A phase I trial of docetaxel and pulse-dose 17-allylamino-17- demethoxygeldanamycin in adult patients with solid tumors Journal Article


Authors: Iyer, G.; Morris, M. J.; Rathkopf, D.; Slovin, S. F.; Steers, M.; Larson, S. M.; Schwartz, L. H.; Curley, T.; Delacruz, A.; Ye, Q.; Heller, G.; Egorin, M. J.; Ivy, S. P.; Rosen, N.; Scher, H. I.; Solit, D. B.
Article Title: A phase I trial of docetaxel and pulse-dose 17-allylamino-17- demethoxygeldanamycin in adult patients with solid tumors
Abstract: Purpose: To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies. Experimental design: Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m 2. 17-AAG was administered over 1-2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m 2 in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot. Results: Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m 2-17-AAG 650 mg/m 2 due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed. Conclusions: The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m 2 and 17-AAG 500 mg/m 2. © 2011 Springer-Verlag.
Keywords: docetaxel; 17-aag; geldanamycin; hsp90; phase i
Journal Title: Cancer Chemotherapy and Pharmacology
Volume: 69
Issue: 4
ISSN: 0344-5704
Publisher: Springer  
Date Published: 2012-04-01
Start Page: 1089
End Page: 1097
Language: English
DOI: 10.1007/s00280-011-1789-3
PROVIDER: scopus
PUBMED: 22124669
PMCID: PMC3471133
DOI/URL:
Notes: --- - "Export Date: 1 May 2012" - "CODEN: CCPHD" - "Source: Scopus"
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MSK Authors
  1. Glenn Heller
    284 Heller
  2. Neal Rosen
    351 Rosen
  3. Susan Slovin
    178 Slovin
  4. Michael Morris
    256 Morris
  5. David Solit
    420 Solit
  6. Lawrence H Schwartz
    275 Schwartz
  7. Gopakumar Vasudeva Iyer
    121 Iyer
  8. Dana Elizabeth Rathkopf
    134 Rathkopf
  9. Steven M Larson
    736 Larson
  10. Howard Scher
    784 Scher
  11. Qing Ye
    24 Ye
  12. Macaulay A Steers
    1 Steers