Ctni-11. A Preclinical and Pilot Clinical Study of Mifepristone as an Adjuvant Treatment to Chemo-Radiation for High-Grade Gliomas: A Fairytale Comes True?

BACKGROUND The standard treatment of high-grade gliomas (HGG) includes chemoradiation after a maximal safe resection. We aimed to develop a translational method to study whether the addition of mifepristone (a glucocorticoid and progesterone receptor inhibitor) to chemoradiation is useful and feasible. METHODS A preclinical study (glioblastoma xenografts) measured the effects of mifepristone (Mf) on tumor size, metabolic activity, and expression of angiogenic factors. A second preclinical study (C6 glioma orthotopical model) measured the effects on proliferation markers (Ki67), tumor growth, MGMT expression, and apoptotic-related protein expression. The third study, a clinical pilot trial involving eight patients with HGG, assessed the safety and clinical efficacy of three different oral doses of mifepristone added to the standard regimen: Scheme 1 = Mf 300mg po daily during radiation, Scheme 2 = Mf 300mg po daily during radiation and each of the adjuvant chemotherapy days, and Scheme 3 = Mf 300mg po from the first day of radiation for 6 months. RESULTS Preclincial studies demonstrated a significant decrease in tumor growth, reduced levels of angiogenesis-promoting VEGF, increased apoptosis-related proteins, and lower expression of drug resistance-associated P-glycoprotein and MGMT. Clinically, Scheme 1 (n = 3) had an overall survival (OS) of 9.6, 10, and 13.8 months; Scheme 2 (n = 3) had OS of 19.4, 19.6, and 22.2 months, and Scheme 3 (n = 2) are still alive after 72.1 and 81.7 months. No CTCAE Grade ≥ 2 toxicities were reported, and none of the patients had an increase in their PRO-CTCAE scores. The median NANO score improvement after Mf was - 5 points (-2 to -9), and the median maximal QLQ-BN20 improvement was 40 points (8 to 45). Improvements in most of QLQ-C30 were also reported. CONCLUSION The addition of mifepristone to chemoradiation is associated with multiple mechanisms of action against HGG and is clinically safe.