A phase 0/1 trigger trial of BDTX-1535 in patients with recurrent high-grade glioma (HGG) with EGFR alterations or fusions.

2069 Background: This Phase 0/1 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of recurrent high-grade glioma (HGG) patients with EGFR alterations and/or fusions to the ATP-competitive, irreversible EGFR inhibitor, BDTX-1535. Methods: Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 (200 mg) prior to planned resection at 2-4 hours following the final dose. In the Phase 0 component of the study, total and unbound drug concentrations were measured in tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug concentration above 5-fold biochemical IC50 in Gadolinium (Gd)-nonenhancing tumor, determined eligibility for Phase 1. PD response was assessed by quantification of percentage of positive pEGFR, pERK and MIB-1 cells in the surgical tumor tissue compared to baseline pre-treatment tissue. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for expansion phase therapeutic dosing of BDTX-1535. Results: A total of 7 patients with recurrent glioblastoma (Arm A) were enrolled in the Phase 0 component of the study. Two patients were excluded from PK analysis due to pseudoprogression. The mean unbound concentrations of BDTX-1535 in Gd-enhancing and nonenhancing tumor regions were 16.0 nM and 10.5 nM respectively. Four of five (80%) evaluable patients exceeded the PK threshold. The suppression of pEGFR and MIB1 was observed in 40% and 60% of patients, respectively. No serious adverse events were observed among patients in the Phase 1 component of the study and a clinical readout is planned in Q2 2024. Conclusions: BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue and is associated with suppression of EGFR signaling. Clinical trial information: NCT06072586 .