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

Cancer. 2004 Apr 1;100(7):1449-58. doi: 10.1002/cncr.20132.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemistry
  • Camptothecin / pharmacokinetics*
  • Camptothecin / 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


  • Antineoplastic Agents
  • Topoisomerase I Inhibitors
  • lurtotecan
  • Camptothecin