CTIM-09. PHASE II RUN-IN STUDY OF DARATUMUMAB IN COMBINATION WITH RADIATION THERAPY AND TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Daratumumab, a CD38-targeted monoclonal antibody, has shown preclinical activity in glioblastoma (GBM). Given the expression of CD38 on GBM cells, daratumumab’s mechanisms, potentially mirroring multiple myeloma, may include direct apoptosis via caspase activation, immune-mediated cytotoxicity through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and immunomodulation by depleting CD38-positive immunosuppressive cells. This phase II trial evaluates daratumumab’s safety in newly diagnosed GBM. METHODS In a single-arm phase II trial with a 3 + 3 safety run-in, patients with newly diagnosed GBM received daratumumab (16 mg/kg IV weekly x 8) with concurrent radiotherapy/temozolomide (6 weeks). Then alongside standard adjuvant temozolomide and tumor-treating fields therapy, daratumumab was given every 2 weeks x 8, then every 4 weeks until disease progression or death. Primary endpoint was safety; secondary endpoints included median overall survival (mOS) and median progression-free survival (mPFS). RESULTS Study accrued 16 patients; all were eligible for toxicity assessment, and 15 for outcomes assessment (1 patient with IDH-mutant grade 4 astrocytoma). Median age was 57.9 years (range, 28–69); ECOG status was 0; sex distribution was 6 women, 10 men. No grade 3/4 toxicities were attributed to daratumumab. mOS was 17.7 months (95% CI, 7.5–27.9) where MGMT-methylated patients (n=8) had a mOS of 23.3 months (95% CI, 14.8–31.8), while MGMT-unmethylated patients (n=7) had a mOS of 11.3 months (95% CI, 7.4–15.6). mPFS was 9.6 months (95% CI, 9.1–10.0), with 7 of 15 patients censored for progression due to bevacizumab use or lack of progression. CONCLUSION Daratumumab with standard GBM therapy was safe and showed survival outcomes comparable to historical data. Future trials should elucidate mechanisms (apoptosis, ADCC, ADCP, immunomodulation) and assess whether efficacy depends on CD38 expression in GBM cells or occurs independently, potentially through tumor microenvironment modulation.