TY - JOUR
T1 - Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML)
AU - Erba, Harry P.
AU - Sayar, Hamid
AU - Juckett, Mark
AU - Lahn, Michael
AU - Andre, Valerie
AU - Callies, Sophie
AU - Schmidt, Shelly
AU - Kadam, Sunil
AU - Brandt, John T.
AU - Van Bockstaele, Dirk
AU - Andreeff, Michael
N1 - Funding Information:
Conflict of Interest M.L., V.A., S.C., S.S., S.K., and J.T.B. are employees and minor shareholders of Eli Lilly and Company, Indianapolis, IN. The other authors have no financial relationship to declare. Supported in part by grants from NIH CA 55164, CA 049639, and CA 016672 (to MA).
Funding Information:
Acknowledgements The authors would like to thank all patients and site personnel for supporting the study. They would also like to thank David Ohannesian PhD and Joseph Durrant (Pharmanet/i3, Indianapolis, IN; an InVentiv Health company) for writing and editorial support and Bret Monia PhD (ISIS Pharmaceuticals, Carlsbad, CA) for his review of the manuscript. This study was sponsored by Eli Lilly and Company, Indianapolis, IN, USA.
PY - 2013/8
Y1 - 2013/8
N2 - Summary: 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/m2 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.
AB - Summary: 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/m2 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.
KW - Acute myeloid leukemia
KW - Antisense
KW - Cytarabine
KW - Idarubicin
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U2 - 10.1007/s10637-013-9935-x
DO - 10.1007/s10637-013-9935-x
M3 - Article
C2 - 23397500
AN - SCOPUS:84880923165
SN - 0167-6997
VL - 31
SP - 1023
EP - 1034
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 4
ER -