Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with refractory leukemia

Abstract

2518 Background: AT9283 inhibits aurora kinase A and B and targets other tyrosine and serine/threonine kinases associated with myeloid cell proliferation. Exposure of leukemia cell lines to AT9283 in vitro induces an “aurora inhibitory” phenotype with creation of large aneuploidal cells with limited replication potential which ultimately undergo mitotic catastrophe and apoptosis. Methods: AT9283 was administered by 72-hour IV continuous infusion (IVCI) to pts with refractory AML, ALL, high risk MDS, and imatinib- and dasatinib-refractory CML. A 3+3 dose escalation phase I design was employed to determine MTD and biological activity, and standard DLT definitions were employed. Results: A total of n=29 patients (med. age 54 years, range 22 to 86; 15M/14F) have been treated at 8 different dose levels: 3 (n=3 pts); 6 (n=3); 12 (n=7); 24 (n=3); 48 (n=4); 72 (n=3); 108 (n=3); and 162 (n=3) mg/m2 daily x 3. Median number of prior treatments was 2 (range 1–5); n=3 pts had prior allografts. Biological activity was seen on correlative pharmcodynamic (PD) studies, with reduction in histone H3 phosphorylation (Aurora kinase B inhibition) and caspase activation in PBMC’s collected at 70 hrs. Treatment at dose of 162 mg/m2/day was accompanied by grade IV elevation in serum aminotransferases, CK & LDH of non-cardiac origin in n=2 pts. A 3rd patient treated at this dose level died from myocardial infarction shortly after completing AT9283 infusion. The only other DLT was tumour lysis syndrome at a dose of 12 mg/m2 daily x 3. AT9283 was associated with predictable myelosuppression, particularly neutropenia, and alopecia at doses >6 mg/m2 daily x 3. Approximately 1/3 of patients with refractory AML experienced a significant reduction in BM blasts following AT9283. Two pts with refractory CML exhibited a hematological response, and one remains on AT9283 with ongoing partial cytogenetic response after 4 cycles of treatment. Conclusions: The MTD of AT9283 administered as a 72 hr IVCI is 108 mg/m2/day. Treatment was associated with early evidence of activity in refractory AML and CML. In vitro studies suggest that expanding the duration of infusion will increase the biological effect of AT9283, and prolonged infusions up to 6 days at lower dose will now be explored based upon the clinical and PD observations in this trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Astex Therapeutics Astex Therapeutics