Tosedostat in combination with low dose cytarabine achieves primary endpoint in Phase 2 study

CTI BioPharma has announced findings from an investigator-sponsored Phase 2 trial in patients with either primary (de novo) acute myeloid leukaemia (AML) or AML that has evolved from myelodysplastic syndrome (MDS).

Results showed the combination of tosedostat with low dose cytarabine/Ara-C (LDAC) resulted in an overall response rate (ORR) of 54% in elderly patients with AML – with 45% of patients achieving durable complete responses (CR).

AML is the most common acute leukaemia affecting adults, and its incidence increases with age. AML may develop from the progression of other diseases, such as MDS, which is a blood cancer that also affects the bone marrow and leads to a decrease in circulating red blood cells. Tosedostat is a potential first-in-class selective inhibitor of aminopeptidases, which are required by tumour cells to provide amino acids necessary for growth and tumour cell survival.

Tosedostat study also identified biomarkers that may help identify high-risk patients

“Both the types and length of responses in this trial with tosedostat are very encouraging – particularly given the limited options and poor outcomes historically observed in elderly patients with acute myeloid leukaemia, either de novo or secondary after myelodysplastic syndrome,” said Dr Giuseppe Visani, Director of Haematology and Stem Cell Transplant Centre at AORMN, Pesaro, Italy, “Importantly, through this study we have also identified potential biomarkers that may help identify high-risk patients in which we are more likely to see these clinically meaningful results – the findings of which are quite compelling and warrant further study.”
Final results show that responding patients had a significant improvement in overall survival based on response rates compared to non-responding patients. In the intent-to-treat population (ITT), the ORR was 54% – with CR observed in 45% of patients. In the responding patients, the median time for achieving best response was 74 days and 55% were still in remission after a median follow-up of 319 days.

One of the secondary endpoints was to identify possible biomarkers associated with sensitivity and/or drug resistance. A gene expression profile (GEP) was performed on purified AML cells obtained from 29 patients. Analysis of these patient cells identified a molecular signature associated with clinical response (CR vs. no CR). Based on the differentially expressed genes, samples were divided according to either CR or no CR. Results showed that these differentially expressed genes were associated with relevant biological functions and pathways, and showed that the achievement of a CR could be efficiently predicted by GEP.

“The results observed with tosedostat in acute myeloid leukaemia add to a growing body of data showing the anti-tumour activity of this aminopeptidase inhibitor and the potential of using this approach to treat blood-related cancers,” said Alan K. Burnett, M.D., Global Lead for Myeloid Diseases at CTI BioPharma.