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

  1. Author:
    Kummar, S.
    Gutierrez, M. E.
    Gardner, E. R.
    Chen, X. H.
    Figg, W. D.
    Zajac-Kaye, M.
    Chen, M.
    Steinberg, S. M.
    Muir, C. A.
    Yancey, M. A.
    Horneffer, Y. R.
    Juwara, L.
    Melillo, G.
    Ivy, S. P.
    Merino, M.
    Neckers, L.
    Steeg, P. S.
    Conley, B. A.
    Giaccone, G.
    Doroshow, J. H.
    Murgo, A. J.

  2. Author Address

    [Kummar, Shivaani; Gutierrez, Martin E.; Chen, Xiaohong; Figg, William D.; Zajac-Kaye, Maria; Chen, Min; Steinberg, Seth M.; Muir, Christine A.; Yancey, Mary Ann; Horneffer, Yvonne R.; Merino, Maria; Neckers, Len; Steeg, Patricia S.; Conley, Barbara A.; Giaccone, Giuseppe; Doroshow, James H.; Murgo, Anthony J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Gardner, Erin R.; Juwara, Lamin; Melillo, Giovanni] NCI, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Ivy, S. Percy; Doroshow, James H.; Murgo, Anthony J.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA.;Kummar, S, NCI, Ctr Canc Res, 10 Ctr Dr, Bethesda, MD 20892 USA.;kummars@mail.nih.gov
    1. Year: 2010
    2. Date: Jan
  2. Journal: European Journal of Cancer
    1. 46
    2. 2
    3. Pages: 340-347
  4. Type of Article: Article
  5. ISSN: 0959-8049
  1. 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/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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External Sources

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  2. DOI: 10.1016/j.ejca.2009.10.026
  3. View record in Web of Science®
  4. WOS: 000274123300019

Library Notes

  1. Fiscal Year: FY2009-2010
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