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

PurposeLimited CNS bioavailability and pharmacodynamics are obstacles to effective systemic therapies for glioblastoma. One strategy to overcome these challenges is drug combinations enhancing CNS penetration and/or tumor chemosensitivity. LP-184, 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 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 NER. PatientsLP-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 glioblastoma received prior standard-of-care therapy and most had received 1 or more additional therapies before enrollment. ResultsPatients with glioblastoma experienced more frequent transaminitis, Grade 1-2 nausea and a trend towards more frequent and severe thrombocytopenia compared to the non-glioblastoma cohort. Otherwise, overall toxicity profiles were similar. 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 BBB permeable 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. ConclusionsLP-184 is well tolerated at the RDE, and we establish a clinically translatable scheme for dosing spironolactone in combination with LP-184 for a future Phase 1b clinical trial. Statement of translational relevanceTreatment failure in glioblastoma reflects inadequate drug brain exposure and DNA repair- mediated resistance. LP-184, a novel acylfulvene alkylator, generates MGMT-independent DNA lesions predominantly repaired by transcription-coupled NER. In a Phase 1a dose finding trial, LP-184 was well-tolerated at the recommended dose for expansion (RDE) in participants with advanced cancers, including recurrent glioblastoma. Plasma drug levels achieved predicted effective systemic exposures but not brain concentrations based on projected 20% brain penetrance. Pharmacokinetic modeling indicates that NER inhibition could increase tumor chemosensitivity with the addition of spironolactone. The optimal dosing regimen for spironolactone combined with LP-184 was identified in orthotopic PDX models, facilitating advancement to Phase 1b/2a testing of LP-184 plus spironolactone.