title: 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.
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.
authors.affiliation: *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.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.forename: Debra
authors.initials: D
authors.lastname: Morrison
authors.forename: Eleny
authors.initials: E
authors.lastname: Romanos-Sirakis
authors.forename: Paul
authors.initials: P
authors.lastname: Gaynon
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Bostrom
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
authors.forename: Elena
authors.initials: E
authors.lastname: Eckroth
authors.forename: Jeannette
authors.initials: J
authors.lastname: Cassar
authors.forename: Jemily
authors.initials: J
authors.lastname: Malvar
authors.forename: Aby
authors.initials: A
authors.lastname: Buchbinder
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D012074:Remission Induction; D000077022:Survivin; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C107489:BIRC5 protein, human; C552302:EZN 3042; D051034:Inhibitor of Apoptosis Proteins; D009841:Oligonucleotides; D012333:RNA, Messenger; D000077022:Survivin