A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combinationwith 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer

Marwan G. Fakih, Lakshmi Pendyala, Gerald Fetterly, Karoli Toth, James A. Zwiebel, Igor Espinoza-Delgado, Alan Litwin, Youcef M. Rustum, Mary Ellen Ross, Julianne L. Holleran, Merrill J. Egorin

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50 Scopus citations

Abstract

Purpose: We conducted a phase I study to determine the maximum tolerated dose of vorinostat in combination with fixed doses of 5-fluorouracil (FU), leucovorin, and oxaliplatin (FOLFOX). Experimental Design: Vorinostat was given orally twice daily for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg twice daily. Escalation occurred in cohorts of three to six patients. Pharmacokinetics of vorinostat, FU, and oxaliplatin were studied. Results: Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose levels of vorinostat. Two of 4 evaluable patients at dose level 4 (vorinostat 400 mg orally twice daily) developed dose-limiting fatigue. One of 10 evaluable patients at dose level 3 (vorinostat 300 mg orally twice daily) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and the area under the curve on days 1 and 5 (Pearson, < 0.001). The vorinostat area under the curve increased (P = 0.005) and clearance decreased (P = 0.003) onday 5 compared with day 1. The median Cmax of FU at each dose level increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between FU and vorinostat. Vorinostat-induced thymidylate synthase (TS) modulation was not consistent; only two of six patients had a decrease in intratumoral TS expression by reverse transcription-PCR. Conclusions: The maximum tolerated dose of vorinostat in combination with FOLFOX is 300 mg orally twice daily x 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.

Original languageEnglish (US)
Pages (from-to)3189-3195
Number of pages7
JournalClinical Cancer Research
Volume15
Issue number9
DOIs
StatePublished - May 1 2009

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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