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Cancer Therapy: Clinical |
Authors' Affiliations: Departments of 1 Medicine, 2 Biostatistics, 3 Nuclear Medicine, 4 Radiology, and 5 Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York; 6 Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, Maryland; and 7 Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Requests for reprints: Howard I. Scher, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 646-422-4323; Fax: 212-988-0851; E-mail: scherh{at}mskcc.org.
Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules.
Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m2 daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily x 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies.
Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m2 on the daily x 5 schedule; 112 mg/m2 on the daily x 3 schedule; and 220 mg/m2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily x 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies.
Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.
Commentary
Clin. Cancer Res. 2007 13: 1625-1629.
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