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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.

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*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.


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.


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