Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

1Department of Clinical Pharmacology, Medical University of Vienna, Währinger gürtel, Vienna, Austria; 2early Oncology Clinical investigation, eli Lilly and Company, indianapolis, in, UsA; 3Department of Pharmacokinetics, eli Lilly and Company, erl Wood Research Centre, Windlesham, surrey, UK; 4Department of internal Medicine i, Division of hematology and hemostaseology, Medical University of Vienna, Währinger gürtel, Vienna, Austria; 5eli Lilly gesmbh, Medical Department, Vienna, Austria; 6Department of statistics, eli Lilly and Company, erl Wood Research Centre, surrey, UK; 7Discovery Chemistry Research and Technology, eli Lilly and Company, indianapolis, in, UsA; 8nonclinical Toxicology, eli Lilly and Company, indianapolis, in, UsA; 9Flow Cytometry and Cell Analysis, esoterix Clinical Trials services, Mechelen, Belgium; 10Universitätsklinikum Ulm, Klinik für innere Medizin iii, Ulm, germany; 11Ludwig Boltzmann Cluster Oncology, Vienna, Austria