Journal article
A Phase I, Pharmacokinetic and Pharmacodynamic Study on Vorinostat in Combination with 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Refractory Colorectal Cancer
Clinical cancer research, Vol.15(9), pp.3189-3195
05/01/2009
DOI: 10.1158/1078-0432.CCR-08-2999
PMCID: PMC4134938
PMID: 19383814
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 close-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 C(max) 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.
Details
- Title: Subtitle
- A Phase I, Pharmacokinetic and Pharmacodynamic Study on Vorinostat in Combination with 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Refractory Colorectal Cancer
- Creators
- Marwan G. Fakih - Roswell Park Cancer InstituteLakshmi Pendyala - Roswell Park Cancer InstituteGerald Fetterly - Roswell Park Cancer InstituteKaroli Toth - Roswell Park Cancer InstituteJames A. Zwiebel - National Institutes of HealthIgor Espinoza-Delgado - National Institutes of HealthAlan Litwin - Department of RadiologyYoucef M. Rustum - Roswell Park Cancer InstituteMary Ellen Ross - Roswell Park Cancer InstituteJulianne L. Holleran - University of PittsburghMerrill J. Egorin - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.15(9), pp.3189-3195
- DOI
- 10.1158/1078-0432.CCR-08-2999
- PMID
- 19383814
- PMCID
- PMC4134938
- NLM abbreviation
- Clin Cancer Res
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 7
- Grant note
- CA16056; N01-CO-124001; P30 CA47904 / Institutional Cancer Center National Cane er Institute (NCI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) MRSG-04-270-01 / American Cancer Society P30CA047904 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 05/01/2009
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359782802771
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