The OPAL study: A phase II study to evaluate the efficacy, safety, and tolerability of tosedostat (CHR-2797) in elderly subjects with treatment refractory or relapsed acute myeloid leukemia.

Abstract

TPS277 Background: Tosedostat (CHR-2797) is a novel oral aminopeptidase inhibitor. Aminopeptidases catalyze hydrolysis of terminal amino acids from (poly)peptides generated by proteasomal degradation. Inhibition of aminopeptidases leads to a deficiency of amino acids for protein synthesis. Malignant cells appear to be more dependent on protein cycling, so this pathway is a potential target for novel agents. In preclinical experiments, tosedostat exerts antineoplastic activity in solid tumor, leukemia and myeloma cell lines in vitro. A phase I-II study with tosedostat included 51 patients with acute myeloid leukemia (AML), and showed promising antileukemia effects and good tolerability. Thirty-five of these patients had relapsed or refractory AML. Complete response (CR) was defined as <5% blasts, partial response (PR) as 5-15% blasts. 11 of 35 had favorable responses (6 CRs, 5 PRs), an overall response of 31.4%. In follow-up, 5 of the 6 CRs were observed to result in 3 Complete Remissions, 1 CRp and 1 CRi. Longer median overall survival was noted for complete (334 days) and partial (361 days) responses compared to all patients (118 days) or nonresponders (97 days). This study formed the basis for the ongoing study. Methods: The OPAL study is a phase II study in 2 parts. Part A is a dose selection part in which 60 patients aged over 65 years with refractory or relapsed AML, whose first induction resulted in a complete remission for up to 12 months (Estey 1996), will be randomized to receive first salvage with tosedostat 120 mg daily for 6 months OR tosedostat 240 mg daily for 2 months followed by 120 mg for 4 months. A benefit-risk analysis will take place to determine the dose for Part B in which a further 130 patients will be treated with tosedostat. Responses will be assessed using IWG criteria (Cheson et al 2003). Results: Five patients were randomized by January 8, 2010. Updated enrollment numbers will be presented. Part B will commence in Q3/2010. Conclusions: Tosedostat is a promising agent for the treatment of refractory or relapsed elderly AML patients. The OPAL study will further evaluate the efficacy and safety of tosedostat in these patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chroma Therapeutics Ltd. Chroma Therapeutics Ltd. Chroma Therapeutics Ltd.