A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer

Background: * Interleukin-15 (IL-15) is a powerful immunostimulatory cytokine with a broad range of biological activities. * In contrast to IL-2, IL-15 inhibits the activation-induced cell death (AICD) of T-cells and is not involved in the maintenance of CD4+CD25+ T regulatory cells that act as inhibitory checkpoints on the immune response. * IL-15 is involved in the proliferation, differentiation and activation of CD8+ T-cells and NK-cells, and the maintenance of long term CD8+ memory T-cells. * In preclinical studies, vaccinia-based vaccines expressing IL-15 induced long lasting, high-avidity cytotoxic CD8+ T-lymphocyte (CTL) mediated immunity, whereas the immunity mediated by IL-2 expressing vaccines was short-lived. Furthermore, IL-15 can overcome the lack of CD4 help in CTL induction. * IL-15 is highly active against a number of syngeneic mouse tumor models and it is also effective in augmenting the activity of NK-cells and CD8+ T-cells in rhesus macaques indicating that it may be active against human cancers. Objectives: * The primary objective of this trial is to determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of intravenous recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in subjects with metastatic malignant melanoma and renal cell cancer. * Secondary objectives include determination of rhIL-15 pharmacokinetics, in particular the time course of the decline of rhIL-15 from the serum following intravenous administration and the definition of the immunogenicity of rhIL-15 in subjects receiving this drug. * To characterize the biological effects of rhIL-15 on the proportions and absolute numbers of circulating NK-cells, and CD45RO+CD8+ T-cells and central or effector memory subsets based on expression of CD28, CD95, CCR7 and CD62L by flow cytometry and to determine its effects on the plasma levels of pro-inflammatory cytokines. * Obtain preliminary information on the antitumor effects of repeat cycles of rhIL-15 in patients with metastatic malignant melanoma and renal cell cancer. Eligibility Criteria: * Patients greater than or equal to 18 years-old with pathologically confirmed metastatic malignant melanoma or metastatic renal cell cancer. * Patients with metastatic renal cell cancer must either have refused treatment with, failed to tolerate, or have progressive disease after receiving sorafenib or sunitinib, and temsirolimus. * Patients with measurable disease. * Absolute granulocyte count (AGC) of at least 1500/mm(3) and a platelet count of at least 75,000/mm(3). Design: * This is a single institution, open-label, non-randomized 3 + 3 design phase I dose-escalation study to determine the safety, toxicity and MTD of rhIL-15 in patients with metastatic malignant melanoma and renal cell cancer. * Groups of 3 to 6 patients will receive rhIL-15 at doses of 0.3, 1, 3, 7, 10, 15, 20 or 25 mcg/kg/day for 12 days provided that DLT had not been observed. * Correlative protocol studies will be obtained prior to treatment and at specific times points during and after treatment including pharmacokinetics for the clearance of rhIL-15 from the serum, immunogenicity testing for the development of neutralizing anti-rhIL-15 antibodies and immunological study endpoint evaluation for the effect of rhIL-15 on immune cell subset populations and pro-inflammatory cytokine levels in the peripheral blood.