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

作者：Raetz Elizabeth A^*; Morrison Debra; Romanos Sirakis Eleny; Gaynon Paul; Sposto Richard; Bhojwani Deepa; Bostrom Bruce C; Brown Patrick; Eckroth Elena; Cassar Jeannette; Malvar Jemily; Buchbinder Aby; Carroll William L

来源：Journal of Pediatric Hematology/Oncology, 2014, 36(6): 458-463.

• relapsed ALL
• survivin
• antisense

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 g-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.

• 出版日期2014-8