Multicenter phase Ib/II study of neoadjuvant zolbetuximab plus docetaxel, oxaliplatin, and S-1 (DOS) followed by adjuvant zolbetuximab/S-1 in patients with CLDN18.2-positive resectable gastric or gastroesophageal junction adenocarcinoma (NEOCLAUD).

TPS4250 Background: Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), has demonstrated significant survival benefit in advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJA) in the phase 3 SPOTLIGHT and GLOW trials, validating CLDN18.2 as a therapeutic target. The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy improved progression-free survival (PFS) and overall survival (OS) compared with surgery followed by adjuvant S-1 for patients with resectable locally advanced gastric cancer (LAGC). Building on this evidence, we designed NEOCLAUD to evaluate whether adding zolbetuximab to neoadjuvant DOS chemotherapy, followed by adjuvant zolbetuximab/S-1, improves outcomes in patients with CLDN18.2-positive LAGC. Methods: This open-label, multicenter, phase Ib/II trial will enroll up to 57 patients with newly diagnosed, resectable G/GEJA positive for CLDN18.2 (≥75% moderate–strong membranous staining by VENTANA 43-14A). Eligible patients must have clinical stage T3–4/N0 or T2–4/N+ disease (AJCC 8th), ECOG 0–1, and no distant metastasis. Primary endpoints are recommended phase II dose (RP2D) (phase Ib) and the pathologic complete regression (pCR) rate (phase II). Phase Ib uses a 3+3 design to determine the RP2D. Phase II will test whether adding zolbetuximab increases the pCR rate from 10% (historical control) to 25%; the primary endpoint will be met if ≥8/40 patients achieve pCR (A’Hern single-stage design, α = 0.05, power = 80%). Secondary endpoints include PFS, OS, objective response rate, disease control rate, R0 resection rate, and safety. Exploratory endpoints include artificial intelligence-based histopathology modeling, spatial transcriptomics, single-cell RNA sequencing, and circulating tumor DNA minimal residual disease analysis. Neoadjuvant therapy consists of zolbetuximab 800 mg/m² on cycle 1 day 1 (C1D1) followed by 600 mg/m² on C2D1/C3D1, with DOS (docetaxel 50 mg/m², oxaliplatin 100 mg/m² IV D1; S-1 40 mg/m² PO BID D1–14) every 3 weeks ×3 cycles. Surgery (D2 gastrectomy) is performed 1–4 weeks post-neoadjuvant therapy. Adjuvant therapy (initiated 3–8 weeks post-surgery) includes zolbetuximab 600 mg/m² D1/D22 Q6W ×8 cycles plus S-1 PO D1–28 Q6W ×8 cycles. Enrollment has been ongoing since February 2025 across multiple sites in Korea. Clinical trial information: NCT06732856 .