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

Research output: Contribution to journalArticle

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

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Topoisomerase I Inhibitors
Leukemia
Pharmacokinetics
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
lurtotecan
Camptothecin
Mucositis
Myeloid Leukemia
SCID Mice
Maximum Tolerated Dose
Hematologic Neoplasms
Intravenous Infusions
Diarrhea
Fluorescence
Bone Marrow
High Pressure Liquid Chromatography
Urine

Keywords

  • Lurtotecan
  • Myeloid
  • Refractory leukemia
  • Topoisomerase I inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase I and Pharmacokinetic Study of a Low-Clearance, Unilamellar Liposomal Formulation of Lurtotecan, a Topoisomerase 1 Inhibitor, in Patients with Advanced Leukemia. / Giles, Francis J.; Tallman, Martin S.; Garcia-Manero, Guillermo; Cortes, Jorge E.; Thomas, Deborah A.; Wierda, William G.; Verstovsek, Srdan; Hamilton, Marta; Barrett, Emma; Albitar, Maher; Kantarjian, Hagop M.

In: Cancer, Vol. 100, No. 7, 01.04.2004, p. 1449-1458.

Research output: Contribution to journalArticle

Giles, FJ, Tallman, MS, Garcia-Manero, G, Cortes, JE, Thomas, DA, Wierda, WG, Verstovsek, S, Hamilton, M, Barrett, E, Albitar, M & Kantarjian, HM 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, vol. 100, no. 7, pp. 1449-1458. https://doi.org/10.1002/cncr.20132
Giles, Francis J. ; Tallman, Martin S. ; Garcia-Manero, Guillermo ; Cortes, Jorge E. ; Thomas, Deborah A. ; Wierda, William G. ; Verstovsek, Srdan ; Hamilton, Marta ; Barrett, Emma ; Albitar, Maher ; Kantarjian, Hagop M. / Phase I and Pharmacokinetic Study of a Low-Clearance, Unilamellar Liposomal Formulation of Lurtotecan, a Topoisomerase 1 Inhibitor, in Patients with Advanced Leukemia. In: Cancer. 2004 ; Vol. 100, No. 7. pp. 1449-1458.
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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.",
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AU - Tallman, Martin S.

AU - Garcia-Manero, Guillermo

AU - Cortes, Jorge E.

AU - Thomas, Deborah A.

AU - Wierda, William G.

AU - Verstovsek, Srdan

AU - Hamilton, Marta

AU - Barrett, Emma

AU - Albitar, Maher

AU - Kantarjian, Hagop M.

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N2 - 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.

AB - 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.

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