CTNI-51. A PHASE 0/1 STUDY OF BDTX-1535 IN RECURRENT GLIOBLASTOMA (GBM) PATIENTS WITH EGFR ALTERATIONS OR FUSIONS

Abstract BACKGROUND Alterations to epidermal growth factor receptor (EGFR) occur frequently in high-grade gliomas (HGG) and are critical to its pathogenesis. This Phase 0/1 study evaluates pharmacokinetic (PK), pharmacodynamic (PD), and clinical response to an ATP-competitive, irreversible EGFR inhibitor, BDTX-1535, in recurrent HGG patients with EGFR alterations and/or fusions. MATERIALS/METHODS Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 at 200 mg/daily (cohort 1) or 400 mg/every other day (cohort 2) 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 (Gd) enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’ was defined as unbound drug concentration above 1 nM and 4.1 nM in Gd non-enhancing tumor in patients with EGFR mutations and amplification, respectively, determined eligibility for Phase 1 therapeutic dosing. 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. RESULTS Eleven recurrent HGG patients were enrolled (Arm A, n=11; Arm B, n=0). Mean unbound concentrations of BDTX-1535 in non-enhancing tumor regions were 11.9 nM and 18.8 nM in cohorts 1 and 2, respectively. Eight of nine (88.9%) evaluable patients exceeded the PK threshold and qualified for Phase 1. Suppression of pEGFR and MIB1 was observed in 55% and 67% of patients, respectively. No serious adverse events related to BDTX-1535 were observed. At the time of submission, median PFS and OS have not yet been reached. CONCLUSIONS BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in non-enhancing tumor tissue, and is associated with suppression of EGFR signaling. Efficacy data accompanying this PK/PD response will be reported.