Phase I study to determine the safety and pharmacokinetics of oral administration of TAS‐102 in patients with solid tumors

Abstract

BACKGROUND The purpose of the current study was to determine the maximum tolerated dose, dose‐limiting toxicities, pharmacokinetic profile, and recommended Phase II dose of oral administration of TAS‐102, a novel nucleoside formed by the combination of α,α,α‐trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI: 5‐chloro‐6‐(2‐iminopyrrolidin‐1‐yl)methyl‐2,4(1H,3H)‐pyrimidinedione). METHODS Eligible patients had advanced solid tumors, adequate organ function, and had not received anticancer therapy in the preceding 4 weeks. TAS‐102 was administered orally once daily for 14 days, followed by a 1‐week rest, repeated every 3 weeks. The initial dose of TAS‐102 administered was 100 mg/m2/day. The first 2 patients treated at that dose experienced substantial toxicity and, therefore, lower dose levels of TAS‐102 were subsequently explored. RESULTS Fourteen patients were enrolled; all patients were evaluable for toxicity assessment and 12 were evaluable for response. The initial dose explored was 100 mg/m2/day, based on a preclinical monkey model. However, the first 2 patients experienced bone marrow suppression of Grade 3 or 4 in course 1. The protocol was amended to study the next cohort of patients at 50 mg/m2/day. At this dose level no Grade 3 or 4 toxicities were observed in course 1. In the subsequent dose level (60 mg/m2/day), 3 of 6 patients experienced Grade 3 or 4 granulocytopenia as dose‐limiting toxicity. Three additional patients for a total of 6 were enrolled at 50 mg/m2/day without occurrence of dose‐limiting toxicity. Thus, 50 mg/m2/day was declared the maximum tolerated dose for this schedule. CONCLUSIONS The authors' study showed that 50 mg/m2/day was a tolerable dose of the novel antimetabolite FTD in combination with an inhibitor of its inactivating enzyme TP, and this is the recommended Phase II dose. Evaluation of this daily dose in malignancies for which fluoropyrimidines have failed is needed. Cancer 2006. © 2006 American Cancer Society.

TAS-102 for Treatment of Advanced Colorectal Cancers That Are No Longer Responding to Other Therapies

“…Because the 2-week rest between doses did not decrease blood concentration of FTD, and because of the higher administered dose, the 2-weekson, 2-weeks-off schedule was recommended. Consistent with the data from the study by Hong and colleagues (12), neutropenia was the DLT for both dosing schedules. No objective responses were seen, but SD was observed in almost 30% of patients (13).…”

“…Of note, 50 mg/m 2 /day was declared the MTD, with neutropenia being the dose-limiting toxicity (DLT). No objective tumor responses were observed, but stable disease (SD) was observed in 29% of patients (12).…”

Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks

“…Intriguingly, in a xenograft model, TAS-102 exhibits similar antitumor activity on FU-resistant cells and their parental cell line (15). In addition, TAS-102 has been developed for use in the clinic (16)(17)(18)(19) and surprisingly, significantly improves overall survival of patients with metastatic colorectal cancer who were refractory or intolerant to fluoropyrimidine, irinotecan, or oxaliplatin in a placebo-controlled, double-blinded randomized phase II study (20). However, it is not fully understood how FTD exerts its cytotoxic effects on tumor cells that are resistant to chemotherapeutic drugs.…”

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

“…TAS-102 is currently evaluated in different treatment schedules in phase I clinical trials (Hong et al, 2006). Trifluorothymidine acts by incorporation into DNA leading to DNA-strand breaks (Emura et al, 2004c), and by inhibition of thymidylate synthase (TS) (Eckstein et al, 1994;Temmink et al, 2004;Temmink et al, 2005), one of the major rate-limiting enzymes in DNA synthesis.…”