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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

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]

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