TY - JOUR
T1 - Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17- demethoxygeldanamycinin pediatric patients with recurrent or refractory solid tumors
T2 - A pediatric oncology experimental therapeutics investigators consortium study
AU - Bagatell, Rochelle
AU - Gore, Lia
AU - Egorin, Merrill J.
AU - Ho, Richard
AU - Heller, Glenn
AU - Boucher, Nichole
AU - Zuhowski, Eleanor G.
AU - Whitlock, James A.
AU - Hunger, Stephen P.
AU - Narendran, Aru
AU - Katzenstein, Howard M.
AU - Arceci, Robert J.
AU - Boklan, Jessica
AU - Herzog, Cynthia E.
AU - Whitesell, Luke
AU - Ivy, S. Percy
AU - Trippett, Tanya M.
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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 270mg/m2 administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.
AB - 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 270mg/m2 administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.
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U2 - 10.1158/1078-0432.CCR-06-1892
DO - 10.1158/1078-0432.CCR-06-1892
M3 - Article
C2 - 17363533
AN - SCOPUS:34250162501
SN - 1078-0432
VL - 13
SP - 1783
EP - 1788
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -