PROSPECTIVE RANDOMIZED TRIAL OF LISOFYLLINE FOR THE PREVENTION OF TOXICITIES OF HIGH-DOSE INTERLEUKIN-2 THERAPY IN ADVANCED RENAL-CANCER AND MALIGNANT-MELANOMA

The therapeutic application of high-dose interleukin (IL) 2 in human m alignancy is limited by severe multiorgan toxicities that are mediated , in part, by tumor necrosis factor (TNF) and IL-1, CT1501R (lisofylli ne; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pat hways, This randomized, placebo-controlled trial was designed to asses s the activity of LSF in reducing the toxicities of high-dose IL-2 the rapy, Fifty-three patients with metastatic renal cancer or malignant m elanoma 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 cours e of IL-2, Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolu s, or placebo every 6 h during IL-2 therapy, All patients were to be t reated to individual maximum tolerance of IL-2 at the intensive care u nit 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 an d placebo groups in the mean number of IL-2 doses tolerated in the ent ire 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 wa s 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 an alysis of major toxicities over the first 14-dose course of therapy sh owed a statistically significant difference favoring the LSE-treated g roup (P = 0.025), LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significan t for the entire first cycle), The antitumor activity was comparable i n both groups (objective responses, 2 of 28 with LSF versus 4 of 24 wi th placebo), The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 mu mol/liter, respectively, In conclu sion, 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 h igher doses of LSF, the development of agents with more potent anti-TN F activity, and/or combined modulating agents that function via distin ct mechanisms to interrupt cytokine-mediated signaling.