title: 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).
abstract: 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.
authors: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA. herba@uabmc.edu
authors: Harry P
authors: HP
authors: Erba
authors: Hamid
authors: H
authors: Sayar
authors: Mark
authors: M
authors: Juckett
authors: Michael
authors: M
authors: Lahn
authors: Valerie
authors: V
authors: Andre
authors: Sophie
authors: S
authors: Callies
authors: Shelly
authors: S
authors: Schmidt
authors: Sunil
authors: S
authors: Kadam
authors: John T
authors: JT
authors: Brandt
authors: Dirk
authors: D
authors: Van Bockstaele
authors: Michael
authors: M
authors: Andreeff
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003561:Cytarabine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003710:Demography; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D012008:Recurrence; D000077022:Survivin; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C529350:LY 2181308; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D000077022:Survivin; D003561:Cytarabine; D015255:Idarubicin
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