LP-184 Phase 1a data in recurrent glioblastoma published: recommended dose set, spironolactone combination heads to Phase 1b/2a

LP-184 was generally well tolerated in patients with recurrent glioblastoma, and the expansion dose was set at 0.39 mg/kg given intravenously on days 1 and 8 of each 21-day cycle. The prior Phase 1a study in advanced solid tumors enrolled 63 patients, 16 of them with recurrent glioblastoma; all 16 had received surgery, radiation and temozolomide, with a median of two prior lines of therapy. The safety profile in glioblastoma patients was consistent with the broader solid tumor population, and no adverse events occurred only in that group; nausea was grade 1 to 2 in all affected patients, severe thrombocytopenia and transaminitis were infrequent, and both grade 3 to 4 liver enzyme elevations occurred at the highest dose level tested, above the expansion dose.

Single-agent LP-184 is not projected to sustain therapeutic concentrations in brain tumors, so the plan uses spironolactone to weaken tumor DNA repair and compensate for limited brain exposure. Pharmacokinetic modeling based on Phase 1a patient data projects that only about 20% of systemic drug reaches brain tumors, so single-agent concentrations are not projected to remain at therapeutic levels for a sustained period. Modeling on plasma data from 11 patients treated at the expansion dose projects that adding spironolactone brings intratumoral LP-184 to approximately 2- to 3-fold above the concentration needed to kill glioblastoma cells.

Spironolactone enhances LP-184 killing by degrading ERCC3, a core protein of transcription-coupled nucleotide excision repair, and this combination provides the dosing basis for the planned Phase 1b/2a trial. LP-184 alkylates DNA at a different site than temozolomide or lomustine, and the resulting lesions are not repaired by MGMT but resolved primarily through transcription-coupled nucleotide excision repair; spironolactone crosses the blood-brain barrier and triggers ERCC3 degradation. In orthotopic glioblastoma patient-derived xenograft models, three daily doses of spironolactone reduced tumor ERCC3 by approximately 80%, versus 49% to 57% after one or two doses; giving LP-184 8 hours after the third dose approximately doubled tumor cell death measured by cleaved caspase-3, and spironolactone did not reduce ERCC3 in the liver.

The reported results cover Phase 1a safety and pharmacokinetic data from 16 patients with recurrent glioblastoma, patient-derived xenograft models and pharmacokinetic modeling based on plasma from 11 patients; efficacy of the combination remains to be evaluated in the planned Phase 1b/2a trial (NCT07431216).

No objective radiographic responses were observed with single-agent LP-184; one patient with MGMT-methylated glioblastoma at first recurrence received LP-184 for six months and remained clinically and radiographically stable for more than 22 months, including more than 17 months off treatment, which is an individual observation. The 2- to 3-fold intratumoral concentration and doubled cell death come from modeling or preclinical models, and the company notes that early observations do not ensure later studies will be consistent.