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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).

Publication ,  Journal Article
Erba, HP; Sayar, H; Juckett, M; Lahn, M; Andre, V; Callies, S; Schmidt, S; Kadam, S; Brandt, JT; Van Bockstaele, D; Andreeff, M
Published in: Invest New Drugs
August 2013

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.

Duke Scholars

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

August 2013

Volume

31

Issue

4

Start / End Page

1023 / 1034

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Survivin
  • Recurrence
  • Oncology & Carcinogenesis
  • Oligonucleotides, Antisense
  • Oligonucleotides
  • Middle Aged
  • Male
  • Leukemia, Myeloid, Acute
  • Inhibitor of Apoptosis Proteins
 

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Erba, H. P., Sayar, H., Juckett, M., Lahn, M., Andre, V., Callies, S., … Andreeff, M. (2013). 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). Invest New Drugs, 31(4), 1023–1034. https://doi.org/10.1007/s10637-013-9935-x
Erba, Harry P., Hamid Sayar, Mark Juckett, Michael Lahn, Valerie Andre, Sophie Callies, Shelly Schmidt, et al. “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).Invest New Drugs 31, no. 4 (August 2013): 1023–34. https://doi.org/10.1007/s10637-013-9935-x.
Erba HP, Sayar H, Juckett M, Lahn M, Andre V, Callies S, Schmidt S, Kadam S, Brandt JT, Van Bockstaele D, Andreeff M. 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). Invest New Drugs. 2013 Aug;31(4):1023–1034.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

August 2013

Volume

31

Issue

4

Start / End Page

1023 / 1034

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Survivin
  • Recurrence
  • Oncology & Carcinogenesis
  • Oligonucleotides, Antisense
  • Oligonucleotides
  • Middle Aged
  • Male
  • Leukemia, Myeloid, Acute
  • Inhibitor of Apoptosis Proteins