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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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

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oxaliplatin
Leucovorin
Fluorouracil
Colorectal Neoplasms
Pharmacokinetics
Thymidylate Synthase
Fatigue
Maximum Tolerated Dose
vorinostat

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Fakih, Marwan G. ; Pendyala, Lakshmi ; Fetterly, Gerald ; Toth, Karoli ; Zwiebel, James A. ; Espinoza-Delgado, Igor ; Litwin, Alan ; Rustum, Youcef M. ; Ross, Mary Ellen ; Holleran, Julianne L. ; Egorin, Merrill J. / A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combinationwith 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 9. pp. 3189-3195.
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title = "A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combinationwith 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer",
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.",
author = "Fakih, {Marwan G.} and Lakshmi Pendyala and Gerald Fetterly and Karoli Toth and Zwiebel, {James A.} and Igor Espinoza-Delgado and Alan Litwin and Rustum, {Youcef M.} and Ross, {Mary Ellen} and Holleran, {Julianne L.} and Egorin, {Merrill J.}",
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Fakih, MG, Pendyala, L, Fetterly, G, Toth, K, Zwiebel, JA, Espinoza-Delgado, I, Litwin, A, Rustum, YM, Ross, ME, Holleran, JL & Egorin, MJ 2009, 'A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combinationwith 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer', Clinical Cancer Research, vol. 15, no. 9, pp. 3189-3195. https://doi.org/10.1158/1078-0432.CCR-08-2999

A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combinationwith 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer. / Fakih, Marwan G.; Pendyala, Lakshmi; Fetterly, Gerald; Toth, Karoli; Zwiebel, James A.; Espinoza-Delgado, Igor; Litwin, Alan; Rustum, Youcef M.; Ross, Mary Ellen; Holleran, Julianne L.; Egorin, Merrill J.

In: Clinical Cancer Research, Vol. 15, No. 9, 01.05.2009, p. 3189-3195.

Research output: Contribution to journalArticle

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T1 - A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combinationwith 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer

AU - Fakih, Marwan G.

AU - Pendyala, Lakshmi

AU - Fetterly, Gerald

AU - Toth, Karoli

AU - Zwiebel, James A.

AU - Espinoza-Delgado, Igor

AU - Litwin, Alan

AU - Rustum, Youcef M.

AU - Ross, Mary Ellen

AU - Holleran, Julianne L.

AU - Egorin, Merrill J.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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.

AB - 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.

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