Abstract BACKGROUND MDNA55 is an IL4R-targeted toxin in development for GBM, a universally fatal disease. IL4R is over-expressed in GBM, the tumor microenvironment, and high expression is associated with poor outcomes in GBM. METHOD MDNA55-05 is an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in rGBM patients at 1st or 2nd recurrence with an aggressive form of GBM (de novo GBM, IDH wild-type, not-resectable at recurrence, ~ 50% expressing high levels of IL4R). Primary endpoint is mOS, secondary endpoint includes impact of IL4R status on mOS. A Synthetic Control Arm (SCA) served as an external comparator constructed from patient registries at neurosurgery centers under IRB-approved protocols. Propensity score weighting corrected for imbalances in baseline characteristics between the two groups. RESULTS MDNA55 showed an acceptable safety profile at doses up to 240μg. In all evaluable subjects (n=44) mOS was 11.6 and OS-12 was 46%. A sub-population (n=32) consisting of all IL4RHigh subjects + only IL4RLow subjects treated with high dose (median 180µg) showed most benefit: mOS is 15 months, OS-12 is 55%. Tumor control, assessed by mRANO criteria, was seen in 81% (26/32) of this sub-population, including those that had pseudo-progression (15/26). In these subjects, tumor control was associated with longer mPFS (4.7 months) and mOS (15.0 months) than those with progressive disease (mPFS 1.0 month, mOS 7.7 months). Comparison against the SCA demonstrated > 100% increase in mOS: 15.7 months vs 7.2 months (HR 0.52, 95% CI 0.30, 0.91). CONCLUSIONS MDNA55 demonstrates improved survival and tumor control in this study design and has potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. There are no approved therapies for rGBM that can extend survival by 50%; the potential for MDNA55 to extend survival by > 100% is promising for this devastating disease.