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A Phase I Study of CNI-1493, an Inhibitor of Cytokine Release, in Combination with High-Dose Interleukin-2 in Patients with Renal Cancer and Melanoma¹

Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215 [M. B. A., J. M., J. G.]; University of Michigan Medical Center, Ann Arbor, Michigan 48109 [B. R.]; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033 [J. W.]; University of Illinois Medical Center, Chicago, Illinois 60612 [J. S.]; and Cytokine PharmaSciences, Inc., West Conshohocken, Pennsylvania 19428 [B. L. M., T. P.]

CNI-1493, an inhibitor of proinflammatory cytokines, was studied in a Phase I trial in melanoma and renal cancer patients receiving high-dose interleukin 2 (IL-2). Objectives of the study were to define the maximum tolerated dose (MTD) and toxicity of CNI-1493, to assess its pharmacological effects, and to define its pharmacokinetics. Twenty-four patients were treated in sequential cohorts with CNI-1493 doses from 2 through 32 mg/m² daily. Patients first received only CNI-1493 daily for 5 days. After a 9-day rest, patients received two 5-day courses of IL-2 of 600,000 IU/kg every 8 h for up to 14 doses/course plus daily CNI-1493; courses were separated by a 9-day rest period. CNI-1493 administered alone was well tolerated at doses through 32 mg/m²; MTD was not reached. The only clinical toxicity attributed to CNI-1493 was occasional injection-site phlebitis. Grade 1 creatinine increases occurred in 1 of 7 patients at 4 mg/m², in 1 of 1 patients at 25 mg/m², and in 3 of 6 patients at 32 mg/m² CNI-1493 alone. In combination with high-dose IL-2, CNI-1493 at 25 mg/m² seemed to exacerbate IL-2-induced nephrotoxicity: grade 3 or 4 creatinine increases developed in 3 of 6 patients at 25 or 32 mg/m², as compared with 1 of 16 patients at doses 16 mg/m². The MTD for CNI-1493 given with high-dose IL-2 was 16 mg/m². The dose-limiting toxicity of IL-2 was hypotension in 63% of patients; overall tolerance to IL-2 was not improved by CNI-1493. However, relative to changes seen in a reference group receiving high-dose IL-2 alone, at doses 4 mg/m² CNI-1493 did show evidence of pharmacological activity as an inhibitor of tumor necrosis factor production.

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