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)

Harry P. Erba, Hamid Sayar, Mark Juckett, Michael Lahn, Valerie Andre, Sophie Callies, Shelly Schmidt, Sunil Kadam, John T. Brandt, Dirk Van Bockstaele, Michael Andreeff

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1023-1034
Number of pages12
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
StatePublished - Aug 2013

Fingerprint

Idarubicin
Antisense Oligonucleotides
Cytarabine
Acute Myeloid Leukemia
Pharmacokinetics
Safety
Intravenous Infusions
Cell Cycle Checkpoints
Combination Drug Therapy
Mitosis
Neoplasms
Cell Death
Bone Marrow
Sodium
Clinical Trials
Apoptosis

Keywords

  • Acute myeloid leukemia
  • Antisense
  • Cytarabine
  • Idarubicin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

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). / Erba, Harry P.; Sayar, Hamid; Juckett, Mark; Lahn, Michael; Andre, Valerie; Callies, Sophie; Schmidt, Shelly; Kadam, Sunil; Brandt, John T.; Van Bockstaele, Dirk; Andreeff, Michael.

In: Investigational New Drugs, Vol. 31, No. 4, 08.2013, p. 1023-1034.

Research output: Contribution to journalArticle

Erba, Harry P. ; Sayar, Hamid ; Juckett, Mark ; Lahn, Michael ; Andre, Valerie ; Callies, Sophie ; Schmidt, Shelly ; Kadam, Sunil ; Brandt, John T. ; Van Bockstaele, Dirk ; Andreeff, Michael. / 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). In: Investigational New Drugs. 2013 ; Vol. 31, No. 4. pp. 1023-1034.
@article{96e642e503954aaa9973074811e21006,
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 = "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.",
keywords = "Acute myeloid leukemia, Antisense, Cytarabine, Idarubicin",
author = "Erba, {Harry P.} and Hamid Sayar and Mark Juckett and Michael Lahn and Valerie Andre and Sophie Callies and Shelly Schmidt and Sunil Kadam and Brandt, {John T.} and {Van Bockstaele}, Dirk and Michael Andreeff",
year = "2013",
month = "8",
doi = "10.1007/s10637-013-9935-x",
language = "English",
volume = "31",
pages = "1023--1034",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "4",

}

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

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

UR - http://www.scopus.com/inward/record.url?scp=84880923165&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880923165&partnerID=8YFLogxK

U2 - 10.1007/s10637-013-9935-x

DO - 10.1007/s10637-013-9935-x

M3 - Article

C2 - 23397500

AN - SCOPUS:84880923165

VL - 31

SP - 1023

EP - 1034

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 4

ER -