Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours.
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.
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.|Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.
Ross Andrew
RA
Soo
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.|Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.
Nicholas
N
Syn
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.|Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.
Soo-Chin
SC
Lee
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.|Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.|Translational Laboratory in Genetic Medicine Agency for Science, Technology and Research (A*STAR), Singapore 8A Biomedical Grove Immunos Level 5, 138648 Singapore.
Lingzhi
L
Wang
Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.
Xn-Yii
XY
Lim
Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.|Translational Laboratory in Genetic Medicine Agency for Science, Technology and Research (A*STAR), Singapore 8A Biomedical Grove Immunos Level 5, 138648 Singapore.
Marie
M
Loh
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.
Sing-Huang
SH
Tan
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.
Ying-Kiat
YK
Zee
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.|Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.
Andrea Li-Ann
AL
Wong
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.
Benjamin
B
Chuah
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.
Daniel
D
Chan
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.
Siew-Eng
SE
Lim
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.|Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.|Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore, 21 Lower Kent Ridge Road, 119077 Singapore.
Boon-Cher
BC
Goh
Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.|Department of Pathology National University Health System National University of Singapore, Lower Kent Ridge Road, 119077 Singapore.
Richie
R
Soong
Department of Haematology-Oncology National University, Cancer Institute 1E Kent Ridge Road, NUHS Tower Block, Level 7, 119228 Singapore.|Cancer Science Institute of Singapore National University of Singapore Centre for Translational Medicine, 14 Medical Drive, #12-01, 117599 Singapore.
Wei-Peng
WP
Yong
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000069287:Capecitabine / Q000627:therapeutic use*; D002985:Clinical Protocols; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D054796:Drug Dosage Calculations; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000071185:Pharmacogenomic Testing; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics*
D000970:Antineoplastic Agents; D000069287:Capecitabine; D013940:Thymidylate Synthase