Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia

Purpose: DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). Experimental Design: DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m²/day for 5 days (3.0 mg/m²/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. Results: Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m²/day for 5 days, two of three treated at 1.2 mg/m²/day for 5 days, and one of six treated at 0.9 mg/m²/day for 7 days. The recommended Phase II dose was 0.9 mg/m²/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model. Conclusions: Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.