Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia

Purpose: Topoisomerase I inhibitors have shown promising anti leukemic acti vity in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In t his phase I study, we investigated the toxicity profile, pharmacokinetics, and activity of a prolonged continuous infusion schedule of the colloidal d ispersion formulation of 9-amino-camptothecin (9-AC/CD) in patients with ac ute leukemia. Patients and methods: Patients with refractory or relapsed AML, acute lymph ocytic leukemia (ALL) or chronic myelogenous leukemia in blastic phase (CML -BP) were included in the study. Eligibility criteria were age greater than 15 years, performance status of 2 or better, creatinine < 1.5 mg/dl, and b ilirubin < 1.5 mg/dl. 9-AC/CD was given as a continuous intravenous infusion over seven days ever y three to four weeks. The starting dose was 0.2 mg/m(2)/d (1.4 mg/m(2)/cou rse). Courses were given every three to four weeks according to toxicity an d anti leukemic efficacy. This phase I study used the classical 3 + 3 desig n. The dose was escalated by 50% until grade 1 toxicity was observed, and t hen by 30% to 35% until the dose limiting toxicity was defined. At the maxi mal tolerated dose (MTD), 8 to 10 patients were planned to be treated to be tter define the toxicity and early-activity profiles. Results: Thirty-nine patients (AML thirty-six patients; ALL two patients; C ML-BP one patient), median age 56 years, were treated. Severe mucositis was the dose limiting toxicity; it occurred in three of six patients treated a t a dose of 1.6 mg/m(2)/d. The MTD was defined as 1.4 mg/m(2)/day by the ph ase I design. Upon expansion of the number of patients, 3 of 10 patients ha d grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and v omiting were uncommon. No complete or partial remission was observed in 37 evaluable patients. However, 9-AC/CD exhibited antileukemic activity, as re flected by the finding of marrow hypoplasia on day 14 in 46% of the patient s. Average steady-state concentration of 9-AC lactone was close to 10 nmol/ l, and the of 9-AC lactone area under curve (AUC) was 1409 +/- 705 nmol/l.h r. Conclusion: The MTD of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m(2)/d (9.8 mg/m(2)/course) in patients with acute leukemia. This r epresents three to fourfold dose escalation compared with the MTD of 9-AC g iven as shorter continuous infusion (three days) in patients with solid tum ors. Future studies will determine the activity of prolonged administration of 9-AC/CD in patients with better prognosis acute leukemia.