Phase Ib/II Study of Zanidatamab Plus Tucatinib and Chemotherapy in HER2-Positive Advanced Breast Cancer

After signing the informed consent form (ICF) and confirmation of eligibility, adult participants (≥18 years) with HER2-positive advanced breast cancer (ABC) will be enrolled in this multicenter, open-label, phase Ib/II clinical trial. In phase Ib, participants will be assigned to one of two non-randomized cohorts and will receive zanidatamab in combination with tucatinib and either capecitabine or eribulin, following a Bayesian optimal interval (BOIN) dose-escalation design to determine the recommended phase II dose (RP2D) of capecitabine and eribulin, when administered with zanidatamab and tucatinib. Dose escalation will be conducted for each drug combination separately, meaning that if the phase Ib Study in one Cohort is stopped due to safety, it can continue in the other. In phase II, eligible participants will be randomized 2:1 to receive zanidatamab plus tucatinib and chemotherapy (capecitabine or eribulin at the RP2D) or a control regimen of trastuzumab, tucatinib, and capecitabine at standard doses. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or study termination, whichever occurs first.