Addition of AEG35156 XIAP antisense oligonucleotide in reinduction chemotherapy does not improve remission rates in patients with primary refractory acute myeloid leukemia in a randomized phase II study
Schimmer A.D.,Ontario Cancer Institute |
Herr W.,Universitatsmedizin Mainz |
Hanel M.,Klinikum Chemnitz GGmbH |
Borthakur G.,University of Texas M. D. Anderson Cancer Center |
And 13 more authors.
Clinical Lymphoma, Myeloma and Leukemia | Year: 2011
XIAP is over-expressed in AML and may contribute to chemoresistance. We report an open-label randomized phase II trial of reinduction chemotherapy with and without the XIAP antisense oligonucleotide AEG35156 in patients with AML patients. The addition of AEG35156 to re-induction chemotherapy did not improve rates of remission. Therefore, alternate therapeutic strategies should be explored in these patients. Background: XIAP (X-linked inhibitor of apoptosis protein) is an inhibitor of caspases 3 and 9 that is overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report an open-label randomized phase II trial of reinduction chemotherapy with and without the XIAP antisense oligonucleotide AEG35156 in patients with AML who did not achieve remission with initial induction chemotherapy. Methods: Twenty-seven patients with AML who were refractory to initial induction chemotherapy were randomized and treated with AEG35156 (650 mg) in combination with high-dose cytarabine and idarubicin. Thirteen patients were randomized and treated with high-dose cytarabine and idarubicin alone. The rates of response and toxicity were determined. Results: Of the 27 patients assigned to AEG35156 in combination with high-dose cytarabine and idarubicin, 3 died during reinduction chemotherapy, 5 achieved complete remission (CR), and 6 achieved CR with incomplete platelet count recovery (CRp), for an overall response rate of 41%. Of the 13 patients assigned to the control arm of the study, none died during reinduction, 6 achieved CR, and 3 achieved CRp, for an overall response rate of 69%. The differences in response rates between patients in the AEG35156 and control arms were not statistically different (P = 0.18 by the χ 2 test). Conclusions: The addition of AEG35156 to reinduction chemotherapy was well tolerated but did not improve rates of remission. Therefore alternative therapeutic strategies should be explored in patients with AML refractory to induction chemotherapy. © 2011 Elsevier Inc. All rights reserved.
Mahadevan D.,Arizona Cancer Center |
Chalasani P.,Arizona Cancer Center |
Rensvold D.,Arizona Cancer Center |
Kurtin S.,Arizona Cancer Center |
And 5 more authors.
American Journal of Clinical Oncology: Cancer Clinical Trials | Year: 2013
OBJECTIVES:: AEG35156 is an antisense oligonucleotide (ASO) that targets the X-linked inhibitor of apoptosis mRNA. Preclinical studies showed potent activity of AEG35156 in combination with gemcitabine in pancreatic ductal adenocarcinoma (PDA). A phase I study was conducted to establish the maximum-tolerated dose, safety, and antitumor activity of AEG35156 plus gemcitabine in metastatic PDA. METHODS:: Fourteen patients with metastatic PDA were enrolled. Nine patients were treated at 350 mg IV and 5 patients at 500 mg IV of AEG35156, 3 weeks on/1 week off of a 28-day cycle. Gemcitabine was administered at 1000 mg/m IV over 30 minutes immediately after AEG35156 in both groups. Because of perceived neurotoxicity dose deescalation to 350 mg was recommended. RESULTS:: All 14 patients were evaluable for tolerability and toxicity. Toxicities include neutropenia (grade 3/4, 6 patients), thrombocytopenia (grade 3, 2 patients), peripheral neuropathy (grade 3, 2 patients), fatigue (grade 3, 4 patients), ascites (grade 3, 2 patients), and nausea/vomiting (grade 4, 2 patients). Five patients (45%) experienced stable disease with a median progression-free survival of 58 days (95% CI, 52-107 d). CONCLUSIONS:: The maximum-tolerated dose is AEG35156 500 mg plus gemcitabine 1000 mg/m given on days 1, 8, and 15 every 28 days. AEG35156 plus gemcitabine failed to show significant clinical activity in advanced PDA. Copyright © 2012 by Lippincott Williams & Wilkins.