Phase I trial of escalating pentoxifylline dose with constant dose thiotepa.
Pentoxifylline, a methylxanthine, is an effective modulator of alkylating agents in tissue culture and in human tumor explants in mice. In this Phase I trial, escalating dose controlled release pentoxifylline was administered p.o. 3 times daily for 5 days (15 doses) with a constant dose of thiotepa, 40 mg/m2 i.v. on day 2. Forty-four courses of escalating doses of pentoxifylline varying from 400 to 2400 mg were administered to 22 patients with refractory malignancies. Gastrointestinal toxicity, consisting mainly of nausea and vomiting, was dose limiting at 2400 mg pentoxifylline and subsided completely within 24 h of cessation of the drug. Nongastrointestinal toxicity of this thiotepa/pentoxifylline combination was infrequent and included bone marrow depression and supraventricular tachycardia. Increasing the dose of pentoxifylline did not increase the frequency of these rare toxic effects. Plasma concentrations of pentoxifylline and its major metabolites were determined by gas chromatography. Drug accumulation was noted within a cycle (i.e., by day 5) in only two patients and between cycles in no patient. The recommended Phase II dose of p.o. pentoxifylline is 1600 mg (four 400-mg tablets) when given 3 times daily for 5 days (15 doses) with 40 mg/m2 i.v. thiotepa. Based on an interspecies comparison, this dose exceeds that predicted from mouse models to enhance chemotherapy. This regimen can be safely administered on an outpatient basis, with adequate control of gastrointestinal symptoms achieved by standard antiemetics and intermittent dosing with meals. Phase II trials are required to determine the activity of alkylator/modulator combinations.
Dezube
B J
BJ
Department of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Eder
J P
JP
Pardee
A B
AB
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010431:Pentoxifylline / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013852:Thiotepa / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity
D013852:Thiotepa; D010431:Pentoxifylline