An ongoing phase 1–2a study of EO1001, an oral brain-penetrant pan-ErbB inhibitor, in patients with advanced ErbB-driven solid tumors including CNS disease.

Abstract

TPS8681 Background: Central nervous system (CNS) metastases and primary brain tumors remain a major cause of morbidity and mortality in patients with ErbB-driven malignancies, particularly as improved systemic therapies prolong survival. Aberrations in the ErbB family of receptor tyrosine kinases—including EGFR, HER2, and HER4—are frequently associated with CNS progression, therapeutic resistance, and poor outcomes across multiple tumor types. In glioblastoma and other CNS malignancies, specific EGFR extracellular domain (ECD) alterations, including EGFRvIII and recurrent ECD missense variants, have been previously reported to promote ligand-independent signaling, invasive tumor biology, and resistance to currently available EGFR-targeted therapies. EO1001 is a novel, oral, irreversible pan-ErbB inhibitor designed to achieve sustained CNS exposure and broad ErbB pathway inhibition. This ongoing Phase 1–2a study is evaluating the safety, pharmacokinetics, and preliminary antitumor activity of EO1001 in patients with advanced ErbB-driven solid tumors, including those with CNS involvement. Methods: This is a first-in-human, multicenter, open-label Phase 1–2a study of once-daily oral EO1001. The Phase 1 dose-escalation component uses an accelerated titration design transitioning to a standard 3+3 schema following the occurrence of ≥Grade 2 treatment-related toxicity. A Phase 2 expansion component is enrolling patients at or below the recommended Phase 2 dose (RP2D). Eligible patients are adults with advanced or metastatic ErbB-expressing solid tumors that have progressed following standard therapy; patients with treated or untreated CNS disease are eligible. EO1001 is administered once daily in 28-day cycles following an initial single-dose pharmacokinetic assessment. The primary objectives are to evaluate safety and tolerability and to determine the RP2D. Secondary objectives include characterization of the pharmacokinetic profile and assessment of preliminary antitumor activity using RECIST v1.1 and/or RANO criteria, as appropriate. Exploratory objectives include evaluation of pharmacodynamic and molecular biomarkers in available tissue and optional cerebrospinal fluid sampling to further assess CNS exposure and pathway modulation. Current Status: Dose escalation has been completed across multiple dose levels, and enrollment is ongoing in Phase 2 expansion cohorts designed to further characterize safety, pharmacokinetics, and CNS-directed antitumor activity at biologically active dose levels. Clinical trial information: ACTRN12620000583943.