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Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours. (Sci Rep, Jun 2016)

Soo RA1,2, Syn N1,2, Lee SC1,2, Wang L1,2,3, Lim XY2, Loh M2,3, Tan SH1, Zee YK1, Wong AL1,2, Chuah B1, Chan D1, Lim SE1, Goh BC1,2,4, Soong R2,5, Yong WP1,2

1Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.
2Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.
3Translational Laboratory in Genetic Medicine Agency for Science, Technology and Research (A*STAR), Singapore 8A Biomedical Grove Immunos Level 5, 138648 Singapore.
4Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore, 21 Lower Kent Ridge Road, 119077 Singapore.
5Department of Pathology National University Health System National University of Singapore, Lower Kent Ridge Road, 119077 Singapore.

Abstract:

The FDA-approved starting dosage of capecitabine is 1,250 mg/m(2), and market research indicates that U.S. physicians routinely prescribe 1,000 mg/m(2). Retrospective analyses however report reduced toxicity and efficacy in a subset of patients with the 3R/3R genotype of the thymidylate synthase gene enhancer region (TSER). This study sought to develop TSER genotype-specific guidelines for capecitabine dosing. Capecitabine was dose-escalated in advanced and/or metastatic cancer patients with TSER 3R/3R (Group A; N = 18) or 2R/2R + 2R/3R (Group B; N = 5) from 1,250 to 1,625 mg/m(2) b.i.d., every 2 weeks on/1 week off for up to 8 cycles. Parent and metabolites pharmacokinetics, adverse events, and tumour response were assessed. The maximum tolerated and recommended doses in 3R/3R patients are 1,625 mg/m(2) and 1,500 mg/m(2). At 1,500 mg/m(2), one in nine 3R/3R patients experienced a dose-limiting toxicity. Dosing guidelines for 2R/2R + 2R/3R remain undetermined due to poor accrual. The results indicate that 3R/3R patients may be amenable to 1,500 mg/m(2) b.i.d. on an intermittent schedule, and is the first to prospectively validate the utility of TSER pharmacogenetic-testing before capecitabine treatment.

PMID: 27296624