PMBCs
Amount of Regulatory T cell (Treg) markers present in PBMCs in treated patients.
Time frame: At Week 16
Regulatory T Cell (Treg) Marker Levels - TIL
Amount of Regulatory T cell (Treg) markers present in TILs in treated patients.
Time frame: At Baseline
Regulatory T Cell (Treg) Marker Levels - TIL
Amount of Regulatory T cell (Treg) markers present in TILs in treated patients.
Time frame: At Week 4
Activation and Maturation of Dendritic Cells - PBMC
Measure of expression of activation and maturation of dendritic cells in PBMCs.
Time frame: At Baseline
Activation and Maturation of Dendritic Cells - PBMC
Measure of expression of activation and maturation of dendritic cells in PBMCs.
Time frame: At Week 4
Activation and Maturation of Dendritic Cells - PBMC
Measure of expression of activation and maturation of dendritic cells in PBMCs.
Time frame: At Week 16
Activation and Maturation of Dendritic Cells - TIL
Measure of expression of activation and maturation of dendritic cells in tumor (TIL).
Time frame: At Baseline
Activation and Maturation of Dendritic Cells - TIL
Measure of expression of activation and maturation of dendritic cells in tumor (TIL).
Time frame: At Week 4
Soluble LAG3 Levels - PBMC
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.
Time frame: At the time of disease progression - up to 4 years
Soluble LAG3 Levels - TIL
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.
Time frame: At the time of disease progression - up to 4 years
Granzyme B Serum Levels
Level of granzyme B (a serine protease secreted cells to mediate apoptosis in target cells) in serum.
Time frame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
T Cell Count
Number of T cells present in TIL or PBMC.
Time frame: At 4 weeks
T Cell Count
Number of T cells present in TIL or PBMC.
Time frame: At 12 weeks
T Cell Count
Number of T cells present in TIL or PBMC.
Time frame: At the time of disease progression - up to 4 years