Dose escalation of N,N',N"-triethylenethiophosphoramide combined with pentoxifylline for advanced breast cancer.

Pentoxifylline potentiates the cytotoxicity of alkylating agents in preclinical models. In this study we sought to define the maximum tolerated dose (MTD) of N,N',N"-triethylenethiophosphoramide (thioTEPA) with pentoxifylline, and to estimate the antitumor response to this combination in previously treated breast cancer patients. Thirty-five previously treated advanced breast cancer patients received 70 cycles (median, 2 cycles/patient; range, 1-6) of 1600 mg of oral sustained release pentoxifylline every 8 h for 4 doses in combination with escalating doses of i.v. bolus thioTEPA 40-65 mg/m2 administered 3 h after the second dose of pentoxifylline. Thrombocytopenia was dose limiting at 65 mg/m2 of thioTEPA, and the MTD was defined as 60 mg/m2. Among 25 patients treated at the MTD, leukopenia was grade 2 in 9 patients (36%), grade 3 in 4 patients (16%), and grade 4 in 2 patients (8%); thrombocytopenia was grade 2 in 3 patients (12%), grade 3 in 4 patients (16%), and grade 4 in 3 patients (12%). No other thioTEPA-related toxicity was observed. Plasma concentrations of thioTEPA, TEPA, and pentoxifylline were measured in 6 patients. The median (range) area under the plasma concentration versus time curve for thioTEPA was 29.4 microM/h (26. 2-40.5) and for TEPA was 16.3 microM/h (9.2-21.7 microM-h). The median (range) maximal plasma concentration of pentoxifylline and major metabolites I, IV, and V were 1.2 microgram/ml (0.2-7.8), 4.0 microgram/ml (0.5-16.4), 0.4 (range 0.1-0.8), and 2.9 (1.1-5.5), respectively. No objective responses were observed among 21 evaluable patients treated at the MTD (95% confidence interval, 0-15%). The combination of pentoxifylline and thioTEPA is well tolerated but not active in previously treated advanced breast cancer patients. Further clinical trials using commercially available oral sustained release pentoxifylline as a modulator of alkylating agents are not warranted.