Description:
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.
Title
- Brief Title: Nivolumab, BMS-936558 in Combination With Relatlimab, BMS-986016 in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting
- Official 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
Clinical Trial IDs
- ORG STUDY ID:
18-071
- NCT ID:
NCT03743766
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Relatlimab | BMS-986016 | Relatlimab |
Nivolumab | BMS-936558 | Nivolumab |
Relatlimab + Nivolumab | BMS-986016 and BMS-936558 | Relatlimab + Nivolumab |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Relatlimab | Experimental | 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. | |
Nivolumab | Experimental | 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. | |
Relatlimab + Nivolumab | Experimental | 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. | |
Eligibility Criteria
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Change in LAG3 Expression |
Time Frame: | At baseline and at 4 weeks |
Safety Issue: | |
Description: | 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. |
Secondary Outcome Measures
Measure: | Clinical Benefit Rate |
Time Frame: | 12 weeks post initial treatment, up to 4 years |
Safety Issue: | |
Description: | 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. |
Measure: | Duration of Response |
Time Frame: | 12 weeks post initial treatment, up to 4 years |
Safety Issue: | |
Description: | 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. |
Measure: | Progression-free Survival (PFS) |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | 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. |
Measure: | Overall Survival (OS) |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | Overall survival is defined as the time between the date of randomization and the date of death due to any cause. |
Measure: | LAG3 Expression |
Time Frame: | At week 16 (2 weeks post combination treatment (3 cycles)) |
Safety Issue: | |
Description: | 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. |
Measure: | PD-1 Expression |
Time Frame: | At week 16 (12 weeks post combination treatment (3 cycles)) |
Safety Issue: | |
Description: | 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. |
Measure: | Change in CD4+ tumor infiltrating lymphocytes |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Percentage and number of CD4+ tumor infiltrating lymphocytes present |
Measure: | Change in CD8+ tumor infiltrating lymphocytes |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Percentage and number of CD8+ tumor infiltrating lymphocytes present |
Measure: | Change in granzyme B serum levels |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Level of granzyme B (a serine protease secreted cells to mediate apoptosis in target cells) in serum. |
Measure: | Change in cell effector/memory status |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Measure of cells that have previously encountered and responded to their cognate antigen. |
Measure: | Change in activation and maturation of dendritic cells |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Measure of expression of activation and maturation of dendritic cells |
Measure: | Change in T cell count |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Number of T cells present in blood and tumor |
Measure: | Change in T cell count |
Time Frame: | At the time of disease progression - up to 4 years |
Safety Issue: | |
Description: | 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. |
Measure: | Change in soluble LAG3 levels |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Amount of LAG3 (cell surface molecule expressed on activated T cells) protein present in blood and tumor tissue. |
Measure: | Soluble LAG3 levels |
Time Frame: | At the time of disease progression - up to 4 years |
Safety Issue: | |
Description: | 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. |
Measure: | Change in Regulatory T cell (Treg) marker level |
Time Frame: | At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks |
Safety Issue: | |
Description: | Amount of Regulatory T cell (Treg) markers present in blood and tumor tissue. |
Measure: | Regulatory T cell (Treg) marker levels |
Time Frame: | At the time of disease progression - up to 4 years |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | John Kirkwood |
Trial Keywords
- Stage IIIB
- Stage IIIC
- Stage IIID
- Stage IV
- immune checkpoint blockade (ICB)
- Lymphocyte activation gene-3 (LAG3; CD223)
- immunotherapy
Last Updated
April 23, 2021