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
42
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
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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: Beginning at 12 weeks post initial treatment, up to 4 years
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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.
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
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
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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: At the time of disease progression - up to 4 years