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


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.
Institut Gustave Roussy, Department of Paediatric and Adolescent Medicine, University Paris-Sud, Villejuif, France. geoerger@igr.fr
Birgit
B
Geoerger
Mark W
MW
Kieran
Stephan
S
Grupp
Danuta
D
Perek
Jill
J
Clancy
Mizue
M
Krygowski
Revathi
R
Ananthakrishnan
Joseph P
JP
Boni
Anna
A
Berkenblit
Sheri L
SL
Spunt
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy*; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus