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

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 w...

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Published in:	Clinical cancer research Vol. 13; no. 12; pp. 3605 - 3610
Main Authors:	RAMALINGAM, Suresh S, PARISE, Robert A, BELANI, Chandra P, RAMANANTHAN, Ramesh K, LAGATTUTA, Theodore F, MUSGUIRE, Lori A, STOLLER, Ronald G, POTTER, Douglas M, ARGIRIS, Athanassios E, ZWIEBEL, James A, EGORIN, Merrill J
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-06-2007
Subjects:	Adult Aged Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Area Under Curve Biological and medical sciences carboplatin Carboplatin - administration & dosage Female histone deacetylase Humans Hydroxamic Acids - administration & dosage Hydroxamic Acids - pharmacokinetics Male Maximum Tolerated Dose Medical sciences Middle Aged Neoplasms - drug therapy non–small cell lung cancer paclitaxel Paclitaxel - administration & dosage Pharmacology. Drug treatments phase I vorinostat Antineoplastic agent Drug combination Malignancy Malignant tumor Histone deacetylase inhibitor Taxane derivatives Vorinostat Paclitaxel Carboplatin Advanced stage Pharmacokinetics Antimitotic Platinum II Complexes
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Summary:	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 × 14 days or 300 mg bd × 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL × min) and paclitaxel (200 mg/m 2 ). Encouraging anticancer activity was noted in patients with previously untreated non–small cell lung cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-07-0162