A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors

A children's oncology group study

Brenda J. Weigel, Susan M. Blaney, Joel M Reid, Stephanie L. Safgren, Rochelle Bagatell, John Kersey, Joseph P. Neglia, S. Percy Ivy, Ashish M. Ingle, Luke Whitesell, Richard J. Gilbertson, Mark Krailo, Matthew Ames, Peter C. Adamson

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Abstract

Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m 2/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+,7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in α-fetoprotein and stable disease over three cycles. At 270 mg/m2/dose, the Cmax and areas under the plasma concentration-time curves of 17-AAG were 5,303 ± 1,591 ng/mL and 13,656 ± 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 ± 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m2 dose level. Conclusions:Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360mg/m2/d. Non-DMSO - containing formulations may improve acceptance of this drug by children and their families.

Original languageEnglish (US)
Pages (from-to)1789-1793
Number of pages5
JournalClinical Cancer Research
Volume13
Issue number6
DOIs
StatePublished - Mar 15 2007

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tanespimycin
Pediatrics
Neoplasms
Pharmacokinetics
Pharmaceutical Preparations
Fetal Proteins
Hepatoblastoma
HSP90 Heat-Shock Proteins
Half-Life
Blood Cells
Research Design
Biomarkers
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors : A children's oncology group study. / Weigel, Brenda J.; Blaney, Susan M.; Reid, Joel M; Safgren, Stephanie L.; Bagatell, Rochelle; Kersey, John; Neglia, Joseph P.; Ivy, S. Percy; Ingle, Ashish M.; Whitesell, Luke; Gilbertson, Richard J.; Krailo, Mark; Ames, Matthew; Adamson, Peter C.

In: Clinical Cancer Research, Vol. 13, No. 6, 15.03.2007, p. 1789-1793.

Research output: Contribution to journalArticle

Weigel, BJ, Blaney, SM, Reid, JM, Safgren, SL, Bagatell, R, Kersey, J, Neglia, JP, Ivy, SP, Ingle, AM, Whitesell, L, Gilbertson, RJ, Krailo, M, Ames, M & Adamson, PC 2007, 'A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors: A children's oncology group study', Clinical Cancer Research, vol. 13, no. 6, pp. 1789-1793. https://doi.org/10.1158/1078-0432.CCR-06-2270
Weigel, Brenda J. ; Blaney, Susan M. ; Reid, Joel M ; Safgren, Stephanie L. ; Bagatell, Rochelle ; Kersey, John ; Neglia, Joseph P. ; Ivy, S. Percy ; Ingle, Ashish M. ; Whitesell, Luke ; Gilbertson, Richard J. ; Krailo, Mark ; Ames, Matthew ; Adamson, Peter C. / A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors : A children's oncology group study. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 6. pp. 1789-1793.
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abstract = "Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m 2/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+,7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in α-fetoprotein and stable disease over three cycles. At 270 mg/m2/dose, the Cmax and areas under the plasma concentration-time curves of 17-AAG were 5,303 ± 1,591 ng/mL and 13,656 ± 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 ± 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m2 dose level. Conclusions:Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360mg/m2/d. Non-DMSO - containing formulations may improve acceptance of this drug by children and their families.",
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T1 - A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors

T2 - A children's oncology group study

AU - Weigel, Brenda J.

AU - Blaney, Susan M.

AU - Reid, Joel M

AU - Safgren, Stephanie L.

AU - Bagatell, Rochelle

AU - Kersey, John

AU - Neglia, Joseph P.

AU - Ivy, S. Percy

AU - Ingle, Ashish M.

AU - Whitesell, Luke

AU - Gilbertson, Richard J.

AU - Krailo, Mark

AU - Ames, Matthew

AU - Adamson, Peter C.

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Y1 - 2007/3/15

N2 - Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m 2/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+,7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in α-fetoprotein and stable disease over three cycles. At 270 mg/m2/dose, the Cmax and areas under the plasma concentration-time curves of 17-AAG were 5,303 ± 1,591 ng/mL and 13,656 ± 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 ± 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m2 dose level. Conclusions:Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360mg/m2/d. Non-DMSO - containing formulations may improve acceptance of this drug by children and their families.

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