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

• Published in: Cancer 2004-04, Vol.100 (7), p.1449-1458
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - pharmacokinetics; Camptothecin - therapeutic use; Dose-Response Relationship, Drug; Female; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; lurtotecan; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Mouth Mucosa - metabolism; myeloid; refractory leukemia; topoisomerase I inhibitor; Topoisomerase I Inhibitors; Treatment Outcome
• ISSN: 0008-543X; 1097-0142
• 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. Cancer 2004;100:1449–58. © 2004 American Cancer Society. On a Phase I study of a low‐clearance, unilamellar liposomal formulation of lurtotecan (OSI‐211) in 20 patients with refractory myeloid leukemias, mucositis, and diarrhea were dose‐limiting toxicities at a maximum tolerated dose of 3.7 mg/m2 per day given intravenously daily for 3 days.