eligibility_summary
Inclusion: consent, ≥18, ECOG 0–2, life expectancy >12 wks, adequate organ function, neg pregnancy, effective contraception, toxicities ≤G1 (neuropathy ≤G2), recovered from surgery, compliant. Exclusion: recent anticancer therapy (per washouts), other IP, severe hypersensitivity, uncontrolled illness, CV disease ≤6m or QTcF>470 ms, active CNS mets, liver disease, major surgery <4w, pregnant/breastfeeding, institutionalized by law, per investigator, other malignancy <2y (exceptions).
trial_source
clinical_trials.gov from Dec 2, 2025
annotation_status
ai
ai_summary
PRE-I-SPY (NCT05868226) is a Phase I/Ib, open-label platform testing two HER2-focused combinations in metastatic settings. 1) ALX148 (evorpacept, protein fusion CD47 inhibitor/SIRPα D1–Fc with inactive Fc) + fam-trastuzumab deruxtecan-nxki (T-DXd, HER2-directed antibody-drug conjugate carrying a topoisomerase I inhibitor). Mechanisms: ALX148 blocks the CD47 “don’t-eat-me” signal to boost macrophage ADCP, T-DXd binds HER2, is internalized to release DXd causing DNA damage and bystander killing, and engages Fc-mediated ADCC/ADCP, increasing neoantigen release. 2) Zanidatamab (bispecific IgG1-like anti-HER2 to ECD2/ECD4) + tucatinib (oral HER2-selective TKI). Mechanisms: zanidatamab induces HER2 clustering, internalization/downregulation, blocks signaling, and activates ADCC/ADCP/CDC, tucatinib inhibits HER2 kinase and is CNS-penetrant. Targets: HER2 on tumor cells, CD47–SIRPα axis, immune effectors (macrophages, NK cells, complement), topoisomerase I, HER2→PI3K/AKT/MAPK signaling.