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Phase I and Pharmacokinetic Study of Vorinostat, A Histone Deacetylase Inhibitor, in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies

Authors' Affiliations: ¹ Division of Hematology-Oncology, Department of Medicine and ² Deparment of Pharmacology, University of Pittsburgh School of Medicine; ³ Molecular Therapeutics/Drug Discovery Program and ⁴ Biostatistics Facility, University of Pittsburgh Cancer Institute; ⁵ Biostatistics Department, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania and ⁶ Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Suresh S. Ramalingam, Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, MD5150 Centre Avenue, Suite 555, UPMC Cancer Pavilion, Pittsburgh, PA 15232. Phone: 412-648-6619; Fax: 412-648-6579; E-mail: ramalingams{at}upmc.edu.

Purpose: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel.

Experimental Design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized.

Results: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non–dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non–small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics.

Conclusions: Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m²). Encouraging anticancer activity was noted in patients with previously untreated non–small cell lung cancer.

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