Melanoma
Conditions
Keywords
Stage IIIB, Stage IIIC, Stage IIID, Stage IV, immune checkpoint blockade (ICB), Lymphocyte activation gene-3 (LAG3; CD223), immunotherapy
Brief summary
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.
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.
Interventions
DRUGRelatlimab
Relatlimab (BMS-986016) - 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV.
DRUGNivolumab
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.
Sponsors
John Kirkwood
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
In the 4-week lead-in phase, subjects will be randomized to one of three arms for 1 cycle (4 weeks) of lead-in treatment with nivolumab, relatlimab, or the combination of nivolumab and relatlimab. Following 1 cycle of lead-in treatment, all subjects will be treated with the combination of relatlimab and nivolumab every 4 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 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. |
| Overall Response Rate (ORR) - ITT (Intent-to-treat) Population | 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. |
| PD1 Expression | At baseline (Week 0) | Percent PD1 (programmed cell death protein 1) expression after completion of lead-in phase. |
| Change in Tumor Size | 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. |
| LAG3 Gene Expression From scRNAseq | At Baseline | Percent Lymphocyte-activation gene 3 (LAG3) level (cell surface molecule expressed on activated T cells) expression from scRNAseq |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Outcome: Clinical Benefit Rate | 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. |
| Clinical Benefit Rate - ITT (Intent-to-treat) Population | 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. |
| Duration of Response | 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. |
| Progression-free Survival (PFS) | 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. |
| Progression-free Survival (PFS) by Lead-in Arm | 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. |
| Overall Survival (OS) | 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. |
| CD8+ Tumor Infiltrating Lymphocytes | At Baseline | Number of CD8+ tumor infiltrating lymphocytes present. |
| CD4+ Tumor Infiltrating Lymphocytes | At Week 4 | Number of CD4+ tumor infiltrating lymphocytes present. |
| LAG3 Levels - PBMC | 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. |
| LAG3 Levels - TIL | 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. |
| PD-1 Expression in PBMC | 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. |
| PD-1 Expression in TIL | 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. |
| Cell Effector/Memory Status - TIL | At Baseline | Measure of cells that have previously encountered and responded to their cognate antigen in TIL. |
| Cell Effector/Memory Status - PBMCs | At Baseline | Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs. |
| Cell Effector/Memory Status - PBMC | At Week 4 | Measure of cells that have previously encountered and responded to their cognate antigen in PBMCs. |
| Soluble LAG3 Levels - PBMC | 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. |
| Soluble LAG3 Levels - TIL | 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. |
| Granzyme B Serum Levels | 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. |
| T Cell Count | At 4 weeks | Number of T cells present in TIL or PBMC. |
| Regulatory T Cell (Treg) Marker Levels - PMBCs | At Baseline | Amount of Regulatory T cell (Treg) markers present in PBMCs in treated patients. |
| Regulatory T Cell (Treg) Marker Levels - TIL | At Baseline | Amount of Regulatory T cell (Treg) markers present in TILs in treated patients. |
| Activation and Maturation of Dendritic Cells - PBMC | At Baseline | Measure of expression of activation and maturation of dendritic cells in PBMCs. |
| Activation and Maturation of Dendritic Cells - TIL | At Baseline | Measure of expression of activation and maturation of dendritic cells in tumor (TIL). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJohn Kirkwood, MD
University of Pittsburgh
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69.00 years |
| BRAF.STATUS Mutated | 7 Participants |
| BRAF.STATUS Unknown | 5 Participants |
| BRAF.STATUS Wild-Type | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 14 | 7 / 15 | 5 / 14 |
| other Total, other adverse events | 14 / 14 | 15 / 15 | 14 / 14 |
| serious Total, serious adverse events | 6 / 14 | 9 / 15 | 7 / 14 |
Outcome results
None listed