Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program

Abstract

Background: Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.

Procedures: Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.

Results: In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1-14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR.

Conclusions: The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine.

Fig. 1

Eribulin in vitro activity: The median rIC₅₀ ratio graph shows the relative rIC₅₀ values for the cell lines of the PPTP panel. Each bar represents the ratio of the panel rIC₅₀ to the rIC₅₀ value of the indicated cell line. Bars to the right represent cell lines with higher sensitivity, while bars to the left indicate cell lines with lesser sensitivity.

Fig. 2

Eribulin in vivo objective response activity for Ewing sarcoma models. Ewing sarcomas (SK-NEP1, EW-8, TC-71, and CHLA258): Kaplan–Meier curves for EFS (left), median relative tumor volume graphs (center), and individual tumor volume graphs (right) are shown for selected lines. Controls (gray lines); treated (black lines), statistical significance (P-values) of the difference between treated and control groups are included.

Fig. 3

Eribulin in vivo objective response activity for osteosarcoma models. Osteosarcomas (OS-1, OS-2, OS-17, and OS-33): Kaplan–Meier curves for EFS (left), median relative tumor volume graphs (center), and individual tumor volume graphs (right) are shown for selected lines. Controls (gray lines); treated (black lines), statistical significance (P-values) of the difference between treated and control groups are included.

Fig. 4

Left: The colored heat map depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥2 but <6, and low activity by a score of <2. Right: representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.