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)

Abstract

To address therapeutic challenges in childhood relapsed ALL, a phase 1 study combining a survivin mRNA antagonist, EZN-3042, with re-induction 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 re-induction platform on days 8, 15, 22 and 29. Toxicity and the biological activity of EZN-3042 were assessed. Six patients enrolled at dose level 1 (EZN-3042 2.5 mg/kg/dose). Two dose limiting toxicities were observed: one patient developed a grade 3 GGT elevation and another patient developed grade 3 gastrointestinal bleeding. Downmodulation of survivin mRNA and protein was assessed after single agent dosing and decreased expression was observed in 2 of 5 patients with sufficient material for analysis. While some biological activity was observed, the combination of EZN-3042 with intensive re-induction 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.

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

“…It was also shown that knockdown of survivin using EZN-3042 in combination with chemotherapy eliminated drug-resistant acute lymphoblastic leukemia cells [143]. Subsequently, a Phase I study of EZN-3042 in pediatric patients with second or greater bone marrow relapses of B-lymphoblastic leukemia was conducted [144]. EZN-3042 was administered as a single agent on days 2 and 5, and then in combination with a 4-drug re-induction platform on days 8, 15, 22, and 29.…”

New targeted therapies for relapsed pediatric acute lymphoblastic leukemia

“…These findings led to a recent phase I trial using an antisense oligonucleotide targeted to survivin in children with second or greater bone marrow relapse of B ALL. While the trial closed due to significant off-target toxicity, it remains an attractive target for future agents [54]. Moreover, IAPs are counterbalanced by second mitochondrial-derived activator of caspases (SMAC) and SMAC mimetics promote cell death through inhibition of IAPs.…”

The Biology of Relapsed Acute Lymphoblastic Leukemia

“…Based on these preclinical studies and preliminary results from a phase 1 trial in adults with relapsed or refractory solid tumors and lymphoma 10 , a clinical trial was designed in children with second or greater bone marrow relapses using a survivin anti-sense oligonucleotide in combination with conventional chemotherapy. Unfortunately patients experienced toxicity, which precluded further clinical development 11 . Nonetheless, survivin remains an attractive target.…”