eligibility_summary
Phase 1: ≥18 with HER2+ MBC and LMD (CSF+ or MRI), ECOG ≤2, >14 d/5 half‑lives from last experimental drug, toxicities ≤G1 (neuropathy ≤G2). Exclude prior WBRT or SRS<7 d, LMD therapy, MRI/pill intolerance, malabsorption, DPD/fructose/Gilbert’s, other malignancy <5 y, prior tucatinib or hypersensitivity. Phase 2: Normal LVEF, adequate organs, last therapy ≥14 d, prior HER2 agents OK. Exclude pregnancy/lactation, strong CYP modulators, recent MI/UA, transfusions to qualify.
trial_source
clinical_trials.gov from Dec 2, 2025
annotation_status
ai
ai_summary
Phase II single-arm study in HER2+ metastatic breast cancer with leptomeningeal disease testing brain/spinal radiotherapy (XRT) followed by tucatinib + trastuzumab + capecitabine. Tucatinib: oral, small-molecule, ATP-competitive HER2 (ERBB2) tyrosine-kinase inhibitor with CNS penetration, suppresses HER2 signaling and downstream PI3K/AKT and MAPK pathways. Trastuzumab: anti-HER2 IgG1 monoclonal antibody, blocks HER2 signaling, promotes receptor downregulation, and triggers antibody‑dependent cellular cytotoxicity (engaging NK cells). Capecitabine: oral antimetabolite prodrug of 5‑FU, inhibits thymidylate synthase to impair DNA synthesis in proliferating cells. XRT: ionizing radiation to brain/spine causing DNA damage. Targets: HER2-overexpressing tumor cells in the leptomeninges/CNS, HER2 pathway and downstream survival signaling, rapidly dividing tumor cells, and immune-mediated ADCC pathways.