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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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 - Dec 1 2005

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tanespimycin
Neoplasms
Proteins
HSP70 Heat-Shock Proteins
Body Surface Area
Liver
Area Under Curve
Blood Cells
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. / Grem, Jean L; Morrison, Geraldine; Guo, Xiao Du; Agnew, Elizabeth; Takimoto, Chris H.; Thomas, Rebecca; Szabo, Eva; Grochow, Louise; Grollman, Frank; Hamilton, J. Michael; Neckers, Len; Wilson, Richard H.

In: Journal of Clinical Oncology, Vol. 23, No. 9, 01.12.2005, p. 1885-1893.

Research output: Contribution to journalArticle

Grem, JL, Morrison, G, Guo, XD, Agnew, E, Takimoto, CH, Thomas, R, Szabo, E, Grochow, L, Grollman, F, Hamilton, JM, Neckers, L & Wilson, RH 2005, 'Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors', Journal of Clinical Oncology, vol. 23, no. 9, pp. 1885-1893. https://doi.org/10.1200/JCO.2005.12.085
Grem, Jean L ; Morrison, Geraldine ; Guo, Xiao Du ; Agnew, Elizabeth ; Takimoto, Chris H. ; Thomas, Rebecca ; Szabo, Eva ; Grochow, Louise ; Grollman, Frank ; Hamilton, J. Michael ; Neckers, Len ; Wilson, Richard H. / Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 9. pp. 1885-1893.
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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.",
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T1 - Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors

AU - Grem, Jean L

AU - Morrison, Geraldine

AU - Guo, Xiao Du

AU - Agnew, Elizabeth

AU - Takimoto, Chris H.

AU - Thomas, Rebecca

AU - Szabo, Eva

AU - Grochow, Louise

AU - Grollman, Frank

AU - Hamilton, J. Michael

AU - Neckers, Len

AU - Wilson, Richard H.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - 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.

AB - 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.

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