Phase I and pharmacokinetic study of a low-clearance, unilamellar liposomal formulation of lurtotecan, a topoisomerase 1 inhibitor, in patients with advanced leukemia.

Abstract

BACKGROUND:

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/m2. 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.

• Authors: 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
• Journal: Cancer (Cancer) Vol. 100 Issue 7 Pg. 1449-58 (Apr 01 2004) ISSN: 0008-543X [Print] United States
• PMID: 15042679 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)
• Copyright: Copyright 2004 American Cancer Society.

Chemical References

• Antineoplastic Agents
• Topoisomerase I Inhibitors
• lurtotecan
• Camptothecin

Topics

• Acute Disease
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (chemistry, pharmacokinetics, therapeutic use)
• Area Under Curve
• Camptothecin (analogs & derivatives, chemistry, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Leukemia, Myeloid (drug therapy)
• Male
• Metabolic Clearance Rate
• Middle Aged
• Mouth Mucosa (metabolism)
• Topoisomerase I Inhibitors
• Treatment Outcome