Phase I and pharmacokinetic study of a low-clearance, unilamellar liposomal formulation of lurtotecan, a topoisomerase 1 inhibitor, in patients with advanced leukemia.
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.
Giles
Francis J
FJ
Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030-4095, USA. frankgiles@aol.com
Tallman
Martin S
MS
Garcia-Manero
Guillermo
G
Cortes
Jorge E
JE
Thomas
Deborah A
DA
Wierda
William G
WG
Verstovsek
Srdan
S
Hamilton
Marta
M
Barrett
Emma
E
Albitar
Maher
M
Kantarjian
Hagop M
HM
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; C091719:lurtotecan; D002166:Camptothecin