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

Najat C. Daw, Victor M. Santana, Lisa C. Iacono, Wayne L. Furman, Dana R. Hawkins, Peter J Houghton, J. Carl Panetta, Amar J. Gajjar, Clinton F. Stewart

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Purpose: 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. Patients and Methods: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m2/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/m2/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/m2/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m2/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. Conclusion: Oral topotecan (1.8 mg/m2/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.

Original languageEnglish (US)
Pages (from-to)829-837
Number of pages9
JournalJournal of Clinical Oncology
Volume22
Issue number5
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Fingerprint

Topotecan
Pharmacokinetics
Pediatrics
Neoplasms
Neutropenia
Capsules
Clostridium Infections
Stomatitis
Epistaxis
Injections
Clostridium difficile
Lactones
Exanthema
Nausea
Biological Availability
Vomiting
Diarrhea
Appointments and Schedules
Radiation
Hemorrhage

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Daw, Najat C.; Santana, Victor M.; Iacono, Lisa C.; Furman, Wayne L.; Hawkins, Dana R.; Houghton, Peter J; Panetta, J. Carl; Gajjar, Amar J.; Stewart, Clinton F.

In: Journal of Clinical Oncology, Vol. 22, No. 5, 01.12.2004, p. 829-837.

Research output: Contribution to journalArticle

Daw, Najat C. ; Santana, Victor M. ; Iacono, Lisa C. ; Furman, Wayne L. ; Hawkins, Dana R. ; Houghton, Peter J ; Panetta, J. Carl ; Gajjar, Amar J. ; Stewart, Clinton F. / 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. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 5. pp. 829-837.
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abstract = "Purpose: 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. Patients and Methods: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m2/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/m2/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/m2/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m2/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. Conclusion: Oral topotecan (1.8 mg/m2/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.",
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AU - Daw, Najat C.

AU - Santana, Victor M.

AU - Iacono, Lisa C.

AU - Furman, Wayne L.

AU - Hawkins, Dana R.

AU - Houghton, Peter J

AU - Panetta, J. Carl

AU - Gajjar, Amar J.

AU - Stewart, Clinton F.

PY - 2004/12/1

Y1 - 2004/12/1

N2 - Purpose: 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. Patients and Methods: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m2/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/m2/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/m2/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m2/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. Conclusion: Oral topotecan (1.8 mg/m2/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.

AB - Purpose: 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. Patients and Methods: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m2/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/m2/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/m2/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m2/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. Conclusion: Oral topotecan (1.8 mg/m2/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.

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