UGT1A1 genotype-guided phase i study of irinotecan, oxaliplatin, and capecitabine

Matthew P. Goetz, Heidi A. McKean, Joel M. Reid, Sumithra J. Mandrekar, Angelina D. Tan, Mary A. Kuffel, Stephanie L. Safgren, Renee M. McGovern, Richard M. Goldberg, Axel A. Grothey, Robert McWilliams, Charles Erlichman, Matthew M. Ames

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Purpose We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN). Experimental design Patients were screened for UGT1A1*28 genotype prior to treatment. The starting dose (mg/m2) was IRIN (150), OX (85) and CAP (400), days 2-15. Doses were escalated or de-escalated within each genotype group (*28/*28,*1/*28 and*1/*1). IRIN pharmacokinetics was performed at the MTD. Results 50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1*28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1*28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1*1/*28 and*1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1*1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1*1/*1. UGT1A1*1/*28 and*1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/- 278 and 350 +/- 159 ng/ml*hr, respectively). UGT1A1*28/*28 patients (n = 3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/- 289 ng/ml*hr, p = 0.14). Antitumor activity was observed in all genotype groups. Conclusions UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).

Original languageEnglish (US)
Pages (from-to)1559-1567
Number of pages9
JournalInvestigational New Drugs
Volume31
Issue number6
DOIs
StatePublished - Dec 1 2013

Keywords

  • Capecitabine
  • Irinotecan
  • Oxaliplatin
  • UGT1A1

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Goetz, M. P., McKean, H. A., Reid, J. M., Mandrekar, S. J., Tan, A. D., Kuffel, M. A., Safgren, S. L., McGovern, R. M., Goldberg, R. M., Grothey, A. A., McWilliams, R., Erlichman, C., & Ames, M. M. (2013). UGT1A1 genotype-guided phase i study of irinotecan, oxaliplatin, and capecitabine. Investigational New Drugs, 31(6), 1559-1567. https://doi.org/10.1007/s10637-013-0034-9