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

Purpose: Topoisomerase 1 inhibitors have shown promising anti leukemic activity in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In this phase 1 study, we investigated the toxicity profile, pharmacokinetics, and activity of a prolonged continuous infusion schedule of the colloidal dispersion formulation of 9-amino-camptothecin (9-AC/CD) in patients with acute leukemia. Patents and methods: Patients with refractory or relapsed AML, acute lymphocytic 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 bilirubin < 1.5 mg/dl. 9-AC/CD was given as a continuous intravenous infusion over seven days every three to four weeks. The starting dose was 0.2 mg/m²/d (1.4 mg/m²/course). Courses were given every three to four weeks according to toxicity and anti leukemic efficacy. This phase I study used the classical 3 + 3 design. The dose was escalated by 50%, until grade 1 toxicity was observed, and then by 30% to 35% until the dose limiting toxicity was defined. At the maximal tolerated dose (MTD). 8 to 10 patients were planned to be treated to better define the toxicity and early-activity profiles. Results: Thirty-nine patients (AML thirty-six patients: ALL two patients: CML-BP one patient), median age 56 years were treated. Severe mucositis was the dose limiting toxicity: it occurred in three of six patients treated at a dose of 1.6 mg/m²/d. The MTD was defined as 1.4 mg/m² day by the phase I design. Upon expansion of the number of patients, 3 of 10 patients had grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and vomiting were uncommon. No complete or partial remission was observed in 37 evaluable patients. However, 9-AC/CD exhibited antileukemic activity, as reflected by the finding of marrow hypoplasia on day 14 in 46% of the patients. Average steady-slate 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 · hr. Conclusion: The MTD of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m²/d (9.8 mg/m²/course) in patients with acute leukemia. This represents three to fourfold dose escalation compared with the MTD of 9-AC given as shorter continuous infusion (three days) in patients with solid tumors. Future studies will determine the activity of prolonged administration of 9-AC/CD in patients with better prognosis acute leukemia.