Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.
Publication/Presentation Date
3-15-2007
Abstract
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/m(2) 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/m(2) on the daily x 5 schedule; 112 mg/m(2) on the daily x 3 schedule; and 220 mg/m(2) 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.
Volume
13
Issue
6
First Page
1775
Last Page
1782
ISSN
1078-0432
Published In/Presented At
Solit, D. B., Ivy, S. P., Kopil, C., Sikorski, R., Morris, M. J., Slovin, S. F., Kelly, W. K., DeLaCruz, A., Curley, T., Heller, G., Larson, S., Schwartz, L., Egorin, M. J., Rosen, N., & Scher, H. I. (2007). Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 13(6), 1775–1782. https://doi.org/10.1158/1078-0432.CCR-06-1863
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
17363532
Department(s)
Administration and Leadership
Document Type
Article