The research protocol involves the determination of the maximal tolerated dose (MTD) of CNI-1493 in two different schedules and also the evaluation of the effect of CNI-1493 administration on the toxicity of high dose interleukin-2 (IL-2) being given as treatment for patiens with metastatic renal cell carcinoma (RCC) or melanoma. CNI-1493 is a guanylhydrazone compound which inhibits the production of pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6, MIP-1alpha, and MIP-1beta) and nitric oxide (NO) from activated macrophages. In preclinical models of tumor bearing rats CNI-1493 has been shown to decrease the toxicity of administered IL-2 but not its antitumor activity. Interleukin-2 is an FDA approved treatment for metastatic RCC and melanoma. The use of high dose IL-2 is limited by the toxicity of its administration manifested mainly by a syndrome referred to as the capillary leak syndrome (hypotension, fluid retention, prerenal azotemia) and systemic symptoms such as fever/chills and diarrhea. The toxicity of IL-2 is felt to be due to pro-inflammatory cytokines released by activated macrophages. CNI-1493 will first be administered by itself in a dose escalation scheme on two different schedules to determine the MTD in human subjects with metastatic RCC and melanoma and after a one week rest patients will be treated with standard high dose IL-2 with CNI-1493 to determine the effect of CNI-1493 administration on the toxicity of IL-2. The pharmacokinetics of CNI-1493 will be determined as well as the effect of CNI-1493 on IL-2 pharmacokinetics and cytokine levels in patients receiving IL-2.
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