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J Pediatr Hematol Oncol. 2014 Aug;36(6):458-63. doi: 10.1097/MPH.0b013e3182a8f58f.

A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.

Author information

1
*NYU Cancer Institute and Department of Pediatrics, NYU Langone Medical Center, New York †Staten Island University Hospital, Staten Island, NY ‡Division of Hematology/Oncology §Department of Preventive Medicine, Keck School of Medicine, University of Southern California ∥Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA ¶St. Jude Children's Research Hospital, Memphis, TN #Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN **Johns Hopkins University, Baltimore, MD ††Enzon Pharmaceuticals Inc., Piscataway, NJ.

Abstract

To address the therapeutic challenges in childhood relapsed ALL, a phase 1 study combining a survivin mRNA antagonist, EZN-3042, with reinduction chemotherapy was developed for pediatric patients with second or greater bone marrow relapses of B-lymphoblastic leukemia. EZN-3042 was administered as a single agent on days -5 and -2 and then in combination with a 4-drug reinduction platform on days 8, 15, 22, and 29. Toxicity and the biological activity of EZN-3042 were assessed. Six patients were enrolled at dose level 1 (EZN-3042 2.5 mg/kg/dose). Two dose-limiting toxicities were observed: 1 patient developed a grade 3 γ-glutamyl transferase elevation and another patient developed a grade 3 gastrointestinal bleeding. Downmodulation of survivin mRNA and protein were assessed after single-agent dosing and decreased expression was observed in 2 of 5 patients with sufficient material for analysis. Although some biological activity was observed, the combination of EZN-3042 with intensive reinduction chemotherapy was not tolerated at a dose that led to consistent downregulation of survivin expression. The trial was terminated following the completion of dose level 1, after further clinical development of this agent was halted.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01186328.

PMID:
24276047
PMCID:
PMC4238428
DOI:
10.1097/MPH.0b013e3182a8f58f
[Indexed for MEDLINE]
Free PMC Article
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