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) on day 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 × 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.
- vorinostat
- 5-fluorouracil
- oxaliplatin
- pharmacokinetics
- phase I
- colon cancer
- thymidylate synthase
Footnotes
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Grant support: Cancer Therapy Evaluation Program, the National Cancer Institute (NCI); an Institutional Cancer Center Support Grant CA16056; an American Cancer Society Grant MRSG-04-270-01; NCI contract N01-CO-124001, subcontract 25XS115-Task Order 2; and NCI grant P30 CA47904.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Presented in part at American Society of Clinical Oncology 2007.
- Accepted January 21, 2009.
- Received November 16, 2008.
- Revision received January 19, 2009.
Volume 15, Issue 9
