Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies☆
Received 13 May 2009; received in revised form 20 October 2009; accepted 29 October 2009. published online 30 November 2009.
Abstract
Purpose
Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer.
Experimental design
17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs).
Results
A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m2/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2–22) months. Both Cmax and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable.
Conclusion
Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.
☆ This paper was written with support from the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National Cancer Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This work was supported by the Intramural Research Programme of the NIH, National Cancer Institute, Center for Cancer Research.
d Both authors contributed equally to the manuscript.
e Present address: Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
ABSTRACT