Background: PEX is an oral small molecule inhibitor of KIT and CSF1 receptor expressed on microglia, blood vessels, and glioblastoma (GBM) tumor cells. PEX achieved good tissue exposure in a prior recurrent GBM study, and preclinical studies indicate PEX may sensitize GBM to standard of care (SOC) therapy through effects on both tumor and microenvironment. Methods: Phase Ib determined the recommended Phase II dose (RP2D) with SOC XRT/TMZ. Phase II primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS) and safety. Patient entry criteria were designed to replicate the RTOG 0525 control arm, which was used as a historical control. Results: The identified RP2D was PEX 400mg BID 5 days/week during and 7 days/week after SOC XRT/TMZ. Of the total RP2D population, 42 were evaluable for comparison and demonstrated similar characteristics to the RTOG 0525 control arm. As of November 2017, mPFS from registration is 6.7 months in PEX patients (95% CI 4.2, 10.2) vs. 7.5 months in historical controls. Estimated mOS for PEX is 15.4 months (95% CI 12.3, 20.7) vs. 18.9 months in controls. PEX was well tolerated, with most common drug-related toxicities including neutropenia and increased ALT/AST. MGMT unmethylated patients comprised 60% of the patients, with estimated mOS of 13.8 months (95% CI 12.3, 20.7) vs. 68% and estimated mOS of 16.6 months in historical controls. MGMT methylated patients comprised 40%, and mOS not yet reached vs. 32% and estimated mOS of 23.5 months in historical controls. Tumors with high expression of monocyte/macrophage marker CD163 and macrophage stimulating factor CSF1 trended to worse overall survival. mOS was 13.8 months for tumors with high expression of CD163 vs. 19.2 in tumors with low expression (p = .323). mOS was 12.3 months in tumors with high CSF1 expression vs. 19.2 in tumors with low (p = .328). Conclusions: PEX can be safely combined with SOC XRT/TMZ in newly diagnosed GBM. Results suggest minimal PEX activity when added to XRT/TMZ in an unselected GBM population for improving PFS and OS compared to robust, well-matched historical controls. Further investigation in relevant biomarker subgroups is ongoing. Clinical trial information: NCT01790503