Phase 1a Evaluation of LP-184 in Recurrent Glioblastoma: Safety, Pharmacokinetics, and Translational Optimization of CNS Exposure

Abstract Purpose: Limited central nervous system (CNS) bioavailability and pharmacodynamics are obstacles to effective systemic therapies for glioblastoma (GBM). One strategy to overcome these challenges is drug combinations enhancing CNS penetration and/or tumor chemosensitivity. LP-184 (zirdafulven), a synthetic acylfulvene class alkylator, induces DNA damage and inhibits glioblastoma cell viability in pre-clinical models. LP-184 is a prodrug converted to active metabolites by intracellular oxidoreductase prostaglandin reductase 1 (PTGR1) that is over-expressed in >70% of glioblastoma. DNA damage induced by LP-184 is MGMT agnostic and reversed by transcription-dependent transcription coupled nucleotide excision repair (TC-NER). Patients and Methods: LP-184 was evaluated in a Phase 1a study (NCT05933265) in 63 adult patients with advanced malignancies including 16 patients with recurrent glioblastoma. All patients with GBM received prior standard-of-care therapy and most had received one or more additional therapies before enrollment. Results: Treatment was overall well-tolerated. Patients with glioblastoma experienced frequent Grade 1-2 nausea and infrequent severe thrombocytopenia and transaminitis. Clinical pharmacokinetic analysis combined with published pre-clinical intra-tumoral bioavailability data (~20% penetration) predicted that LP-184 at the recommended dose for expansion (RDE) would achieve cytotoxic levels if combined with spironolactone, a brain-penetrant ERCC3 degrader and TC-NER inhibitor that sensitizes glioblastoma cells to LP-184 3-6-fold. We show that three daily doses of spironolactone deplete orthotopic glioblastoma PDX ERCC3 protein by ~ 80% and increases tumor LP-184 cytotoxicity 2-fold. Conclusions: LP-184 is well tolerated at the RDE, and we establish a clinically translatable plan for dosing spironolactone in combination with LP-184 for a future Phase 1b/2a clinical trial.