Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor.
OBJECTIVE
To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients.


METHODS
After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization.


RESULTS
Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range.


CONCLUSIONS
Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.
Stewart
Clinton F
CF
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794, USA.
Iacono
Lisa C
LC
Chintagumpala
Murali
M
Kellie
Stewart J
SJ
Ashley
David
D
Zamboni
W C
WC
Kirstein
M N
MN
Fouladi
Maryam
M
Seele
Louis G
LG
Wallace
Dana
D
Houghton
Peter J
PJ
Gajjar
Amar
A
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D012307:Risk Factors; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019772:Topotecan