Tocilizumab, Ipilimumab, and Nivolumab for the Treatment of Advanced Melanoma, Non-Small Cell Lung Cancer, or Urothelial Carcinoma

PRIMARY OBJECTIVES: I. To characterize the safety and tolerability of systemic tocilizumab, an IL-6 receptor antagonist, in combination with Ipilimumab and nivolumab as front-line treatment for patients with advanced cutaneous melanoma, urothelial carcinoma and in EGFR mutant non-small cell lung cancer (NSCLC). II. To determine the grade 3 or higher toxicity rate of Tocilizumab in combination with Ipilimumab and nivolumab for patients with advanced cutaneous melanoma. SECONDARY OBJECTIVES: I. To estimate the objective response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR), and durable response rate (DRR), defined as the proportion of patients with objective responses of \> 6 months duration, as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and immune related RECIST (irRECIST). II. To estimate progression-free survival (PFS) defined as the time from the start of treatment to disease progression or death, whichever occurs first. III. To estimate overall survival (OS) defined as the time from the start of treatment to death from any cause. EXPLORATORY OBJECTIVE: I. To assess pre- and post-treatment blood/tumor biopsies for immunologic assessment and to explore any potential association between biomarker measurements and antitumor activity. OUTLINE: OUTLINE: Patients are assigned to 1 of 3 cohorts: 1=melanoma, 2=Urothelial, 3=NSCLC. COHORT 1: Patients with melanoma will receive ipilimumab intravenously (IV) over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment with ipilimumab and nivolumab repeats every 3 weeks for 4 doses, then treatment with nivolumab repeats every 4 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Cohort 1 will be divided into 2 sub-groups: sub-group 1 of 25 patients, and subgroup 2 of 10 patients that will consist of varying Tocilizumab administration doses. For sub-group 1, Tocilizumab 162mg will be administered subcutaneously every 2 weeks starting week 0, up to 12 weeks for a total of 6 doses. For sub-group 2 , Tocilizumab 162mg will be administered subcutaneously once every week starting at week 0 up to week 6 followed by Tocilizumab administered subcutaneously every 2 weeks starting at week 6 up to 12 weeks for a total of 9 doses. COHORT 2: Patients with urothelial cancer will receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment with ipilimumab and nivolumab repeats every 3 weeks for 4 doses, then treatment with nivolumab repeats every 4 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Starting on week 1, patients also receive tocilizumab SC every 2 weeks for up to 12 weeks (6 doses) in the absence of disease progression or unacceptable toxicity. COHORT 3: Patients with NSCLC receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 2 weeks for up to 2 years. Patients also receive tocilizumab SC every 2 weeks for up to 12 weeks (6 doses). Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 2 years.