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Tosedostat/Cytarabine Combo Shows Promise in Elderly Patients With Leukemia

Mid-stage trial reports 54% response rate

Positive findings have been reported from an investigator-sponsored phase II trial in patients with either primary (de novo) acute myeloid leukemia (AML) or AML that has evolved from myelodysplastic syndrome (MDS). The results showed that the combination of tosedostat (CTI BioPharma) 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 a durable complete response (CR).

The results were presented during the 20th Congress of the European Hematology Association (EHA), held June 11–14 in Vienna, Austria.

AML is the most common acute leukemia 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 erythrocytes. Tosedostat is a potential first-in-class selective inhibitor of aminopeptidases, which are required by tumor cells to provide amino acids necessary for growth and tumor-cell survival.

The study results presented at the EHA meeting showed that responding patients had a significant improvement in overall survival, based on response rates, compared with nonresponding patients (P = 0.018). In the intent-to-treat population, the ORR was 54%, with CRs observed in 45% of patients (15/33). In the responding patients, the median time for achieving the best response was 74 days (range: 22 to 145 days), and 55 percent (10/18) were still in remission after a median follow-up period of 319 days.

A safety analysis showed that tosedostat in combination with LDAC was generally well tolerated. The most common adverse events included pneumonitis (12%), cardiac hemorrhage (6%), brain hemorrhage (3%), and asthenia (3%).

The phase II multicenter clinical trial was designed to assess oral tosedostat (once daily) in combination with intermittent LDAC (twice daily) in 33 elderly patients (median age, 75 years) with either primary AML or secondary AML after MDS. Courses of LDAC were repeated every 4 weeks for up to eight cycles in the absence of disease progression or unacceptable toxicity. The study’s primary objective was to exceed the upper limit of institutional expected CR rates (i.e., P0 = 10%, P1 = 25%, alpha = 0.05, and 1-beta = 80%).

Tosedostat is an oral aminopeptidase inhibitor that has demonstrated antitumor responses in blood-related cancers and solid tumors in phase I and II clinical studies. The drug is being evaluated in multiple phase II clinical trials for the treatment of patients with AML or high-risk MDS. These studies are intended to inform the design of a phase III registration study to support potential regulatory approval. Tosedostat is not currently approved or commercially available for the treatment of AML.

AML is the most common acute leukemia affecting adults, and its incidence increases with age. The symptoms of the disease are caused by the replacement of normal bone marrow with leukemic cells, which causes a drop in erythrocytes, platelets, and normal leukocytes, leading to infections and bleeding. AML progresses rapidly and is typically fatal within weeks or months after diagnosis if left untreated. In 2015, approximately 20,830 new cases of AML are expected to be diagnosed in the U.S., and an estimated 10,460 individuals are expected to die from the disease. While AML may occur at any age, adults at least 60 years old are more likely than younger individuals to develop the disease. AML in elderly people typically responds poorly to standard therapy, with few complete remissions.

Source: PR Newswire; June 15, 2015.


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