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Results of a phase II upfront window of pharmacokinetically
guided topotecan in high-risk medulloblastoma and supratentorial primitive
neuroectodermal tumor
Stewart CF, Iacono LC, Chintagumpala M, Kellie SJ, Ashley D, Zamboni WC,
Kirstein MN, Fouladi M, Seele LG, Wallace D, Houghton PJ,
Gajjar A
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332
N Lauderdale, Memphis, TN 38105-2794, USA.
Purpose. 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.
Patients and 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.
Conclusion. 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.
PMID: 15310781 [PubMed - in process]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15310781
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