TIP-09. A phase 0/1 study of PRMT5 inhibitor BMS-986504 in recurrent glioblastoma participants with MTAP deletion

Abstract BACKGROUND Approximately 40% of glioblastoma (GBM) tumors harbor deletions in methylthioadenosine phosphorylase (MTAP), resulting in methylthioadenosine (MTA) accumulation and creating a selective vulnerability to PRMT5 inhibition. BMS-986504 is a potent MTA-cooperative PRMT5 inhibitor designed to exploit this synthetic lethal interaction. This Phase 0/1 study (NCT06883747) evaluates the intratumoral pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of BMS-986504 in recurrent GBM patients with confirmed MTAP deletions. MATERIALS/METHODS Patients with recurrent GBM (n=9) and MTAP deletion (confirmed in archival or recent biopsy tissues) receive once-daily oral BMS-986504 for six days at escalating doses of 200 mg (cohort 1), 400 mg (cohort 2), or 600 mg (cohort 3) prior to planned tumor resection, conducted 3–5 hours after the final dose. In Phase 0, total and unbound BMS-986504 levels in plasma, CSF, and both gadolinium (Gd)-enhancing and non-enhancing regions of the tumor are quantified by LC-MS/MS. A PK threshold—unbound drug concentration >18nM (5x biochemical IC50) in Gd-non-enhancing tissue—defines eligibility for continued Phase 1 dosing. PD endpoints (secondary and exploratory) include changes in SDMA, phosphorylated H2AX, cleaved caspase-3, and MIB-1 in resected tissue compared to baseline biopsy. Patients meeting the PK threshold continue dosing in 21-day treatment cycles at the same level. RESULTS As of 06/06/25, six patients have been screened, two enrolled, and one patient completed surgery in cohort 1 (200 mg). Unbound BMS-986504 levels were 111.3 nM (plasma), 54.7 nM (CSF), 269.0 nM (Gd-enhancing), and 45.1 nM (Gd-non-enhancing). The non-enhancing tumor concentration exceeded the PK threshold, qualifying the patient for Phase 1. Post-treatment tissue showed 77% reduction in SDMA H-score compared to baseline. CONCLUSIONS This study presents the first PK/PD evidence of PRMT5 inhibition in infiltrative GBM. The Phase 0/1 trial marks a critical step toward leveraging synthetic lethality in MTAP-deleted GBM.