ATNT-21: PRECLINICAL AND INITIAL PHASE 1 EXPERIENCE FOR USE OF MEBENDAZOLE AS UP FRONT THERAPY FOR HIGH GRADE GLIOMA

INTRODUCTION: Identifying drugs that can reach brain cancers in effective concentrations has been a serious challenge. There has been a body of evidence implicating anti-cancer mechanisms and utility for antihelminthics benzimidazoles, and preclinical and clinical development of repurposed mebendazole is gaining momentum. Mebendazole has been used safely as an anti-parasitic drug, and in high doses, in humans starting in 1972. METHODS: Multiple intracranial models of glioblastoma and medulloblastoma have been used for efficacy studies on intracranial tumors. Studies with orally administered mebendazole demonstrate favorable pharmacokinetics with 70 to 80% of mebendazole serum levels measured in the in the mouse brain and brain tumors. RESULTS: Our laboratory serendipitously identified benzimidazole anti-cancer activity in brain cancers and found that of the approved benzimidazoles, mebendazole showed the best survival benefit. We observe in preclinical testing it reaches effective concentrations in intracranial tumors, acts to prevent tubulin polymerization, has an additional anti-VEGR2 and anti-angiogenesis mechanisms and significantly improves survival in a variety of intracranial malignancy models. We have translated our preclinical findings into a Phase I trial, using mebendazole for upfront therapy, concurrent with temozolomide therapy for newly diagnosed patients with a high grade glioma. We have further improved mebendazole with drug combinations. CONCLUSION: The preclinical and phase 1 clinical findings are consistent with safe and possibly effective use of an improved formulation of oral mebendazole. We provide evidence that continued optimization of mebendazole based oral therapy and planning of future clinical trials may yield an additional tool for therapy of GBM and other intracranial tumors.