Phase I/II Study to Assess the Safety and Efficacy of the Aurora B Kinase Inhibitor, AZD1152, in Patients with Advanced Acute Myeloid Leukemia.

Aurora B kinase is one of the key regulators of mitosis that is overexpressed in various malignancies, including acute myeloid leukemia (AML). AZD1152 is a highly potent and selective inhibitor of Aurora B kinase that has been shown to significantly inhibit the growth of human tumor xenografts in vivo. Methods: A Phase I/II, open-label, two-part study was conducted to assess the safety and efficacy of AZD1152 in patients aged >18 years with advanced AML. In part A, the maximum tolerated dose (MTD) of AZD1152 administered as a continuous 7-day infusion every 21 days was determined. In part B the efficacy of AZD1152, at the MTD determined in part A, was evaluated. Objective response rate was evaluated according to the Cheson AML clinical response criteria. Adverse events (AEs) and serious AEs (SAEs) were evaluated throughout the study according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Results: At the data cut-off on 28 April 2009 (data validation ongoing), 32 patients had been treated with AZD1152 (n=3, 50 mg; n=3, 100 mg; n=3, 200 mg; n=4, 400 mg; n=7, 800 mg; n=6, 1200 mg; n=6, 1600 mg) in part A. Mean age was 66 years (range 45–82), 18 (56%) were male and all but one patient (Black) were Caucasian. At baseline, 14 (44%) patients had de novo AML, 12 (38%) had AML secondary to myelodysplastic syndrome and three (9%) had AML secondary to chemotherapy. Four (13%) patients were newly diagnosed, 23 (72%) were on first relapse, and one (3%) was on second relapse. The majority of patients (63%) had received ≥3 prior chemotherapy regimens and two (6%) had radiotherapy. All 32 patients received at least one cycle of treatment, 19 received ≥2 cycles and one received six cycles. Dose-limiting toxicities were reported in the 800 mg (mucositis), 1200 mg (stomatitis) and 1600 mg (n=2 mucositis) groups. The MTD was defined as 1200 mg. All patients had at least one AE; the most common were febrile neutropenia (41%), pyrexia (41%) and nausea (38%). The most common CTCAE grade 3/4 were febrile neutropenia (31%) and stomatitis (16%). There were 16 (50%) deaths, 14 were due to disease progression and one due to disease progression and SAE (sepsis). Seven (22%) had a clinical response: 1 complete remission (CR) (1200 mg cohort), 2 complete remissions with incomplete blood count recovery (CRi) (400 mg and 800 mg cohorts) and 4 partial remissions (PR) (100 mg, 800 mg, 1200 mg and 1600 mg cohorts). In part B, 32 patients were treated with AZD1152 1200 mg. Mean age was 68 years (range 48–87 years), 19 (59%) were male and all but one patient (Asian) were Caucasian. At baseline, 10 (31%) patients had de novo AML, 11 (34%) had AML secondary to myelodysplastic syndrome, four (13%) had AML secondary to chemotherapy and one (3%) had AML secondary to myeloproliferative disorder. Fourteen (44%) were newly diagnosed, 12 (38%) were on first relapse, and three (9%) were on second relapse. All but two patients had received prior chemotherapy; 12 (38%) had ≥3 chemotherapy regimens and three (9%) had radiotherapy. All 32 patients received at least one cycle of treatment; 10 received ≥2 cycles, and one had received four cycles to date. All patients had at least one AE; the most common AEs were fatigue (41%), febrile neutropenia (38%) and stomatitis (38%). The most common CTCAE grade 3/4 were febrile neutropenia (28%) and stomatitis (13%). To date there have been five (16%) deaths, three due to disease progression, one due to disease progression and SAE (Escherichia sepsis), and one due to SAE (fungal infection). Eight (25%) patients had a clinical response: 2 CR, 3 CRi and 3 PRs. Cytogenetic data were available at baseline for approximately 75% of patients participating in the study. Analysis of these data indicated that clinical responses (CR, CRi or PR) were seen across all Medical Research Council prognostic groups. Conclusions: The MTD of AZD1152 was defined as 1200 mg in patients with relapsed AML. An overall clinical response rate (CR+CRi+PR) of 23% was observed in study parts A and B combined. AZD1152 had an acceptable tolerability profile in patients with AML and reported AEs are similar to those in patients with solid tumors treated with the agent. The development of AZD1152 is continuing with a study in elderly patients with AML considered unfit for intensive chemotherapy.

Off Label Use: Clinical trial investigating AZD1152 in patients with acute myeloid leukemia. Rousselot:BMS: Advisory Board. Goudie:AstraZeneca: Employment. Stockman:AstraZeneca: Employment, Equity Ownership, Holds Stock. Kantarjian:AstraZeneca: Research Funding.