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.
OBJECTIVE
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.


METHODS
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/m(2); 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m(2). 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/m(2) 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.


CONCLUSIONS
17-AAG was well tolerated at a dose of 270 mg/m(2) administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.
Bagatell
Rochelle
R
Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, AZ 85724, USA. bagatell@peds.arizona.edu
Gore
Lia
L
Egorin
Merrill J
MJ
Ho
Richard
R
Heller
Glenn
G
Boucher
Nichole
N
Zuhowski
Eleanor G
EG
Whitlock
James A
JA
Hunger
Stephen P
SP
Narendran
Aru
A
Katzenstein
Howard M
HM
Arceci
Robert J
RJ
Boklan
Jessica
J
Herzog
Cynthia E
CE
Whitesell
Luke
L
Ivy
S Percy
SP
Trippett
Tanya M
TM
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010372:Pediatrics; D012008:Recurrence; D017211:Treatment Failure
D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D047029:Lactams, Macrocyclic; C112765:tanespimycin