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Phase I Pharmacokinetic and Pharmacodynamic Study of 17-N-Allylamino-17-Demethoxygeldanamycin in Pediatric Patients with Recurrent or Refractory Solid Tumors: A Pediatric Oncology Experimental Therapeutics Investigators Consortium Study

Authors' Affiliations: ¹ Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, Arizona; ² University of Colorado Health Sciences Center, Denver, Colorado; ³ Departments of Medicine and Pharmacology and Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁴ Vanderbilt University Medical Center, Nashville, Tennessee; ⁵ Memorial Sloan-Kettering Cancer Center, New York, New York; ⁶ University of Florida, Gainesville, Florida; ⁷ University of Calgary and Southern Alberta Children's Cancer Program, Calgary, Alberta, Canada; ⁸ Children's Healthcare of Atlanta, Atlanta, Georgia; ⁹ Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, Maryland; ¹⁰ Phoenix Children's Hospital, Phoenix, Arizona; ¹¹ The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ¹² Whitehead Institute, Cambridge, Massachusetts; and ¹³ Investigational Drug Branch, Cancer Therapy and Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Rochelle Bagatell, Department of Pediatrics, Pediatric Hematology/Oncology, Arizona Health Sciences Center, Room 5341, 1501 North Campbell Avenue, Tucson, AZ 85724. Phone: 520-626-4851; Fax: 520-626-6986; E-mail: bagatell{at}peds.arizona.edu.

Purpose: Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. We conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory neuroblastoma, Ewing's sarcoma, osteosarcoma, and desmoplastic small round cell tumor to determine the maximum tolerated dose, define toxicity and pharmacokinetic profiles, and generate data about molecular target modulation.

Experimental Design: Escalating doses of 17-AAG were administered i.v. over 1 to 2 h twice weekly for 2 weeks every 21 days until patients experienced disease progression or toxicity. harmacokinetic and pharmacodynamic studies were done during cycle 1.

Results: Fifteen patients were enrolled onto dose levels between 150 and 360 mg/m²; 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m². DLTs were grade 3 transaminitis and hypoxia. Two patients with osteosarcoma and bulky pulmonary metastases died during cycle 1 and were not evaluable for toxicity. No objective responses were observed. 17-AAG pharmacokinetics in pediatric patients were linear; clearance and half-life were 21.6 ± 6.21 (mean ± SD) L/h/m² and 2.6 ± 0.95 h, respectively. Posttherapy increases in levels of the inducible isoform of Hsp70, a marker of target modulation, were detected in peripheral blood mononuclear cells at all dose levels.

Conclusion: 17-AAG was well tolerated at a dose of 270 mg/m² administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.

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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