title: Randomized multicenter phase II trial of subcutaneous recombinant human interleukin-12 versus interferon-alpha 2a for patients with advanced renal cell carcinoma.
abstract: Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial. A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2. Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions. The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority.
authors.affiliation: Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. motzerr@mskcc.org
authors.forename: R J
authors.initials: RJ
authors.lastname: Motzer
authors.forename: A
authors.initials: A
authors.lastname: Rakhit
authors.forename: J A
authors.initials: JA
authors.lastname: Thompson
authors.forename: J
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: B A
authors.initials: BA
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Ellerhorst
authors.forename: L H
authors.initials: LH
authors.lastname: Schwartz
authors.forename: W J
authors.initials: WJ
authors.lastname: Berg
authors.forename: R M
authors.initials: RM
authors.lastname: Bukowski
mesh_terms: D000328:Adult; D000368:Aged; D001201:Ascites / Q000209:etiology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013280:Stomatitis / Q000209:etiology
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D018664:Interleukin-12