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
Notes: --- - "Export Date: 1 May 2012" - "CODEN: CCPHD" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Glenn Heller
    352 Heller
  2. Neal Rosen
    381 Rosen
  3. Susan Slovin
    213 Slovin
  4. Michael Morris
    349 Morris
  5. David Solit
    546 Solit
  6. Lawrence H Schwartz
    282 Schwartz
  7. Gopakumar Vasudeva Iyer
    172 Iyer
  8. Dana Elizabeth Rathkopf
    176 Rathkopf
  9. Steven M Larson
    878 Larson
  10. Howard Scher
    976 Scher
  11. Qing Ye
    25 Ye
  12. Macaulay A Steers
    1 Steers