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  • Title: Phase I and pharmacokinetic study of tomudex combined with 5-fluorouracil plus levofolinic acid in advanced head and neck cancer and colorectal cancer.
    Author: Caponigro F, Avallone A, McLeod H, Cartenì G, De Vita F, Casaretti R, Morsman J, Blackie R, Budillon A, De Lucia L, Gravina A, Catalano G, Comella P, Comella G.
    Journal: Clin Cancer Res; 1999 Dec; 5(12):3948-55. PubMed ID: 10632324.
    Abstract:
    In vitro studies have shown a schedule-dependent synergism between Tomudex and 5-fluorouracil (5-FU). Incubation of different types of head and neck and colorectal cancer cells with levofolinic acid (LFA) plus 5-FU for 4 or 24 h, after 24-h incubation with Tomudex, produces a clear synergism. The purpose of this study was to evaluate the tolerability and activity of a combination of Tomudex, LFA, and 5-FU in advanced head and neck and colorectal cancer. Furthermore, the potential for 5-FU pharmacomodulation by Tomudex was also evaluated through an intrapatient assessment of dihydropyrimidine dehydrogenase (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/m2 on day 1, LFA at a fixed dose of 250 mg/m2 on day 2, immediately followed by bolus 5-FU at the starting dose of 600 mg/m2. Tomudex and 5-FU doses were alternately escalated. Courses were repeated every 2 weeks. In the second course, LFA and 5-FU were administered on day 1 and Tomudex 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 and 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 [14C]FU and quantitation of metabolite formation. Fifty-eight patients were enrolled in the study. Dose escalation was stopped at step 8, because of the occurrence of dose-limiting toxicity in two of three patients. The dose level immediately before (3 mg/m2 Tomudex, 1050 mg/m2 5-FU) was selected for further evaluation. Tomudex and 5-FU mean dose intensities actually delivered at the seventh step were 1.32 and 462 mg/m2/week, respectively. Six of 40 patients with metastatic colorectal cancer obtained an objective response (15%; 95% confidence interval, 6-30%). In particular, three complete responses and three partial responses were observed. Six of 17 patients with locally advanced or metastatic head and neck cancer obtained an objective response (1 complete response + 5 partial responses; 35%; 95% confidence interval, 14-62%). Median duration of response in colorectal cancer patients was 12 months. 5-FU AUC was not significantly different between the two courses (median intrapatient difference, 9.3%; P = 0.28). DPD activity in course 1 was significantly higher than course 2 (P = 0.041) in the 16 patients in which values were evaluable. 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 actually delivered is higher than usually achieved in monotherapy. The absence of a clear pharmacokinetic interaction suggests that the synergism of Tomudex and 5-FU might occur at the cellular level.
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