Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia.

Abstract

PURPOSE:

X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy.

PATIENTS AND METHODS:

Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m(2)) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m(2) in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA.

RESULTS:

Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m(2) of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m(2) AEG35156. Among the patients receiving 350 mg/m(2) of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156.

CONCLUSION:

At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen.

• Authors: Aaron D Schimmer, Elihu H Estey, Gautam Borthakur, Bing Z Carter, Gary J Schiller, Martin S Tallman, Jessica K Altman, Judith E Karp, Jeannine Kassis, David W Hedley, Joseph Brandwein, Wei Xu, Duncan H Mak, Eric LaCasse, Christine Jacob, Stephen J Morris, Jacques Jolivet, Michael Andreeff
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 28 Pg. 4741-6 (Oct 01 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19652057 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AEG 35156
• Oligonucleotides
• RNA, Messenger
• X-Linked Inhibitor of Apoptosis Protein
• Cytarabine
• Idarubicin

Topics

• Acute Disease
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Cytarabine (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Idarubicin (administration & dosage, adverse effects)
• Leukemia, Myeloid (drug therapy, pathology)
• Male
• Middle Aged
• Oligonucleotides (administration & dosage)
• Peripheral Nervous System Diseases (chemically induced)
• RNA, Messenger (genetics, metabolism)
• Recurrence
• Reverse Transcriptase Polymerase Chain Reaction
• Treatment Outcome
• X-Linked Inhibitor of Apoptosis Protein (genetics)