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Eur J Cancer. 2010 Jan;46(2):340-7. doi: 10.1016/j.ejca.2009.10.026. Epub 2009 Nov 27.

Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.

Author information

1
Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. kummars@mail.nih.gov

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/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) 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.

PMID:
19945858
PMCID:
PMC2818572
DOI:
10.1016/j.ejca.2009.10.026
[Indexed for MEDLINE]
Free PMC Article

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