Related Experiment Video
Updated: Jul 16, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors: a
Brenda J Weigel1, Susan M Blaney, Joel M Reid
1University of Minnesota Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA. weige007@umn.edu
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/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.
Insights
The heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG), showed promising results in pediatric patients without dose-limiting toxicities. The recommended phase II dose was established at 360 mg/m(2)/d, with evidence of Hsp90 inhibition.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Heat shock protein (Hsp) 90 is a molecular chaperone crucial for the stability and function of numerous client proteins involved in cancer cell survival and proliferation.
- Targeting Hsp90 with inhibitors like 17-allylaminogeldanamycin (17-AAG) offers a therapeutic strategy to disrupt these oncogenic pathways.
Purpose of the Study:
- To determine the recommended phase II dose (RP2D) of 17-AAG in pediatric patients.
- To evaluate the dose-limiting toxicities (DLTs), pharmacokinetic (PK) profile, and pharmacodynamic (PD) effects of 17-AAG.
- To assess the safety and tolerability of 17-AAG in a pediatric oncology setting.
Main Methods:
- A standard dose escalation scheme was employed, administering 17-AAG via a 60-minute infusion on days 1, 4, 8, and 11 of a 21-day cycle.
- Dose levels ranged from 150 to 360 mg/m(2)/dose.
- PK studies and evaluation of Hsp72 and Akt levels in peripheral blood mononuclear cells were conducted during the first cycle.
Main Results:
- Seventeen pediatric patients (median age 7 years) were enrolled. No DLTs were observed across the dose levels.
- Pharmacokinetic exposure of 17-AAG at 270 mg/m(2)/dose was comparable to adult exposures, with a mean terminal half-life of 3.24 hours.
- Induction of Hsp72, a marker of Hsp90 inhibition, was detected at the 270 mg/m(2) dose level. Three patients achieved stable disease, with one showing a reduction in alpha-fetoprotein.
Conclusions:
- 17-AAG can be safely administered to pediatric patients, achieving drug exposures associated with anticancer activity without dose-limiting toxicities.
- Systemic modulation of the Hsp90 system was confirmed, supporting the drug's mechanism of action.
- The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO formulations may enhance patient and family acceptance.
Related Concept Videos
02:56Treatment Resistent Cancers
01:11Clinical Trials: Overview
02:56Treatment Resistant Cancers