Nivolumab and Ipilimumab in Estimating Anti-Tumor Activity and Identifying Potential Predictors of Response in Patients with Melanoma That is Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To assess objective response rate (ORR, defined as complete response [CR] + partial response [PR] per investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients with mucosal melanoma (MCM).

SECONDARY OBJECTIVES:

I. To assess objective response rate (ORR, defined as complete response [CR] + partial response [PR] per investigator-assessed RECIST 1.1 criteria in patients with acral lentiginous melanoma (ALM).

II. To determine progression-free survival (PFS), and overall survival (OS) in each cohort.

III. To determine whether pre-existing immune cells infiltrate, as well as Ki-67 and PD-L1 expressing cells at the invasive tumor margin correlate with clinical response to a combination of CTLA-4 and PD-1 blocking therapy.

IV. To evaluate subject’s cancer genomic landscape using whole exome sequence profiling, identify the mutational pattern, and the frequency of somatic mutations and their relationship to tumor response in MCM and ALM, as well as subject’s cancer genomic landscape using whole exome sequence profiling and utilize bioinformatic tools to translate mutations in exomes to identify specific driver mutations in MCM and ALM.

EXPLORATORY OBJECTIVES:

I. To evaluate tumor’s putative neoantigen epitopes from le exome sequencing data and determine binding affinity to major histocompatibility complex (MHC) class I molecules as a potential predictor of response to combined checkpoint inhibitors treatment.

II. To determine clonal preservation, expansion, and selection of T-cell receptor rearrangement of tumor infiltrating lymphocytes before and after treatment with combined ipilimumab/nivolumab therapy as a correlative biomarker of treatment response.

III. To identify MCM and ALM gene expression profiling pattern associated with treatment response or resistance to combined checkpoint inhibitors treatment.

IV. To identify relationship of specific gut microbiota in MCM and ALM with CD8+T cell function and anti-tumor immunity.

V. To identify circulating cell-free nucleic acids and its pattern that might be associated with combined checkpoint inhibitor treatment response/resistance in order to further narrow the application of combined checkpoint inhibitors to those who will benefit the most.

OUTLINE:

INDUCTION: Patients receive nivolumab intravenously (IV) and ipilimumab IV on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive nivolumab IV every 2 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.