PRMT5抑制剂BMS-986504治疗伴MTAP缺失的复发性胶质母细胞瘤受试者的0/1期研究

Background: Conventional therapy for recurrent glioblastoma (rGBM) are inadequate, and survival is remains short. Homozygous deletions in methylthioadenosine phosphorylase ( MTAP ) occurs in ~40% of GBM tumors creating a selective vulnerability to PRMT5 inhibition. BMS-986504 is a potent MTA-cooperative PRMT5 inhibitor that exploits this synthetic lethality. This hybrid Phase 0/1 study (NCT06883747) evaluates the intratumoral pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of BMS-986504 in rGBM patients with MTAP deletions. Materials/Methods: Patients with recurrent GBM (n=9) and MTAP deletion receive once-daily oral BMS-986504 for six days in three escalating dose cohorts 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 (5 × biochemical IC 50 ) in Gd-non-enhancing tissue-defines eligibility for continued Phase 1 dosing. PD endpoints include changes in SDMA, pH2AX, cleaved caspase-3, and Ki67 in resected tissue compared to baseline biopsy. Patients meeting the PK threshold continue 21-day treatment cycles at the same dose level until progression per RANO 2.0. Results: As of 12/12/25, 9 patients enrolled and completed surgery. Median (min, max) unbound BMS-986504 levels were 134 nM (23, 265), 59 nM (14, 521), 400 nM (97, 2033), and 35 nM (14, 521) in intraoperative plasma, CSF, Gd-enhancing and non-enhancing samples, respectively. The non-enhancing tumor concentration exceeded the PK threshold, confirming eligibility for Phase 1 entry (n=8). Of 8 eligible patients, 6 enrolled in Phase 1; one did not enroll due to participant decision and one due to concurrent malignancy. Suppression of SDMA was observed in 50% (2/4) of cohort 1 and 67% (2/3) of cohort 2, with median H-score decreases of 65 and 111, respectively; cohort 3 (0/1) showed no change in SDMA expression so far. No serious adverse events related to BMS-986504 were reported and no new safety signals were identified. Median clinical follow-up in Phase 1 is currently 3.5 months; mature PFS data will be provided at the time of presentation. Conclusions: This hybrid Phase 0/1 study confirms the safety and tolerability of BMS-98504 in rGBM patients and also provides an initial account of human rGBM PK/PD response to PRMT5 inhibition. In GBM, marked biological heterogeneity necessitates tissue-level pharmacodynamic validation to interpret uncontrolled survival outcomes.