Journal
EUROPEAN JOURNAL OF CANCER
Volume 46, Issue 2, Pages 340-347Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2009.10.026
Keywords
Clinical trial; Phase I; 17-DMAG; Hsp90
Categories
Funding
- Division of Cancer Treatment and Diagnosis
- Center for Cancer Research of the National Cancer institute
- National Cancer Institute, National institutes of Health [N01-CO-12400]
- NIH, National Cancer Institute, Center for Cancer Research
- NATIONAL CANCER INSTITUTE [ZIDSC007202, ZIASC010074, ZICSC006537, ZIEBC011271, ZICBC010548, ZIABC011032, ZIABC011078, ZICSC006536] Funding Source: NIH RePORTER
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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 21 mg/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. Published by Elsevier Ltd.
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