Clinical Trials /

Nivolumab, BMS-936558 in Combination With Relatlimab, BMS-986016 in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting

NCT03743766

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

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

  • Melanoma

Interventions

DrugSynonymsArms
RelatlimabBMS-986016Relatlimab
NivolumabBMS-936558Nivolumab
Relatlimab + NivolumabBMS-986016 and BMS-936558Relatlimab + 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

NameTypeDescriptionInterventions
RelatlimabExperimentalCycle 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.
  • Relatlimab
NivolumabExperimentalCycle 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.
  • Nivolumab
Relatlimab + NivolumabExperimentalCycle 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.
  • Relatlimab + Nivolumab

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

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