title: 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 melanoma.
abstract: 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 > or = 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 < or = 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 > or = 4 mg/m2 CNI-1493 did show evidence of pharmacological activity as an inhibitor of tumor necrosis factor production.
authors: Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors: M B
authors: MB
authors: Atkins
authors: B
authors: B
authors: Redman
authors: J
authors: J
authors: Mier
authors: J
authors: J
authors: Gollob
authors: J
authors: J
authors: Weber
authors: J
authors: J
authors: Sosman
authors: B L
authors: BL
authors: MacPherson
authors: T
authors: T
authors: Plasse
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy; D015331:Cohort Studies; D003404:Creatinine / Q000652:urine; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000813:Anilides; D006146:Guanidines
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003404:Creatinine; D016207:Cytokines; D006835:Hydrazones; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines