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

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

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.

Trial registration: ClinicalTrials.gov NCT01186328.

Conflict of interest statement

Conflict of interest for authors: None

Figures

Figure 1. Survivin Expression Following Treatment with…
Figure 1. Survivin Expression Following Treatment with EZN-3042
Messenger RNA and protein expression analysis of patient samples before (day -6) and after (day 0) pre-phase treatment with EZN-3042 is shown. Quantitative RT-PCR (A, B) and ELISA (C) assays were performed on bone marrow samples from patients on days -6 and 0. mRNA expression for survivin main form (A) and survivin splice variants (B) is plotted relative to the pretreatment expression level at day -6. Absolute protein concentration for survivin (C) on days -6 and 0 were determined by standard curve and expressed as pg of target protein per mg of total protein. Each data point was measured in triplicate (* p <0.05 pre-post treatment).

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