Background: CNS metastases is a prominent driver of morbidity and mortality, especially as targeted therapies have improved systemic outcomes. There is a desperate need for new CNS-penetrating agents that are less toxic and more effective, particularly against treatment-resistant phenotypes.
Mutations in the ErbB kinase family are known oncodrivers in many cancers. Extensive cross talk among ErbB/HER receptors is correlated with treatment resistance. EO1001 is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile.
We will report on an ongoing Phase 1-2 first-in-human clinical trial of EO1001 currently underway at multiple centres in Australia.
Trial Design: Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care, with adequate bone marrow, renal and liver function are eligible. One subject per dose cohort is being enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first dosing cycle, after which dose escalation will revert to a 3+3 design. Dose Escalation: Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single dose pharmacokinetics are performed. Beginning day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are performed. Cycles 2-6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. Expansion: EO1001 will be administered once daily at the RP2D in continuous 28-day cycles for up to 24 weeks, or longer if the participant is judged to be receiving benefit from treatment.
Outcome Measures: Toxicity is assessed by NCI CCTCAEv5 and tumor response is assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement. Biomarker evaluations are conducted if medically feasible at the discretion of the investigator.
Results of the study will inform design of future clinical trials with EO1001,