P12.27.b a Phase 0/1 Study of Prmt5 Inhibitor BMS-986504 in Recurrent Glioblastoma Participants With Mtap Deleted Tumors.

Abstract BACKGROUND Methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 40% of glioblastoma (GBM) tumors, leading to accumulation of methylthioadenosine and rendering tumor cells selectively vulnerable to inhibition of protein arginine methyltransferase 5 (PRMT5). BMS-986504 is a potent PRMT5 inhibitor designed to exploit this synthetic lethality in MTAP-deleted tumors. This Phase 0/1 trial (NCT06883747) investigates the tumor pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of BMS-986504 in patients with recurrent GBM harboring MTAP deletions. MATERIALS/METHODS Recurrent GBM patients (n=9) with confirmed MTAP deletion in their archival or pretreatment biopsy tissue receive BMS-986504 daily for 6 days at 200 mg (cohort1), 400 mg (cohort 2), or 600 mg (cohort 3) doses prior to planned resection 3-5 hours after their final dose. In the Phase 0 study component, total and unbound drug concentrations are measured in tumor tissue (gadolinium (Gd)-enhancing and non-enhancing regions), cerebrospinal fluid, and plasma using validated LC-MS/MS methods. A PK trigger, defined as unbound drug concentrations above 5-fold biochemical IC50 (18nM) within the Gd non-enhancing tumor, determines patient eligibility for Phase 1 therapeutic dosing. PD response is evaluated by comparing the percentage of symmetric dimethylarginine (SDMA), pH2AX, cleaved caspase 3, and MIB-1 positive cells in surgical tumor tissue to baseline pre-treatment tissue. Patients with tumors exceeding the PK threshold continue treatment at the same dose received during Phase 0 in 3-week (21-day) cycles (Phase 1). RESULTS As of 4/28/25, six patients have been screened and one patient is on drug with BMS-986504. Tumor PK/PD analysis, drug safety and tolerability, as well as clinical outcomes data are all pending. CONCLUSIONS This study will report, for the first time, unbound drug concentrations of a PRMT5-targeted inhibitor in gadolinium-nonenhancing tumor tissue from recurrent GBM patients, as well as associated on-target drug effects. This hybrid Phase 0/1 study is an important first-step to evaluate the use of PRMT5-inhibition to exploit synthetic lethality in MTAP-deleted GBM.