European Journal of Cancer
Volume 46, Issue 2 , Pages 340-347 , January 2010

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

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
    • Corresponding Author InformationCorresponding author: Tel.: +1 301 435 5402; fax: +1 301 402 0172.
    • Both authors contributed equally to the manuscript.
  • ,
  • Martin E. Gutierrez

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
    • Both authors contributed equally to the manuscript.
  • ,
  • Erin R. Gardner

      Affiliations

    • Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA
  • ,
  • Xiaohong Chen

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • William D. Figg

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Maria Zajac-Kaye

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Min Chen

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Seth M. Steinberg

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Christine A. Muir

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Mary Ann Yancey

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Yvonne R. Horneffer

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Lamin Juwara

      Affiliations

    • Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA
  • ,
  • Giovanni Melillo

      Affiliations

    • Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA
  • ,
  • S. Percy Ivy

      Affiliations

    • Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA
  • ,
  • Maria Merino

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Len Neckers

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Patricia S. Steeg

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • Barbara A. Conley

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
    • Present address: Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
  • ,
  • Giuseppe Giaccone

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
  • ,
  • James H. Doroshow

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
    • Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA
  • ,
  • Anthony J. Murgo

      Affiliations

    • Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA
    • Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA

Received 13 May 2009 ,Revised 20 October 2009 ,Accepted 29 October 2009.

References 

  1. Banerji U. Heat shock protein 90 as a drug target: some like it hot. Clin Cancer Res. 2009;15:9–14
  2. Banerji U, O’Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol. 2005;23:4152–4161
  3. Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med. 2002;8:S55–S61
  4. Nimmanapalli R, O’Bryan E, Bhalla K. Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res. 2001;61:1799–1804
  5. Ochel HJ, Eichhorn K, Gademann G. Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones. Cell Stress Chaperones. 2001;6:105–112
  6. Sato S, Fujita N, Tsuruo T. Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA. 2000;97:10832–10837
  7. Schulte TW, Blagosklonny MV, Romanova L, et al. Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. Mol Cell Biol. 1996;16:5839–5845
  8. Smith DF, Whitesell L, Nair SC, Chen S, Prapapanich V, Rimerman RA. Progesterone receptor structure and function altered by geldanamycin, an hsp90-binding agent. Mol Cell Biol. 1995;15:6804–6812
  9. Xu W, Mimnaugh E, Rosser MF, et al. Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem. 2001;276:3702–3708
  10. Blagosklonny MV. Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia. 2002;16:455–462
  11. Glaze ER, Lambert AL, Smith AC, et al. Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance. Cancer Chemother Pharmacol. 2005;56:637–647
  12. Smith V, Sausville EA, Camalier RF, Fiebig HH, Burger AM. Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models. Cancer Chemother Pharmacol. 2005;56:126–137
  13. Hollingshead M, Alley M, Burger AM, et al. In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol. 2005;56:115–125
  14. Eiseman JL, Lan J, Lagattuta TF. Et al. Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer Chemother Pharmacol. 2005;55:21–32
  15. Ramanathan RK, Trump DL, Eiseman JL, et al. Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res. 2005;11:3385–3391
  16. Ramanathan R, Egorin M, Erlichman C, et al. Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, (17DMAG, NSC 707545), an inhibitor of heat shock protein 90 (HSP90), in patients with advanced solid tumors: Final results. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, San Francisco, CA, October 22–26, 2007 [Abstr B212].
  17. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997;89:1138–1147
  18. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216
  19. Chen X, Gardner ER, Gutierrez M, Kummar S, Figg WD. Determination of 17-dimethylaminoethylamino-17-demethoxygeldanamycin in human plasma by liquid chromatography with mass-spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;858:302–306
  20. Pacey S, Wilson R, Walton M, et al. A phase I trial of the heat shock protein 90 (HSP90) inhibitor alvespimycin (17-dimethylaminoethylamino-17-demethoxygeldanamycin 17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumors. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, San Francisco, CA, October 22-26, 2007 [abstr PR-6].
  21. Lancet J, Gojo I, Baer M, et al. Phase 1, pharmacokinetic (PK), pharmacodynamic (PD) study of of the Hsp-90 inhibitor, KOS-1022 (17-DMAG), in patients with refractory hematological malignancies. J Clin Oncol. 2006;24:2081
  22. Miller K, Rosen LS, Modi S, et al. Phase I trial of alvespimycin (KOS-1022; 17-DMAG) and trastuzumab (T). J Clin Oncol. 2007;25:1115
  23. Bristol-Myers Squibb. Phase 2 Clinical Trial of Intravenous Alvespimycin [KOS-1022] in Patients With Her2 Positive Breast Cancer. In: ClinicalTrials.gov. NLM Identifier: NCT00780000. http://www.clinicaltrials.gov/ct2/show/NCT00780000 [accessed on March 25, 2009].
  24. Bristol-Myers Squibb. Phase 1 Clinical Trial of the Combination of Intravenous Alvespimycin (KOS-1022), Trastuzumab With or Without Paclitaxel. In: ClinicalTrials.gov. NLM Identifier: NCT00803556. http://www.clinicaltrials.gov/ct2/show/NCT00803556 [accessed on March 25, 2009].
  25. Holdsworth CH, Badawi RD, Manola JB, et al. CT and PET: early prognostic indicators of response to imatinib mesylate in patients with gastrointestinal stromal tumor. AJR Am J Roentgenol. 2007;189:W324–W330
  26. Niu G, Li Z, Cao Q, Chen X. Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with (64)Cu-DOTA-trastuzumab. Eur J Nucl Med Mol Imaging. 2009;36:1510–1519
  27. Smith-Jones PM, Solit D, Afroze F, Rosen N, Larson SM. Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET. J Nucl Med. 2006;47:793–796
  28. Eiseman JL, Guo J, Ramanathan RK, et al. Evaluation of plasma insulin-like growth factor binding protein 2 and Her-2 extracellular domain as biomarkers for 17-allylamino-17-demethoxygeldanamycin treatment of adult patients with advanced solid tumors. Clin Cancer Res. 2007;13:2121–2127
  29. Elfiky A, Saif MW, Beeram M, et al. BIIB021, an oral, synthetic non-ansamycin Hsp90 inhibitor: phase I experience. J Clin Oncol. 2008;26:2503
  30. Flaherty KT, Gore L, Avadhani AN, et al. First use of an oral Hsp90 inhibitor in patients (Pts) with solid tumors: Alvespimycin (A) administered QOD or QD. J Clin Oncol. 2008;26:2502

 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.

PII: S0959-8049(09)00813-2

doi: 10.1016/j.ejca.2009.10.026

European Journal of Cancer
Volume 46, Issue 2 , Pages 340-347 , January 2010