Clinical trial NCT03743766: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Melanoma
Keywords: Stage IIIB
Stage IIIC
Stage IIID
Stage IV
immune checkpoint blockade (ICB)
Lymphocyte activation gene-3 (LAG3; CD223)
immunotherapy
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2018-11-16
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in LAG3 Expression
timeFrame: At baseline and at 4 weeks
measure: Change in PD1 expression
timeFrame: At baseline and at 4 weeks
measure: Change in Tumor Size
timeFrame: At baseline and at 4 weeks
measure: Overall Response Rate (ORR)
timeFrame: Beginning at 12 weeks post initial treatment, up to 4 years
Secondary outcomes:
measure: Clinical Benefit Rate
timeFrame: 12 weeks post initial treatment, up to 4 years
measure: Duration of Response
timeFrame: 12 weeks post initial treatment, up to 4 years
measure: Progression-free Survival (PFS)
timeFrame: Up to 4 years
measure: Overall Survival (OS)
timeFrame: Up to 4 years
measure: LAG3 Expression
timeFrame: At week 16 (2 weeks post combination treatment (3 cycles))
measure: PD-1 Expression
timeFrame: At week 16 (12 weeks post combination treatment (3 cycles))
measure: Change in CD4+ tumor infiltrating lymphocytes
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Change in CD8+ tumor infiltrating lymphocytes
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Change in granzyme B serum levels
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Change in cell effector/memory status
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Change in activation and maturation of dendritic cells
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Change in T cell count
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Change in T cell count
timeFrame: At the time of disease progression - up to 4 years
measure: Change in soluble LAG3 levels
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Soluble LAG3 levels
timeFrame: At the time of disease progression - up to 4 years
measure: Change in Regulatory T cell (Treg) marker level
timeFrame: At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks
measure: Regulatory T cell (Treg) marker levels
timeFrame: At the time of disease progression - up to 4 years
Other outcomes:
measure: Single cell RNA sequencing
timeFrame: 2 weeks
measure: Single cell RNA sequencing
timeFrame: At 4 weeks post Cycle 1
measure: Single cell RNA sequencing
timeFrame: At week 16 (12 weeks post combination treatment (3 cycles)
measure: Single cell RNA sequencing
timeFrame: At the time of disease progression - up to 4 years
Locations:
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: John Kirkwood, MD
role: PRINCIPAL_INVESTIGATOR
References: