title: Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma.
abstract: The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.
authors.affiliation: City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: K
authors.initials: K
authors.lastname: Margolin
authors.forename: M
authors.initials: M
authors.lastname: Atkins
authors.forename: J
authors.initials: J
authors.lastname: Sparano
authors.forename: J
authors.initials: J
authors.lastname: Sosman
authors.forename: G
authors.initials: G
authors.lastname: Weiss
authors.forename: M
authors.initials: M
authors.lastname: Lotze
authors.forename: J
authors.initials: J
authors.lastname: Doroshow
authors.forename: J
authors.initials: J
authors.lastname: Mier
authors.forename: K
authors.initials: K
authors.lastname: O'Boyle
authors.forename: R
authors.initials: R
authors.lastname: Fisher
authors.forename: E
authors.initials: E
authors.lastname: Campbell
authors.forename: J
authors.initials: J
authors.lastname: Rubin
authors.forename: D
authors.initials: D
authors.lastname: Federighi
authors.forename: S
authors.initials: S
authors.lastname: Bursten
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009010:Monte Carlo Method; D009325:Nausea / Q000139:chemically induced; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010919:Placebos; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007376:Interleukin-2; D010919:Placebos; D011994:Recombinant Proteins; D003404:Creatinine; C025189:lisofylline; D010431:Pentoxifylline