A Phase I Study of 17-Allylaminogeldanamycin in Relapsed/Refractory Pediatric Patients with Solid Tumors: A Children's Oncology Group Study
| Autor: | Joel M. Reid, Peter C. Adamson, Rochelle Bagatell, Susan M. Blaney, Stephanie L. Safgren, Mark Krailo, Richard J. Gilbertson, John H. Kersey, S. Percy Ivy, Ashish M. Ingle, Matthew M. Ames, Joseph P. Neglia, Luke Whitesell, Brenda J. Weigel |
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| Rok vydání: | 2007 |
| Předmět: |
Drug
Cancer Research medicine.medical_specialty Hepatoblastoma M.2 business.industry Surrogate endpoint media_common.quotation_subject medicine.disease Gastroenterology Peripheral blood mononuclear cell Surgery Stable Disease Oncology Pharmacokinetics Internal medicine Pharmacodynamics Medicine business media_common |
| Zdroj: | Clinical Cancer Research. 13:1789-1793 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-06-2270 |
| Popis: | 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 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 360 mg/m2/d. Non-DMSO–containing formulations may improve acceptance of this drug by children and their families. |
| Databáze: | OpenAIRE |
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