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Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours.


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.

SUBMITTER: Soo RA 

PROVIDER: S-EPMC4906519 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours.

Soo Ross Andrew RA   Syn Nicholas N   Lee Soo-Chin SC   Wang Lingzhi L   Lim Xn-Yii XY   Loh Marie M   Tan Sing-Huang SH   Zee Ying-Kiat YK   Wong Andrea Li-Ann AL   Chuah Benjamin B   Chan Daniel D   Lim Siew-Eng SE   Goh Boon-Cher BC   Soong Richie R   Yong Wei-Peng WP  

Scientific reports 20160614


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 TSE  ...[more]

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