CTNI-29. A PHASE 1B STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND OBJECTIVE RESPONSE OF LP-184 ALONE AND IN COMBINATION WITH SPIRONOLACTONE IN IDH WILD TYPE GLIOBLASTOMA AT FIRST PROGRESSION

Abstract LP-184 is a fully synthetic small molecule alkylator of the acylfulvene therapeutics class that induces DNA double-strand breaks and improves survival in orthotopic GBM xenograft models. In preclinical studies, LP-184 is brain penetrant with a brain tumor/plasma concentration ratio of 0.2. DNA damage induced by acylfulvenes is repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes. GBM with intrinsic or pharmacologically induced DNA Damage Repair deficiency (dDDR) may preferentially respond to LP-184, independent of MGMT status. LP-184 is currently under investigation in a first-in-human Phase 1a dose-escalation safety study (NCT05933265) in adult patients with advanced solid tumors including GBM, with no dose-limiting toxicities to date at dose level 6. Following determination of the Maximum Tolerated Dose and/or Recommended Phase 2 Dose from Phase 1a, the selected expansion dose will be assessed in a Phase 1b study to evaluate the safety, pharmacokinetics, and objective response of LP-184 alone and in combination with spironolactone in IDH wild type glioblastoma at first progression. Spironolactone is a brain penetrant FDA approved agent that proteolytically degrades the TC-NER component ERCC3, thereby creating dDDR. Two rGBM cohorts will be enrolled according to a Simon’s 2-stage optimal design: (i) LP-184 alone (days 1 and 8 in a 21-day cycle, as intravenous infusion over 30 minutes) and (ii) combination of LP-184 and spironolactone (200 mg orally daily in conjunction and before the LP-184 infusion). In the first stage, 10 response evaluable subjects will be enrolled. If 1 or more of the first 10 response evaluable subjects achieve an objective response, 19 further subjects may be accrued in the second stage. In each cohort, at least 5 subjects will undergo planned tumor resection and will be treated with LP-184 or the combination the day prior to surgery to evaluate PK/PD.