TY - JOUR
T1 - 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)
T2 - A report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium
AU - Raetz, Elizabeth A.
AU - Morrison, Debra
AU - Romanos-Sirakis, Eleny
AU - Gaynon, Paul
AU - Sposto, Richard
AU - Bhojwani, Deepa
AU - Bostrom, Bruce C.
AU - Brown, Patrick
AU - Eckroth, Elena
AU - Cassar, Jeannette
AU - Malvar, Jemily
AU - Buchbinder, Aby
AU - Carroll, William L.
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
KW - antisense
KW - relapsed ALL
KW - survivin
UR - http://www.scopus.com/inward/record.url?scp=84905108842&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905108842&partnerID=8YFLogxK
U2 - 10.1097/MPH.0b013e3182a8f58f
DO - 10.1097/MPH.0b013e3182a8f58f
M3 - Article
C2 - 24276047
AN - SCOPUS:84905108842
SN - 1077-4114
VL - 36
SP - 458
EP - 463
JO - Journal of Pediatric Hematology/Oncology
JF - Journal of Pediatric Hematology/Oncology
IS - 6
ER -