PHASE-I STUDY OF BRYOSTATIN-1 - ASSESSMENT OF INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCTION IN-VIVO

Background: Many oncogenes have been shown to code for growth factor r eceptors that are involved in regulation of cell growth and proliferat ion and can activate transcription via protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, has demonstrated potent antitu mor activity in vitro and in vivo in human tumor xenografts. Purpose: The aim of this phase I study was to determine the optimal dosage and toxicity profile of bryostatin 1 and its influence on cytokine release in vivo. Methods: Three successive cohorts consisting of 35 patients with various malignant tumors were treated with bryostatin 1 by intrav enous infusion over 1 hour as follows: cohort A-35 mug/m2 (three patie nts) or 50 mug/m2 (eight patients) once every 2 weeks; cohort B-25 mug /m2 once a week (eight patients); and cohort C-25 mug/m2 once a week f or 3 weeks, with no treatment during the 4th week (16 patients). Plasm a levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) were measured by immunoradiometric assay and by radioimmunoassa y, respectively. Results: The dose-limiting toxicity was grade 3 or 4 myalgia in four of 11 patients in cohort A, in two of eight in cohort B, and in none of 16 in cohort C. Occurrence of myalgia was dose relat ed. There was no significant myelosuppression, apart from a small and transient fall in platelet count. Six patients experienced acute but t ransient skin flushing, dyspnea, hypotension, and bradycardia, probabl y related to the bryostatin 1 vehicle. TNF-alpha and IL-6 were detecte d in plasma at 2 and 24 hours after treatment, respectively, and the l evels were dose related (P = .02). Two patients with metastatic malign ant melanoma had partial remission after three or four cycles of thera py; remission lasted 6 weeks and 10+ months, respectively. Conclusions : The dose-limiting toxicity of bryostatin 1 was myalgia. Plasma IL-6 and TNF-alpha concentrations were increased within 24 hours of therapy . Antitumor activity against malignant melanoma was observed early in the course of treatment. Implications: The recommended dosage of bryos tatin 1 for phase II studies is 25 mug/m2 by intravenous infusion for 1 hour once a week for 3 weeks, with no treatment in the 4th week. IL- 6 and TNF-alpha plasma concentrations may be useful in monitoring biol ogical activity of bryostatin 1. Future studies should explore use of this drug with other conventional immune modulators and conventional c ytotoxic drugs.