Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17- demethoxygeldanamycinin pediatric patients with recurrent or refractory solid tumors: A pediatric oncology experimental therapeutics investigators consortium study Journal Article


Authors: Bagatell, R.; Gore, L.; Egorin, M. J.; Ho, R.; Heller, G.; Boucher, N.; Zuhowski, E. G.; Whitlock, J. A.; Hunger, S. P.; Narendran, A.; Katzenstein, H. M.; Arceci, R. J.; Boklan, J.; Herzog, C. E.; Whitesell, L.; Ivy, S. P.; Trippett, T. M.
Article Title: Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17- demethoxygeldanamycinin pediatric patients with recurrent or refractory solid tumors: A pediatric oncology experimental therapeutics investigators consortium study
Abstract: 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. © 2007 American Association for Cancer Research.
Keywords: osteosarcoma; adolescent; adult; child; clinical article; controlled study; preschool child; child, preschool; treatment failure; unclassified drug; clinical trial; disease course; neutropenia; area under the curve; diarrhea; side effect; antineoplastic agents; antineoplastic agent; anorexia; neoplasm; neoplasms; controlled clinical trial; multiple cycle treatment; pharmacodynamics; anemia; leukopenia; thrombocytopenia; peripheral neuropathy; aspiration; tumor markers, biological; recurrence; bradycardia; creatinine blood level; pathology; tumor marker; childhood cancer; aspartate aminotransferase blood level; drug dose escalation; ewing sarcoma; hypoxia; confusion; lung metastasis; neuroblastoma; drug clearance; nausea and vomiting; recurrent disease; alkaline phosphatase blood level; maximum plasma concentration; maximum tolerated dose; phase 1 clinical trial; drug half life; rhabdomyosarcoma; bilirubin blood level; tachycardia; peripheral blood mononuclear cell; benzoquinones; lactams, macrocyclic; pediatrics; desmoplastic small round cell tumor; 17-(allylamino)-17-demethoxygeldanamycin; benzoquinone derivative; macrocyclic lactam; albumin blood level; transaminitis; 17 allylamino 17 demethoxygeldanamycin; paroxysmal coughing; respiratory acidosis; respiratory tract allergy
Journal Title: Clinical Cancer Research
Volume: 13
Issue: 6
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2007-03-15
Start Page: 1783
End Page: 1788
Language: English
DOI: 10.1158/1078-0432.ccr-06-1892
PUBMED: 17363533
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 46" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Glenn Heller
    295 Heller