195TiP - GLOW: Phase III study of first-line zolbetuximab + CAPOX versus placebo + CAPOX in Claudin18.2⁺/HER2⁻ advanced/metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ)

Background

Capecitabine + oxaliplatin (CAPOX) is a standard first-line treatment for advanced gastric cancer. Claudin (CLDN)18.2 is a promising targetable biomarker. In healthy tissue, CLDN18.2, a tight junction protein, is confined to gastric mucosa (ie, cells in the pit and base regions of gastric glands). Upon malignant transformation, structural loss in G/GEJ cells may allow antibodies more access to previously unavailable CLDN18.2. Zolbetuximab, a chimeric IgG1 monoclonal antibody, specifically binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Phase II (NCT01630083) results showed prolonged survival of patients with CLDN18.2-positive (CLDN18.2⁺) advanced G/GEJ treated with zolbetuximab + epirubicin, oxaliplatin, and capecitabine (EOX) vs EOX alone.

Trial design

GLOW (NCT03653507) will enroll ∼500 adults from global sites, including China, Japan, Korea, Malaysia, and Thailand. Patients must have CLDN18.2⁺/human epidermal growth factor receptor 2-negative (HER2^–) locally advanced unresectable or metastatic G/GEJ that is radiographically evaluable per RECIST v1.1. Prior treatment with chemotherapy for advanced/metastatic G/GEJ is not permitted. Patients will be randomized 1:1 to zolbetuximab + CAPOX or placebo + CAPOX. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Zolbetuximab will be administered at a loading dose of 800 mg/m² IV on Cycle 1 Day 1 followed by 600 mg/m² IV every 3 weeks. Central testing of tumor tissue will determine CLDN18.2 and HER2 status (if unknown); patients will be considered CLDN18.2⁺if ≥75% of tumor cells demonstrate moderate-to-strong membranous immunohistochemical staining. The primary endpoint is progression-free survival assessed by independent review committee. Secondary endpoints are overall survival, objective response rate, and duration of response, as well as the safety/tolerability, pharmacokinetics, and immunogenicity of zolbetuximab. As of June 30, 2020, 148 sites have been initiated.

Clinical trial identification

NCT03653507.

Legal entity responsible for the study

Astellas Pharma, Inc.

Funding

Astellas Pharma, Inc.

Disclosure

R-H. Xu: Honoraria (institution): Roche; Honoraria (institution): Merck. J.A. Ajani: Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma. S-E. Al-Batran: Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Celgene; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Nordic Pharma; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: MSD Sharp & Dohme; Speaker Bureau/Expert testimony: AIO gGmbH; Speaker Bureau/Expert testimony: MCI; Speaker Bureau/Expert testimony: promedicis; Speaker Bureau/Expert testimony: Forum für Medizinische Fortbildung; Officer/Board of Directors: IKF Klinische Krebsforschung GmbH; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Vifor; Research grant/Funding (institution): Medac; Research grant/Funding (institution): Hospira; Research grant/Funding (institution): German Cancer Aid (Krebshilfe); Research grant/Funding (institution): German Research Foundation; Research grant/Funding (institution): Federal Ministry of Education and Research. Y-J. Bang: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Merck Serano; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): BeiGene; Advisory/Consultancy, Research grant/Funding (institution): GreenCross; Advisory/Consultancy: Samyang Biopharm; Advisory/Consultancy: Hanmi; Advisory/Consultancy, Research grant/Funding (institution): Genexine; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Boeringer-Ingelheim; Research grant/Funding (institution): MacroGenics. D. Catenacci: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: Merck; Advisory/Consultancy: BMS; Advisory/Consultancy: Lilly; Advisory/Consultancy: Gritstone; Advisory/Consultancy: Taiho; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Daichii Sankyo. P.C. Enzinger: Advisory/Consultancy: Merck; Advisory/Consultancy: Astellas; Advisory/Consultancy: Celgene; Advisory/Consultancy: Lilly; Advisory/Consultancy: Loxo; Advisory/Consultancy: Taiho; Advisory/Consultancy: Zymeworks. D.H. Ilson: Advisory/Consultancy: Astellas Pharma. S. Kim: Travel/Accommodation/Expenses: Astellas Pharma. F. Lordick: Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Eli Lilly; Travel/Accommodation/Expenses: Elsevier; Travel/Accommodation/Expenses: Biontech GmbH; Travel/Accommodation/Expenses: Excerpta Medica; Travel/Accommodation/Expenses: Medscape; Travel/Accommodation/Expenses: E-Cancer; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Merck Serono; Travel/Accommodation/Expenses: Merck Sharpe & Dohme; Travel/Accommodation/Expenses: Springer Nature Verlag GmbH. K. Shitara: Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical; Research grant/Funding (institution): Dainippon Sumitomo Pharma; Advisory/Consultancy, Research grant/Funding (institution): MSD; Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Chugai Pharm; Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Medi Science; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution), Advisory/Consultancy: AbbVie; Honoraria (institution): Yakult; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Glaxo Smith Kline. E. van Cutsem: Advisory/Consultancy: Astellas; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Advisory/Consultancy: Incyte; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): Merck KGaA; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Servier; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Ipsen. A. Arozullah: Full/Part-time employment: Astellas Pharma. J.W. Park: Full/Part-time employment: Astellas Pharma. All other authors have declared no conflicts of interest.