This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weigel, B. J. Articles by Adamson, P. C. Search for Related Content PubMed PubMed Citation Articles by Weigel, B. J. Articles by Adamson, P. C. Related Collections Commentary

A Phase I Study of 17-Allylaminogeldanamycin in Relapsed/Refractory Pediatric Patients with Solid Tumors: A Children's Oncology Group Study

Authors' Affiliations: ¹ University of Minnesota Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; ² Texas Children's Cancer Center/Baylor College of Medicine, Houston, Texas; ³ Mayo Clinic and Foundation, Rochester, Minnesota; ⁴ University of Arizona, Tucson, Arizona; ⁵ National Cancer Institute, Washington, District of Columbia; ⁶ Children's Oncology Group, Arcadia, California; ⁷ Whitehead Institute, Cambridge, Massachusetts; ⁸ St. Jude Children's Research Hospital, Memphis, Tennessee; and ⁹ The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Requests for reprints: Brenda J. Weigel, University of Minnesota, MMC 366, 420 Delaware Street SE, Minneapolis, MN 55455. Phone: 612-626-5501; Fax: 612-624-3913; E-mail: weige007{at}umn.edu.

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/m²/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 -fetoprotein and stable disease over three cycles. At 270 mg/m²/dose, the C_max 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 360 mg/m²/d. Non-DMSO–containing formulations may improve acceptance of this drug by children and their families.

Commentary

Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells

Wanping Xu and Len Neckers
Clin. Cancer Res. 2007 13: 1625-1629. [Full Text] [PDF]

This article has been cited by other articles:

				R. H. Kim, R. Kim, W. Chen, S. Hu, K.-H. Shin, N.-H. Park, and M. K. Kang Association of hsp90 to the hTERT promoter is necessary for hTERT expression in human oral cancer cells Carcinogenesis, December 1, 2008; 29(12): 2425 - 2431. [Abstract] [Full Text] [PDF]

				P. J. Gray Jr., M. A. Stevenson, and S. K. Calderwood Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells Cancer Res., December 15, 2007; 67(24): 11942 - 11950. [Abstract] [Full Text] [PDF]

				W. Xu and L. Neckers Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells Clin. Cancer Res., March 15, 2007; 13(6): 1625 - 1629. [Full Text] [PDF]