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.

Advances in emerging drugs for osteosarcoma

“…Eribulin mesylate proved to inhibit cancer cell proliferation at nanomolar concentrations and showed a favorable pharmacokinetic and pharmacodynamic profile in comparison to other microtubule inhibitors, such as vinca alkaloids and taxanes [106]. Eribulin mesylate showed activity in human OS xenograft models [107], and it is presently under clinical evaluation in patients with recurrent or refractory OS inside a Phase II trial ( Table 1).…”

Eribulin Mesylate: Mechanism of Action of a Unique Microtubule-Targeting Agent

“…In addition, eribulin also had activity in cells from a range of pediatric solid tumors and acute lymphocytic leukemia in vitro and in xenograft models (20). Collectively, these preclinical studies established eribulin as a promising compound, that retained the unique properties of halichondrin B and had excellent preclinical in vivo activity.…”

Future directions in the treatment of osteosarcoma

“…The first phase II trial to be developed under this paradigm included eribulin mesylate, a microtubule inhibitor that demonstrated activity in osteosarcoma cell lines and xenografts in the Pediatric Preclinical Testing Program. [15] While expected to enroll 1.3 patients per month based on prior phase II studies, the trial rapidly accrued 19 patients in 3.5 months. [16] The brief interval observed from enrollment to analysis demonstrates the potential success of such a clinical trial model to expedite the analysis of novel agents for clinical effectiveness, and the willingness of patients to continue to seek new therapies when available.…”