Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors

Jean L. Grem, Geraldine Morrison, Xiao Du Guo, Elizabeth Agnew, Chris H. Takimoto, Rebecca Thomas, Eva Szabo, Louise Grochow, Frank Grollman, J. Michael Hamilton, Len Neckers, Richard H. Wilson

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222 Scopus citations

Abstract

Purpose: To determine the clinical toxicities of 17-(allylamino)-17- demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks. Patients and Methods: Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m2) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells. Results: Toxicity was acceptable at doses up to 28 mg/m 2. The cohort was expanded to three patients at 40 mg/m2 because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m2 had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m 2; none had dose-limiting toxicity. The maximum plasma concentrations (Cmax) of 17-AAG at 40 and 56 mg/m2 were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours-ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with ≥ 14 mg/m 2 and decreased protein content of either Lck or Raf1 with ≥ 28 mg/m2 of 17-AAG. Conclusion: 17-AAG 40 mg/m2 (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.

Original languageEnglish (US)
Pages (from-to)1885-1893
Number of pages9
JournalJournal of Clinical Oncology
Volume23
Issue number9
DOIs
StatePublished - 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Grem, J. L., Morrison, G., Guo, X. D., Agnew, E., Takimoto, C. H., Thomas, R., Szabo, E., Grochow, L., Grollman, F., Hamilton, J. M., Neckers, L., & Wilson, R. H. (2005). Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. Journal of Clinical Oncology, 23(9), 1885-1893. https://doi.org/10.1200/JCO.2005.12.085