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

Shivaani Kummar, Martin E. Gutierrez, Erin R. Gardner, Xiaohong Chen, William D. Figg, Maria Zajac-Kaye, Min Chen, Seth M. Steinberg, Christine A. Muir, Mary Ann Yancey, Yvonne R. Horneffer, Lamin Juwara, Giovanni Melillo, S. Percy Ivy, Maria Merino, Len Neckers, Patricia S. Steeg, Barbara A. Conley, Giuseppe Giaccone, James H. DoroshowAnthony J. Murgo

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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 21 mg/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.

Original languageEnglish (US)
Pages (from-to)340-347
Number of pages8
JournalEuropean Journal of Cancer
Volume46
Issue number2
DOIs
StatePublished - Jan 2010
Externally publishedYes

Keywords

  • 17-DMAG
  • Clinical trial
  • Hsp90
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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