Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma

Abstract

Purpose: A phase II study of temsirolimus was conducted in children and adolescents with high-grade glioma, neuroblastoma or rhabdomyosarcoma.

Patients and methods: Temsirolimus 75 mg/m(2) was administered once weekly until disease progression or intolerance. Using the Simon 2-stage design, further enrolment in each disease cohort required ≥ 2 objective responses within the first 12 weeks for the first 12 evaluable patients (those who received ≥ 3 temsirolimus doses).

Results: Fifty-two heavily pretreated patients with relapsed (12%) or refractory (88%) disease, median age 8 years (range 1-21 years), were enroled and treated. One patient with neuroblastoma achieved confirmed partial response within the first 12 weeks; thus, none of the 3 cohorts met the criterion for continued enrolment. Disease stabilisation at week 12 was observed in 7 of 17 patients (41%) with high-grade glioma (5 diffuse pontine gliomas, 1 glioblastoma multiforme and 1 anaplastic astrocytoma), 6 of 19 (32%) with neuroblastoma and 1 of 16 (6%) with rhabdomyosarcoma (partial response confirmed at week 18). In the three cohorts, median duration of stable disease or better was 128, 663 and 75 d, respectively. The most common treatment-related adverse events were thrombocytopaenia, hyperlipidaemia and aesthenia. Pharmacokinetic findings were similar to those observed in adults.

Conclusions: Temsirolimus administered weekly at the dose of 75 mg/m(2) did not meet the primary objective efficacy threshold in children with high-grade glioma, neuroblastoma or rhabdomyosarcoma; however, meaningful prolonged stable disease merits further evaluation in combination therapy.

Trial registration: ClinicalTrials.gov NCT00106353.

Conflict of interest statement

Conflict of interest statement

No author received an honorarium or other forms of financial support related to the development of this manuscript. D. Perek, and S. Spunt received research funding from Wyeth for the conduct of this study. B. Geoerger, M.W. Kieran and S. Grupp disclose no potential conflicts of interest. J. Clancy is an employee of inVentiv Clinical Solutions, a paid consultant to Pfizer Inc. Mizue Krygowski is an employee of Wyeth Pharmaceuticals/Pfizer Inc. R. Ananthakrishnan is an employee of inVentiv Clinical Solutions, a paid consultant to Pfizer Inc. J.P. Boni and A. Berkenblit are employees of and stockholders in Wyeth Pharmaceuticals/Pfizer Inc. No other potential conflicts of interest were disclosed.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

Best tumour response within 12 weeks of treatment and duration on treatment for individual patients with high-grade glioma (A), neuroblastoma (B), and rhabdomyosarcoma (C). Of the 8 patients with best tumour response as ‘unknown,’ 6 discontinued owing to early disease progression or symptomatic deterioration (includes 3 deaths due to disease progression), 1 stopped treatment for surgery, and 1 discontinued because of an adverse event. *Patient achieved confirmed partial response during week 18.