Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia.

PURPOSE: To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor.

PATIENTS AND METHODS: In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome.

RESULTS: In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML.

CONCLUSION: This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.