A phase I and pharmacological study of protracted infusions of crisnatol mesylate in patients with solid malignancies

This Phase I and pharmacological study was performed to assess the feasibil ity of administering the polycyclic aromatic hydrocarbon crisnatol in incre asingly prolonged continuous i.v. infusions to patients with advanced solid malignancies. The study also sought to characterize the principal toxiciti es of crisnatol on this schedule, to recommend doses for subsequent disease -directed studies, and to characterize possible associations between pharma cological parameters and toxicity. Sixteen patients were treated with 40 co urses of crisnatol administered as a continuous i.v. infusion. The initial dose-schedule was 750 mg/m(2)/day for 6 days, and the duration of the infus ion was to he progressively increased by 3-day increments to 9, 12, 15, 18, and 21. Courses were to be repeated every 4 weeks. Moderate to severe cent ral nervous system (CNS) toxicity precluded the administration of crisnatol 750 mg/m(2)/day for longer than 6 days, and, therefore, the dose of crisna tol was reduced to 600 mg/m(2)/day. At this dose, three of five patients re ceiving a 12-day infusion experienced dose-limiting toxicity, which consist ed of pulmonary thromboembolism (two patients) and grade 4 thrombocytopenia (one patient). None of the six patients completing a 9-day infusion at 600 mg/m(2)/day developed dose-limiting toxicity during the first or second co urse of crisnatol. At this dose level, the plasma concentrations at steady state (C-ss) averaged 1607.8 +/- 261.1 ng/ml, which exceeds minimal inhibit ory concentrations for most tumors in vitro (1000 ng/ml). In fact, the admi nistration of crisnatol at a dose of 600 mg/m(2)/day for 9 days resulted in the longest duration that biologically relevant plasma crisnatol concentra tions have been sustained. Plasma C-ss values were significantly higher in patients who experienced severe CNS toxicity compared,vith those who did no t (2465.3 +/- 1213.5 versus 1342 +/- 447.3 ng/ml; P = 0.04). There were no relationships evident between the clearance of crisnatol and indices reflec ting renal and hepatic functions. One patient with a glioblastoma multiform e experienced a partial response lasting 14 months. The relative lack of in tolerable CNS toxicity at the recommended dose for Phase II studies of cris natol, 600 mg/m(2)/day for 9 days, as well as the magnitude of the C-ss val ues achieved and the antitumor activity observed at this dose, are encourag ing. However, the mechanisms for the apparently increased thrombogenicity o bserved in this trial are unclear and require further elucidation.