A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors: a Children's Oncology Group study.
OBJECTIVE
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).


METHODS
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/m(2)/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 alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C(max) 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/m(2) 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/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families.
Weigel
Brenda J
BJ
University of Minnesota Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA. weige007@umn.edu
Blaney
Susan M
SM
Reid
Joel M
JM
Safgren
Stephanie L
SL
Bagatell
Rochelle
R
Kersey
John
J
Neglia
Joseph P
JP
Ivy
S Percy
SP
Ingle
Ashish M
AM
Whitesell
Luke
L
Gilbertson
Richard J
RJ
Krailo
Mark
M
Ames
Matthew
M
Adamson
Peter C
PC
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*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010372:Pediatrics; D012008:Recurrence; D017211:Treatment Failure
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; C515136:17-aminogeldanamycin