Phase I and pharmacokinetic study of Tomudex combined with 5-fluorouracil plus levofolinic acid in advanced head and neck cancer and colorectal cancer

In vitro studies have shown a schedule-dependent synergism between Tomudex and 5-fluorouracil (5-FU), Incubation of different types of head and neck a nd colorectal cancer cells with levofolinic acid (LFA) plus 5-FU for 4 or 2 4 h, after 24-h incubation with Tomudex, produces a clear synergism, The pu rpose of this study was to evaluate the tolerability and activity of a comb ination of Tomudex, LFA, and 5-FU in advanced head and neck and colorectal cancer, Furthermore, the potential for 5-FU pharmacomodulation by Tomudex w as also evaluated through an intrapatient assessment of dihydropyrimidine d ehydrogenase (DPD) activity and 5-FU AUC with and without pretreatment with Tomudex, Eligible patients were treated with Tomudex at the starting dose of 1.5 mg/m(2) on day 1, LFA at a fixed dose of 250 mg/m(2) on day 2, immed iately followed by bolus 5-FU at the starting dose of 600 mg/m(2). Tomudex and 5-FU doses were alternately escalated. Courses were repeated every 2 we eks, In the second course, LFA and 5-FU were administered on day 1 and Tomu dex on day 2; further treatment was given according to the sequence used in the first course. Plasma 5-FU concentrations were analyzed on courses 1 an d 2 using a high-performance liquid chromatography assay with UV detection. DPD activity was measured in peripheral blood mononuclear cells on courses 1 and 2 using incubation of cytosol with [C-14]FU and quantitation of meta bolite formation, Fifty-eight patients were enrolled in the study. Dose esc alation was stopped at step 8, because of the occurrence of dose-limiting t oxicity in two of three patients. The dose level immediately before (3 mg/m (2) Tomudex, 1050 mg/m(2) 5-FU) was selected for further evaluation. Tomude x and 5-FU mean dose intensities actually delivered at the seventh step wer e 1.32 and 462 mg/m(2)/week, respectively. Six of 40 patients with metastat ic colorectal cancer obtained an objective response (15%; 95% confidence in terval, 6-30%). In particular, three complete responses and three partial r esponses were observed, Six of 17 patients with locally advanced or metasta tic head and neck cancer obtained an objective response (1 complete respons e + 5 partial responses; 35%; 95% confidence interval, 14-62%), Median dura tion of response in colorectal cancer patients was 12 months. 5-FU AUC was not significantly different between the two courses (median Intrapatient di fference, 9.3%; P = 0.28), DPD activity in course 1 was significantly highe r than course 2 (P = 0.041) in the 16 patients in which values were evaluab le. The combination of Tomudex, LFA, and 5-FU is well tolerated and active in colorectal and head and neck cancer. The Tomudex mean dose intensity act ually delivered is higher than usually achieved in monotherapy, The absence of a clear pharmacokinetic interaction suggests that the synergism of Tomu dex and 5-FU might occur at the cellular level.