E. Anders Kolb, MD
Eribulin has demonstrated a high level of antitumor activity that was equivalent or superior to vincristine across several sarcoma xenograft models, including at low dose levels, suggesting the drug may effectively treat pediatric patients with sarcoma.
In the analysis, presented at a special conference on pediatric cancers held by the American Association for Cancer Research, the level of response to eribulin was consistent across a range of doses and schedules in 3 of 4 sarcoma xenografts. Moreover, a high level of response was noted even when the dose of the drug was reduced to produce levels of systemic exposure not possible in the clinical setting.
“We had previously published that eribulin is effective at what we would consider a standard dosing,” said E. Anders Kolb, MD, director of blood and bone marrow transplantation at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware, in a statement. “We now find eribulin to be effective across a range of dosing: The drug was highly effective at doses and schedules that achieve blood levels at or below those that are toxic in humans. These results give us confidence that eribulin will be effective across a wide range of dosing and sarcoma types.”
In the study, eribulin was evaluated against the Rh30R, Rh41 rhabdomyosarcomas, EW-8, and CHLA-258 Ewing sarcomas xenograft models in mice. The study explored several doses and schedules of intraperitoneally administered eribulin or vincristine followed by an observational period of up to 12 weeks. Eribulin was administered at 1 mg/kg, 0.5 mg/kg, and 0.25 mg/kg every 4 days for 3 cycles. Vincristine was administered at 1 mg/kg every 7 days for 6 cycles.
The study found that eribulin, at the every 4-day schedule, was highly active against the Rh30R, EW-8, and CHLA-258 xenografts. Eribulin, even at the smallest dose, was most effective in the EW-8 xenografts. In this group, 70% of mice maintained a complete response (CR) following the 12 weeks of observation. Similarly, for the CHLA-258 models, 70% of mice maintained a CR at 12 weeks for the 1.0 mg/kg and 0.5 mg/kg doses. A CR was not noted for the 0.25 mg/kg dose. For the Rh30R xenografts, both the 1.0 mg/kg and 0.5 mg/kg dose of eribulin demonstrated CRs, with regrowth beginning at week 9 of the observation period.
Treatment with vincristine showed similar efficacy against Rh30R tumors. In general, vincristine was able to induce CRs in the EW-8 xenografts; however, these tumors commonly regrew following the completion of treatment. Additionally, in the CHLA-258 models, vincristine was unable to induce any CRs with rapid tumor regrowth in 1 to 2 weeks after treatment stopped.
Both eribulin and vincristine were relatively ineffective against the Rh41 xenograft model. Most Rh41 tumors were resistant to eribulin at doses less than 1 mg/kg.
In an attempt to mimic the clinical schedule of eribulin, researchers administered the 1 mg/kg dose of the drug every 4 days for 2 cycles repeated at day 21. This schedule did not dramatically alter the effectiveness of eribulin in the Rh30R, EW-8, and CHLA-258 models. In general, the CR rates were similar, with only a 1-week variation in CR rates at the end of 12 weeks observation.
“Eribulin is the same type of drug, but it may be more effective than vincristine in some malignancies and in tumors that have proven to be resistant to treatment with vincristine. The effect of eribulin on microtubules is different from vincristine and therefore, may provide new opportunities,” said Kolb. “This is an example of how having access to these drugs through Pediatric Preclinical Testing Program and having well collated results help clinicians prioritize new agents for clinical testing in pediatric cancers.”
Based on these results, future studies will examine eribulin in pediatric patients more thoroughly. At this time, an open-label, single-arm, phase III trial is currently ongoing that is investigating the combination of eribulin with dacarbazine as a treatment for patients 18 years and older with soft tissue sarcoma following treatment with at least two standard therapies.
In this trial, eribulin mesylate will be administered intravenously at 1.4 mg/m2 along with intravenous dacarbazine at 850 mg/m2, 1000 mg/m2, or 1200 mg/m2. The primary endpoint of the study, which launched in 2011, is overall survival. The study was estimated to take 29 months to complete.