A randomized phase III study of elacytarabine versus limited investigator’s choice in patients with refractory acute myeloid leukemia (AML).

Abstract

Background: Elacytarabine is a novel chemical entity developed as an antineoplastic agent. It is a fatty acid derivative (elaidic acid ester) of cytarabine (Ara‐C). In contrast to cytarabine, preclinical data show that elacytarabine is independent of transporters (hENT1) to enter leukemic cells, and might therefore overcome one of the resistance mechanisms for cytarabine. Elacytarabine has in a phase II study (61 patients with 2nd salvage AML), shown a median survival of 5.3 months compared to 1.5 months in a matched historical control population The remission rate was 18% versus 4.1% and the short term mortality was 13% (O'Brien et al, EHA abstract 2010). Methods: The pivotal phase III study (CLAVELA) is an open‐label, randomized controlled trial designed to compare efficacy and safety of elacytarabine single agent with a limited investigator's choice of treatment in patients with refractory AML. The primary objective is to compare overall survival and secondary objectives are to compare the response rates, duration of response, and safety profile of elacytarabine with investigator's choice treatments (HIDAC, MEC, FLAG/FLAG‐IDA, Low‐dose Ara‐C, hypomethylating agents, hydroxyurea or palliative care). The investigator will determine the control treatment prior to randomization. In addition, blast cells will be collected for exploratory hENT analysis and the effect on possible outcome will be studied. The study is powered to detect a hazard ratio of 0.70, i.e. a 30% proportional reduction in mortality with 80% power at the p<0.05 significance level. This requires 250 deaths (events of interest). A total of up to 350 patients will be recruited at 75 sites in the USA, Canada, Australia and Europe. The DMC last reviewed the trial in November 2010 and suggested that the trial continue as planned. The key inclusion criteria: Adult patients with AML, who have received 2 or 3 previous induction regimens, and never attained a CR or failed initial induction, attained CR after salvage therapy(ies), and relapsed after < 6 months or attained CR after initial induction, relapsed after < 12 months and failed to respond to salvage therapy(ies) or relapsed within < 6 months after the latest CR.