A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-desk interleukin-2 in patients with renal cancer and melanoma

CNI-1493, an inhibitor of proinflammatory cytokines, was studied in a Phase I trial in melanoma and renal cancer patients receiving high-dose interleu kin 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 s equential cohorts with CNI-1493 doses from 2 through 32 mg/m(2) daily. Pati ents first received only CNI-1493 daily for 5 days. After a 9-day rest, pat ients 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 r est period. CNI-1493 administered alone was well tolerated at doses through 32 mg/m(2); MTD was not reached. The only clinical toxicity attributed to CNI-1493 was occasional injection-site phlebitis, Grade 1 creatinine increa ses occurred in 1 of 7 patients at 4 mg/m(2), in 1 of 1 patients at 25 mg/m (2), and in 3 of 6 patients at 32 mg/m(2) CNI-1493 alone. In combination wi th high-dose IL-2, CNI-1493 at greater than or equal to 25 mg/m(2) seemed t o exacerbate IL-2-induced nephrotoxicity: grade 3 or 4 creatinine increases developed in 3 of 6 patients at 25 or 32 mg/m(2), as compared with 1 of 16 patients at doses less than or equal to 16 mg/m(2). The MTD for CNI-1493 g iven with high-dose IL-2 was 16 mg/m(2). The dose-limiting toxicity of IL-2 was hypotension in 63% of patients; overall tolerance to IL-2 was not impr oved by CNI-1493, However, relative to changes seen in a reference group re ceiving high-dose IL-2 alone, at doses greater than or equal to4 mg/m(2) CN I-1493 did show evidence of pharmacological activity as an inhibitor of tum or necrosis factor production.