Phase I and Pharmacokinetic Study of a Low-Clearance, Unilamellar Liposomal Formulation of Lurtotecan, a Topoisomerase 1 Inhibitor, in Patients with Advanced Leukemia

Francis J. Giles, Martin S. Tallman, Guillermo Garcia-Manero, Jorge E. Cortes, Deborah A. Thomas, William G. Wierda, Srdan Verstovsek, Marta Hamilton, Emma Barrett, Maher Albitar, Hagop M. Kantarjian

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34 Scopus citations

Abstract

OSI-211 is a low-clearance, unilamellar liposomal formulation of a water-soluble camptothecin analogue, lurtotecan. OSI-211 has significant activity in severe combined immunodeficient mouse models of human leukemia. METHODS. This study was conducted to define the dose-limiting toxicities (DLT) and pharmacokinetics of OSI-211 in patients with refractory myeloid leukemias. Patients with refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were eligible. OSI-211 was given as an intravenous infusion over 30 minutes daily for 3 days. The starting dose was 1.5 mg/m2 per day (4.5 mg/m2 per course). The dose was escalated by 50% until Grade 2 toxicity was observed and then by 30-35% until the DLT was defined. Serial plasma and urine samples were collected, and drug levels were determined by high-performance liquid chromatography with fluorescence detection. RESULTS. Twenty patients (18 patients [90%] with AML, and 1 patient each [5%] with MDS and CML-BP) were treated. Mucositis and diarrhea were considered to be the DLTs. The maximum tolerated dose was 3.7 mg/m2 per day. Fourteen of 18 evaluable patients (78%) with AML or MDS achieved transient bone marrow aplasia. The mean systemic clearance of lurtotecan in plasma was 0.946 ± 1.53 L/hour/m 2. Urinary recovery of lurtotecan was 6.66% ± 5.26% (range, 1.05-18.4%). CONCLUSIONS. Liposomal encapsulation of lurtotecan altered its metabolism significantly. There was no evident correlation between exposure, as measured by plasma pharmacokinetics of lurtotecan, and clinical response or toxicities. OSI-211 merits further study in hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)1449-1458
Number of pages10
JournalCancer
Volume100
Issue number7
DOIs
StatePublished - Apr 1 2004
Externally publishedYes

Keywords

  • Lurtotecan
  • Myeloid
  • Refractory leukemia
  • Topoisomerase I inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Giles, F. J., Tallman, M. S., Garcia-Manero, G., Cortes, J. E., Thomas, D. A., Wierda, W. G., Verstovsek, S., Hamilton, M., Barrett, E., Albitar, M., & Kantarjian, H. M. (2004). Phase I and Pharmacokinetic Study of a Low-Clearance, Unilamellar Liposomal Formulation of Lurtotecan, a Topoisomerase 1 Inhibitor, in Patients with Advanced Leukemia. Cancer, 100(7), 1449-1458. https://doi.org/10.1002/cncr.20132