Dose Escalation of N,N’,N’ ‘-Triethylenethiophosphoramide Combined with Pentoxifylline for Advanced Breast Cancer1

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. Thirtyfive 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/rn2 administered 3 h after the second dose of pentoxifylline. Thrombocytopenia was dose limiting at 65 mg/rn2 of thioTEPA, and the MTD was defined as 60 mg/rn2. 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 isi/h (26.2-40.5) and for TEPA was 16.3 ui/h (9.2-21.7 uM-h). The median (range) maximal plasma concentration of pentoxifylline and major metabolites I, IV, and V were 1.2 ig/ml (0.2-7.8), 4.0 iWml (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 MTh (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 commerReceived 1/20/95; revised 5/15/95; accepted 5/18/95. I Supported in part by P01-CA 19589. Presented in part at the American Association for Cancer Research, May 1993, and a workshop entitled ‘ ‘ Pentoxifylline, Leukocytes, and Cytokines, ‘ ‘ Scottsdale, AZ, March 1991. 2 To whom requests for reprints should be addressed, at Breast Evaluation Center, Room 1508, Dana-Farber Cancer Institute, Boston, MA 021 15. C. L. S. is a recipient of the American Cancer Society Clinical Oncology Career Development Award. 3 Present Address: Department of Medical Oncology, University of California at San Francisco, San Francisco, CA 94143. cially available oral sustained release pentoxifylline as a modulator of alkylating agents are not warranted.