A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors

Marwan G. Fakih, Gerald Fetterly, Merrill J. Egorin, Josephia R. Muindi, Igor Espinoza-Delgado, James A. Zwiebel, Alan Litwin, Julianne L. Holleran, Kangsheng Wang, Robert B Diasio

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Abstract

Purpose: We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Experimental Design: Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hours followed by FU 400 mg/m 2 i.v. bolus and 2,400 mg/m2 over 46 hours (sLV5FU2). Results: Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. Conclusions: The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination.

Original languageEnglish (US)
Pages (from-to)3786-3794
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number14
DOIs
StatePublished - Jul 15 2010

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Leucovorin
Fluorouracil
Appointments and Schedules
Pharmacokinetics
Maximum Tolerated Dose
Neoplasms
Fatigue
Colorectal Neoplasms
Hand-Foot Syndrome
Thymidylate Synthase
Clinical Trials, Phase I
Mucositis
vorinostat
Research Design
Down-Regulation
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors. / Fakih, Marwan G.; Fetterly, Gerald; Egorin, Merrill J.; Muindi, Josephia R.; Espinoza-Delgado, Igor; Zwiebel, James A.; Litwin, Alan; Holleran, Julianne L.; Wang, Kangsheng; Diasio, Robert B.

In: Clinical Cancer Research, Vol. 16, No. 14, 15.07.2010, p. 3786-3794.

Research output: Contribution to journalArticle

Fakih, Marwan G. ; Fetterly, Gerald ; Egorin, Merrill J. ; Muindi, Josephia R. ; Espinoza-Delgado, Igor ; Zwiebel, James A. ; Litwin, Alan ; Holleran, Julianne L. ; Wang, Kangsheng ; Diasio, Robert B. / A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 14. pp. 3786-3794.
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T1 - A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors

AU - Fakih, Marwan G.

AU - Fetterly, Gerald

AU - Egorin, Merrill J.

AU - Muindi, Josephia R.

AU - Espinoza-Delgado, Igor

AU - Zwiebel, James A.

AU - Litwin, Alan

AU - Holleran, Julianne L.

AU - Wang, Kangsheng

AU - Diasio, Robert B

PY - 2010/7/15

Y1 - 2010/7/15

N2 - Purpose: We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Experimental Design: Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hours followed by FU 400 mg/m 2 i.v. bolus and 2,400 mg/m2 over 46 hours (sLV5FU2). Results: Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. Conclusions: The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination.

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