Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors.
OBJECTIVE
We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors.


METHODS
Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m(2)/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only.


RESULTS
Dose-limiting toxicity occurred at 2.3 mg/m(2)/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m(2)/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m(2)/d; the mean (+/- standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 +/- 8.4 ng/mL. h. The population mean (+/- standard error) oral bioavailability of the injectable formulation was 0.27 +/- 0.03; that of capsules was 0.36 +/- 0.06 (P =.16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months.


CONCLUSIONS
Oral topotecan (1.8 mg/m(2)/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.
Daw
Najat C
NC
Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794, USA. najat.daw@stjude.org
Santana
Victor M
VM
Iacono
Lisa C
LC
Furman
Wayne L
WL
Hawkins
Dana R
DR
Houghton
Peter J
PJ
Panetta
J Carl
JC
Gajjar
Amar J
AJ
Stewart
Clinton F
CF
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016879:Salvage Therapy; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D019772:Topotecan