Phase Ia Evaluation of LP-184 in Recurrent Glioblastoma: Safety, Pharmacokinetics, and Translational Optimization of CNS Exposure
4 affiliations
- 1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
- 2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
- 3Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland.
- 4Lantern Pharma Inc., Dallas, Texas.
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 GBM cell viability in preclinical models. LP-184 is a prodrug converted to active metabolites by intracellular oxidoreductase prostaglandin reductase 1 that is overexpressed in >70% of GBM. DNA damage induced by LP-184 is O6-methylguanine-DNA methyltransferase (MGMT) agnostic and reversed by transcription-dependent transcription-coupled nucleotide excision repair (TC-NER).
Patients and Methods:: LP-184 was evaluated in a phase Ia study (NCT05933265) in 63 adult patients with advanced malignancies, including 16 patients with recurrent GBM. 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 GBM experienced frequent grade 1 to 2 nausea and infrequent severe thrombocytopenia and transaminitis. Clinical pharmacokinetic analysis combined with published preclinical intratumoral 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 GBM cells to LP-184 3- to 6-fold. We show that three daily doses of spironolactone deplete orthotopic GBM patient-derived xenograft (PDX) ERCC3 protein by ∼80% and increase 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 Ib/IIa clinical trial.
Significance:: Treatment failure in GBM reflects inadequate drug brain exposure and DNA repair–mediated resistance. LP-184 (zirdafulven), a novel acylfulvene alkylator, generates MGMT-independent DNA lesions predominantly repaired by TC-NER. In a phase Ia dose-finding trial, LP-184 was well tolerated at the RDE in participants with recurrent GBM. 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 Ib/IIa testing of LP-184 plus spironolactone.
Trial Registration:: ClinicalTrials.gov Identifier: NCT05933265.
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BibTeX
@article{schreck2026phase,
title = {{Phase Ia Evaluation of LP-184 in Recurrent Glioblastoma: Safety, Pharmacokinetics, and Translational Optimization of CNS Exposure}},
author = {Karisa C. Schreck and Bachchu Lal and Jianli Zhou and Hernando Lopez-Bertoni and Matthias Holdhoff and Reginald Ewesuedo and Kishor Bhatia and Marc Chamberlain and John Laterra},
journal = {Cancer Research Communications},
year = {2026},
month = oct,
doi = {10.1158/2767-9764.crc-26-0518},
url = {https://doi.org/10.1158/2767-9764.crc-26-0518},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Phase Ia Evaluation of LP-184 in Recurrent Glioblastoma: Safety, Pharmacokinetics, and Translational Optimization of CNS Exposure
AU - Karisa C. Schreck
AU - Bachchu Lal
AU - Jianli Zhou
AU - Hernando Lopez-Bertoni
AU - Matthias Holdhoff
AU - Reginald Ewesuedo
AU - Kishor Bhatia
AU - Marc Chamberlain
AU - John Laterra
PY - 2026
DA - 2026/10/27
JO - Cancer Research Communications
DO - 10.1158/2767-9764.crc-26-0518
UR - https://doi.org/10.1158/2767-9764.crc-26-0518
AB - 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 GBM cell viability in preclinical models. LP-184 is a prodrug converted to active metabolites by intracellular oxidoreductase prostaglandin reductase 1 that is overexpressed in >70% of GBM. DNA damage induced by LP-184 is O6-methylguanine-DNA methyltransferase (MGMT) agnostic and reversed by transcription-dependent transcription-coupled nucleotide excision repair (TC-NER). Patients and Methods:: LP-184 was evaluated in a phase Ia study (NCT05933265) in 63 adult patients with advanced malignancies, including 16 patients with recurrent GBM. 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 GBM experienced frequent grade 1 to 2 nausea and infrequent severe thrombocytopenia and transaminitis. Clinical pharmacokinetic analysis combined with published preclinical intratumoral 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 GBM cells to LP-184 3- to 6-fold. We show that three daily doses of spironolactone deplete orthotopic GBM patient-derived xenograft (PDX) ERCC3 protein by ∼80% and increase 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 Ib/IIa clinical trial. Significance:: Treatment failure in GBM reflects inadequate drug brain exposure and DNA repair–mediated resistance. LP-184 (zirdafulven), a novel acylfulvene alkylator, generates MGMT-independent DNA lesions predominantly repaired by TC-NER. In a phase Ia dose-finding trial, LP-184 was well tolerated at the RDE in participants with recurrent GBM. 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 Ib/IIa testing of LP-184 plus spironolactone. Trial Registration:: ClinicalTrials.gov Identifier: NCT05933265.
SN - 2767-9764
ER -