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. Cancer 2004;100:1449–58. © 2004 American Cancer Society.

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

“…infusions were administered for three consecutive days to patients with leukemia. 238 An MTD similar to what was found previously (3.7 mg/m 2 ) provided an AUC value of 7.1 μg•h/mL after a single injection with a mean half-life of 7.2 h. In patients with refractory solid tumors administered liposomal lurtotecan as a 30 min i.v. infusion on days 1, 2 and 3 for three consectutive weeks found MTDs of 2.1 mg/m 2 (~0.057 mg/kg) and 1.8 mg/m 2 (~0.049 mg/kg) for minimally pretreated patients and heavily pretreated patients, respectively.…”

Liposomal, Nanoparticle, and Conjugated Formulations of Anticancer Agents

“…Immunoliposomes that contain an antibody conjugated to a liposome are being developed to provide targeted delivery to cancer cells expressing specific proteins (8, 67). Future studies need to evaluate the mechanism of clearance of liposomal and nanoparticle drug formulations and the factors associated with pharmacokinetic variability (19,37,41,42,50,67). In addition, additional preclinical models are needed for toxicity, efficacy, and pharmacokinetic studies, especially because liposomes may not be allometrically scaled across species and toxicity in certain species may not predict human toxicity (50,68).…”

Experimental designs for phase I and phase I/II dose-finding studies

“…In this study, six different dose levels of lurtotecan were studied, namely, 1.5, 2.2, 3.3, 3.7, 4.0 and 4.9 mg m À2 (Giles et al, 2004). A total of 20 patients were included in the trial of which two (10%) patients were at dose level 1, 2 patients (10%) at dose level 2, 2 (10%) patients at dose level 3, 6 (30%) patients at dose level 4, 6 (30%) patients at dose level 5 and 2 (10%) patients at dose level 6.…”