Phase II Study of Aldesleukin (IL-2) Following the Administration of Zanolimumab (Anti-CD4mAb) in Metastatic Melanoma and Metastatic Renal Cancer

Background: Zanolimumab is a human monoclonal antibody (mAb) that specifically recognizes CD4 protein expressed on a subset of T lymphocytes and on monocytes from humans, and non-human primates. Ongoing clinical studies have identified a 14 mg/kg dose of zanolimumab weekly as a safe and efficacious dose. Toxicities of zanolimumab included headache, influenza-like illness, injection/infusion site reaction, nasopharyngitis, pyrexia, diarrhea, fatigue, and cytokine release syndrome at the time of infusion. The current protocol is based on the hypothesis that transient elimination of CD4+ T-regulatory cells with zanolimumab will enhance the clinical effectiveness of aldesleukin (IL-2) administration by decreasing T-regulatory cell generation. Objectives: Primary objective: Determine the ability of a combination of aldesleukin and zanolimumab (anti-CD4 mAb) administration to mediate tumor regression in patients with metastatic melanoma and metastatic kidney cancer. Secondary objectives: Determine the rate of depletion and repopulation of CD4+ cells. Determine the toxicity of this treatment. Determine the potential for pharmacokinetic interaction between zanolimumab and aldesleukin. Eligibility: Patients who are 18 years of age or older must have: measurable metastatic melanoma or metastatic kidney cancer; clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, or 1. Patients may not have: previously received high dose aldesleukin. Design: Patients will receive zanolimumab at a dose of 14 mg/kg as an intravenous (i.v.) infusion weekly for 9 weeks. After the fifth and seventh dose of zanolimumab, aldesleukin will administered as an i.v. bolus at a dose of 720,000 IU/kg every 8 hours for a maximum of 15 doses. Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) and clinical laboratory evaluation 2 weeks after zanolimumab administration. If the patient has stable disease (SD) or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will be followed with this evaluation every 3-4 months until off study criteria are met. If patients have stable disease or a partial response to treatment after the initial evaluation, or if a patient recurs or progresses after a clinical response, they may be eligible for re-treatment. Patients will be entered into one of two strata: metastatic melanoma or metastatic renal cancer. Each of the strata will be conducted using an optimal two-stage phase II design to rule out an unacceptably low 15% clinical response rate, in favor of a modestly high response rate of 35% (p1=0.35).