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 feasibility of administering the polycyclic aromatic hydrocarbon crisnatol in increasingly prolonged continuous i.v. infusions to patients with advanced solid malignancies. The study also sought to characterize the-principal toxicities of crisnatol on this schedule, to recommend doses for subsequent disease-directed studies, and to characterize possible associations between pharmacological parameters and toxicity. Sixteen patients were treated with 40 courses of crisnatol administered as a continuous i.v. infusion. The initial dose-schedule was 750 mg/m2/day for 6 days, and the duration of the infusion was to be progressively increased by 3-day increments to 9, 12, 15, 18, and 21. Courses were to be repeated every 4 weeks. Moderate to severe central nervous system (CNS) toxicity precluded the administration of crisnatol 750 mg/m2/day for longer than 6 days, and, therefore, the dose of crisnatol was reduced to 600 mg/m2/day. At this dose, three of five patients receiving a 12-day infusion experienced dose-limiting toxicity, which consisted of pulmonary thromboembolism (two patients) and grade 4 thrombocytopenia (one patient). None of the six patients completing a 9-day infusion at 600 mg/m2/day developed dose-limiting toxicity during the first or second course of crisnatol. At this dose level, the plasma concentrations at steady state (Css) averaged 1607.8+/-261.1 ng/ml, which exceeds minimal inhibitory concentrations for most tumors in vitro (1000 ng/ml). In fact, the administration of crisnatol at a dose of 600 mg/m2/day for 9 days resulted in the longest duration that biologically relevant plasma crisnatol concentrations have been sustained. Plasma Css values were significantly higher in patients who experienced severe CNS toxicity compared with those who did not (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 reflecting renal and hepatic functions. One patient with a glioblastoma multiforme experienced a partial response lasting 14 months. The relative lack of intolerable CNS toxicity at the recommended dose for Phase II studies of crisnatol, 600 mg/m2/day for 9 days, as well as the magnitude of the Css values achieved and the antitumor activity observed at this dose, are encouraging. However, the mechanisms for the apparently increased thrombogenicity observed in this trial are unclear and require further elucidation.
Villalona-Calero
M A
MA
Institute for Drug Development, Cancer Therapy and Research Center, and The University of Texas Health Science Center at San Antonio, 78229, USA. villalona-1@medctr.osu.edu
Petit
T
T
Kuhn
J
J
Cobb
P
P
Kraynak
M
M
Eckhardt
S G
SG
Drengler
R
R
Simmons
C
C
Santabarbara
P
P
Von Hoff
D D
DD
Rowinsky
E K
EK
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002911:Chrysenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011409:Propylene Glycols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011655:Pulmonary Embolism / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D002911:Chrysenes; D011409:Propylene Glycols; C056722:crisnatol