Phase I and Pharmacologic study of liposomal lurtotecan, NX 211: Urinary excretion predicts hematologic toxicity

Purpose: To determine the maximum-tolerated and recommended dose, toxicity profile, and pharmacokinetics of the liposomal topoisomerase 1 inhibitor lurtotecan (NX 211) administered as a 30-minute intravenous infusion once every 3 weeks in cancer patients. Patients and Methods: NX211 was administered by peripheral infusion. Dose escalation decisions were based on all toxicities during the first cycle as well as pharmacokinetic parameters. Serial plasma, whole blood, and urine samples were collected for up to 96 hours after the end of infusion, and drug levels were determined by high-performance liquid chromatography. Results: Twenty-nine patients (16 women; median age, 56 years; range, 39 to 74 years) received 77 courses of NX 211 at dose levels of 0.4 (n = 3), 0.8 (n = 6), 1.6 (n = 3), 3.2 (n = 6), 3.8 (n = 6), and 4.3 mg/m(2) (n = 5). Neutropenia and thrombocytopenia were the dose-limiting toxicities and were not cumulative. Other toxicities were mild to moderate. Nine patients had stable disease while undergoing treatment. The systemic clearance of lurtotecan in plasma and whole blood was 0.82 +/- 0.78 L/h/m(2) and 1.15 +/- 0.96 L/h/ m(2), respectively. Urinary recovery (Fu) of lurtotecan was 10.1 +/- 4.05% (range, 4.9% to 18.9%). In contrast to systemic exposure measures, the dose excreted in urine (ie, dose x Fu) was significantly related to the percent decrease in neutrophil and platelet counts at nadir (P < .00001). Conclusion: The dose-limiting toxicities of NX 211 are neutropenia and thrombocytopenia. The recommended dose for phase II studies is 3.8 mg/m2 once every 3 weeks. Pharmacologic data suggest a relationship between exposure to lurtotecan and NX 211-induced clinical effects. (C) 2002 by American Society of Clinical Oncology.