Acadesine (Acadra‘) for Patients with Resistant/Relapsed Chronic B-Cell Lymphocytic Leukemia (B-CLL): A Multicentre Phase I/II Study.

Abstract 4405

Acadesine (Acadra^‘) is a nucleoside that induces cell death in B-cell chronic lymphocytic leukemia (B-CLL) cells ex vivo in a dose-dependent manner over the concentration range 50 mM to 1 mM. Acadesine enters B-cells and is phosphorylated to its active metabolite, ZMP, which induces apoptosis independently of ATM or p53. It is active against B-CLL cells from patients who have not responded to prior treatment with fludarabine and/or chlorambucil (Campas et al, 2003).

Based on this pre-clinical data, a Phase I/II clinical study was designed to determine the safety and tolerability of acadesine given intravenously as a 4-hour infusion to patients with B-CLL. This is an open-label dose escalation study of acadesine with two parts. In Part I, the dose escalation part of the study, patients receive a single dose of acadesine on Day 1 and are followed up to Day 22. In Part II, patients will receive up to 5 doses of acadesine at the maximum tolerated dose (MTD) identified in Part I over a period of up to 20 days starting on Day 1. The patient population includes B-CLL patients with refractory or relapsed disease who have received one or more (≥ 1) prior lines of treatment which must have included either a fludarabine or an alkylator based regimen. Primary endpoints of the study evaluate the safety and tolerability of acadesine. Secondary endpoints evaluate the pharmacokinetics of acadesine in plasma, its metabolite ZMP in whole blood, and changes in peripheral blood B-cell and T-cell counts as efficacy biomarkers. Optimal Biological Dose (OBD) is defined as the minimal acadesine dose that gives a maximum Cmax for ZMP in whole blood with a good safety profile.

Twelve patients (6 males and 6 females) have been administered acadesine to date in 3 cohorts in Part I. Acadesine has an excellent safety profile to date. The principal safety finding was asymptomatic acadesine-related hyperuricaemia of short duration in four patients. Prophylactic allopurinol has significantly reduced the incidence of hyperuricaemia.

Pharmacokinetic data showed acadesine rapidly disappears from plasma to be converted into ZMP inside blood cells. The OBD has not been reached yet and maximum dose administered to date is 139.5 mg/kg. The next cohort will receive 210 mg/kg. Additional safety, pharmacokinetics and efficacy data will be presented at the meeting.