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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    Weigel, B. J., Blaney, S. M., Reid, J. M., Safgren, S. L., Bagatell, R., Kersey, J., Neglia, J. P., Ivy, S. P., Ingle, A. M., Whitesell, L., Gilbertson, R. J., Krailo, M., Ames, M., & Adamson, P. C. (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, 13(6), 1789-1793. https://doi.org/10.1158/1078-0432.CCR-06-2270