A Clinical Trial of a New Combination Treatment, Domvanalimab and Zimberelimab, Plus Chemotherapy, for People With an Upper Gastrointestinal Tract Cancer That Cannot be Removed With Surgery That Has Spread to Other Parts of the Body (STAR-221)

A Randomized, Open-Label, Multicenter Phase 3 Trial of Domvanalimab, Zimberelimab, and Chemotherapy Versus Nivolumab and Chemotherapy in Participants With Previously Untreated Locally Advanced Unresectable or Metastatic Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma

This randomized Phase 3 open-label study will compare the efficacy of the T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) monoclonal antibody domvanalimab, the anti programmed cell death protein 1 (PD-1) monoclonal antibody zimberelimab, and multiagent chemotherapy versus the anti PD-1 monoclonal antibody nivolumab and multiagent chemotherapy in the first-line treatment of participants with locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Upper Gastrointestinal Tract Adenocarcinoma
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Leucovorin; Drug: Fluorouracil; Drug: Capecitabine; Drug: Nivolumab; Drug: Domvanalimab; Drug: Zimberelimab

• Study Type: Interventional
• Enrollment (Actual): 1040
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Research Site
  • La Rioja, Argentina
    • Research Site
  • Mar del Plata, Argentina
    • Research Site
• Australia
  • Clayton, Australia
    • Research Site
  • Murdoch, Australia
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• Brazil
  • Barretos, Brazil
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  • Ijuí, Brazil
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  • Natal, Brazil
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  • Porto Alegre, Brazil
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• Canada
  • Halifax, Canada
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  • Montreal, Canada
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  • Ottawa, Canada
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  • Toronto, Canada
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• Chile
  • La Florida, Chile
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  • Port Montt, Chile
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  • Providencia, Chile
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  • Recoleta, Chile
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  • Santiago, Chile
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  • Talca, Chile
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• China
  • Changchun, China
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  • Changzhou, China
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  • Fuzhou, China
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  • Guangzhou, China
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  • Haikou, China
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  • Hangzhou, China
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  • Hefei, China
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  • Shanghai, China
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  • Tianjin, China
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  • Zhengzhou, China
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• France
  • Bordeaux, France
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  • Brest, France
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  • Caen, France
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  • Lille, France
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  • Lyon, France
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  • Montpellier, France
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  • Plérin, France
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  • Poitiers, France
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  • Toulouse, France
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  • Villejuif, France
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• Georgia
  • Kutaisi, Georgia, 4600
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  • Tbilisi, Georgia, 112
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  • Tbilisi, Georgia, 186
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  • Tbilisi, Georgia, 144
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  • Tbilisi, Georgia, 159
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• Guatemala
  • Guatemala City, Guatemala
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  • Quetzaltenango, Guatemala
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• Hong Kong
  • Happy Valley, Hong Kong
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  • Hong Kong, Hong Kong
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  • Tuenmen, Hong Kong
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• Hungary
  • Budapest, Hungary
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  • Kecskemét, Hungary
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  • Pécs, Hungary
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• Israel
  • Jerusalem, Israel
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  • Petah Tikva, Israel
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  • Tel Aviv, Israel
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• Italy
  • Florence, Italy
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  • Milan, Italy
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  • Ravenna, Italy
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  • Rozzano, Italy
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  • Udine, Italy
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• Japan
  • Akashi, Japan
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  • Bunkyō City, Japan
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  • Chiba, Japan
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  • Fukuoka, Japan
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  • Kashiwa-shi, Japan
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  • Kawasaki, Japan
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  • Kōtō City, Japan
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  • Matsuyama, Japan
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  • Nagaizumi-cho, Japan
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  • Nagoya, Japan
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  • Niigata, Japan
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  • Osaka, Japan
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  • Osakasayama-shi, Japan
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  • Ota-shi, Japan
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  • Saitama, Japan
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  • Tokyo, Japan
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  • Yokohama, Japan
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• Lithuania
  • Kaunas, Lithuania
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  • Klaipėda, Lithuania
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  • Vilnius, Lithuania
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• Malaysia
  • George Town, Malaysia
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  • Kuala Lumpur, Malaysia
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  • Kuching, Malaysia
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• Mexico
  • Colonia Centro, Mexico, 94300
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  • Mexico City, Mexico, 3100
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  • Mérida, Mexico, 97134
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  • San Pedro Garza García, Mexico, 66278
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  • Toluca, Mexico, 50120
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• Peru
  • San Isidro, Peru
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  • San Juán de Miraflores, Peru
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  • Surquillo, Peru
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• Philippines
  • Bacolod City, Philippines
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  • Baguio City, Philippines
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  • Cebu City, Philippines
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  • Manila, Philippines
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• Poland
  • Lublin, Poland
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  • Tychy, Poland
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  • Warsaw, Poland
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• Portugal
  • Coimbra, Portugal
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  • Lisbon, Portugal
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  • Porto, Portugal
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• Romania
  • Baia Mare, Romania
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  • Bucharest, Romania
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  • Cluj-Napoca, Romania
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  • Craiova, Romania
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  • Florești, Romania
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  • Iași, Romania
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  • Suceava, Romania
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• Serbia
  • Belgrade, Serbia
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  • Kragujevac, Serbia
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• South Korea
  • Busan, South Korea
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  • Daegu, South Korea
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  • Seongnam, South Korea
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  • Seoul, South Korea
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• Spain
  • Barcelona, Spain
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  • Madrid, Spain
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  • Santander, Spain
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  • Valencia, Spain
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  • Zaragoza, Spain
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• Thailand
  • Bang Phlat, Thailand
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  • Hat Yai, Thailand
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  • Ubon Ratchathani, Thailand
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• Turkey (Türkiye)
  • Adana, Turkey (Türkiye)
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  • Ankara, Turkey (Türkiye)
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  • Edirne, Turkey (Türkiye)
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  • Istanbul, Turkey (Türkiye)
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  • Malatya, Turkey (Türkiye)
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  • Mamak, Turkey (Türkiye)
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  • Van, Turkey (Türkiye)
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  • Yakutiye, Turkey (Türkiye)
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  • Yüreğir, Turkey (Türkiye)
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  • İzmit, Turkey (Türkiye)
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• United Kingdom
  • London, United Kingdom
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  • Manchester, United Kingdom
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  • Oxford, United Kingdom
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  • Sutton, United Kingdom
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• United States
  • California
    • Los Angeles, California, United States, 90033
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    • Orange, California, United States, 92868
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    • Santa Monica, California, United States, 90404
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  • Connecticut
    • New Haven, Connecticut, United States, 06520
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  • District of Columbia
    • Washington D.C., District of Columbia, United States, 22057
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  • Florida
    • Fort Myers, Florida, United States, 33901
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    • St. Petersburg, Florida, United States, 33705
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    • Tallahassee, Florida, United States, 32308
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  • Kentucky
    • Louisville, Kentucky, United States, 40202
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    • Louisville, Kentucky, United States, 40217
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  • Louisiana
    • New Orleans, Louisiana, United States, 70121
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  • Massachusetts
    • Boston, Massachusetts, United States, 02114
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  • Michigan
    • Ann Arbor, Michigan, United States, 48109
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  • Minnesota
    • Saint Louis Park, Minnesota, United States, 55426
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  • New York
    • Mineola, New York, United States, 11501
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    • New York, New York, United States, 10016
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    • New York, New York, United States, 10065
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  • North Carolina
    • Durham, North Carolina, United States, 27710
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  • Ohio
    • Cleveland, Ohio, United States, 44106
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    • Cleveland, Ohio, United States, 44111
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    • Columbus, Ohio, United States, 43219
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    • Mayfield Heights, Ohio, United States, 44124
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  • Oregon
    • Portland, Oregon, United States, 97225
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  • Tennessee
    • Nashville, Tennessee, United States, 37203
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    • Nashville, Tennessee, United States, 37232
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  • Texas
    • Dallas, Texas, United States, 75390
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    • Fort Worth, Texas, United States, 76104
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    • Houston, Texas, United States, 77054
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  • Virginia
    • Fairfax, Virginia, United States, 22031
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  • Washington
    • Seattle, Washington, United States, 98109
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  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Capable of giving signed informed consent which is in compliance with the requirements and restrictions listed in the informed consent form (ICF) and in protocol.
• Histologically confirmed diagnosis of locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• At least one measurable target lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Key Exclusion Criteria:

• Underlying medical or psychiatric conditions that, in the investigator's or sponsor's opinion, will make the administration of study-specified therapy hazardous, including but not limited to:
• Interstitial lung disease, including history of interstitial lung disease or non-infectious pneumonitis. Active viral, bacterial, or fungal infections requiring parenteral treatment within 14 days of randomization.
• Clinically significant cardiovascular disease, such as New York Heart Association Class II or greater cardiac disease or cerebrovascular accident within 3 months prior to randomization, unstable angina, or new onset angina within 3 months prior to randomization, myocardial infarction within 6 months prior to randomization, or unstable arrhythmia within 3 months prior to randomization.
• History of prior solid-organ transplantation, including allogenic bone marrow transplantation.
• Dementia, psychiatric, or substance abuse disorders that would interfere with satisfying the requirements of the trial.
• Known human epidermal growth factor receptor 2 (HER-2) positive tumor.
• Known untreated, symptomatic, or actively progressing central nervous system (CNS) (brain) metastases. Participants with leptomeningeal metastases are excluded from enrollment.
• Received prior systemic treatment for locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma.
• Disease progression within 6 months of completion of neoadjuvant or adjuvant therapy.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Domvanalimab + Zimberelimab + FOLFOX/CAPOX (PI Choice); Participants in this arm will receive Domvanalimab and zimberelimab doses once every 4 weeks (Q4W) in addition to chemotherapy with FOLFOX (oxaliplatin, leucovorin, fluorouracil) once every 2 weeks (Q2W) or Domvanalimab and zimberelimab once every 3 weeks (Q3W) in addition to chemotherapy with CAPOX (capecitabine and oxaliplatin) Q3W.	Drug: Oxaliplatin; IV Aqueous Solution; Drug: Leucovorin; IV Aqueous Solution; Drug: Fluorouracil; IV Aqueous Solution; Drug: Capecitabine; Oral Tablets; Drug: Domvanalimab; Intravenous (IV) Aqueous Solution; Other Names: AB154; Drug: Zimberelimab; IV Aqueous Solution; Other Names: AB122
Active Comparator: Nivolumab + FOLFOX/CAPOX (PI Choice); Participants in this arm will receive Nivolumab Q2W and FOLFOX Q2W or Nivolumab Q3W + CAPOX Q3W.	Drug: Oxaliplatin; IV Aqueous Solution; Drug: Leucovorin; IV Aqueous Solution; Drug: Fluorouracil; IV Aqueous Solution; Drug: Capecitabine; Oral Tablets; Drug: Nivolumab; IV Aqueous Solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	From date of randomization until date of death from any cause (Approximately 15 months)]

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival (PFS)	From date of randomization to date of the first documentation of disease progression or date of death from any cause, whichever comes first (Approximately 15 months)
Objective response rate (ORR)	Proportion of randomized participants who achieved a confirmed best overall response of complete response (CR) or partial response (PR) (Approximately 15 months)
Duration of response (DOR)	From the date of first confirmed response (CR or PR), until the date of first documented disease progression or date of death from any cause, whichever comes first (Approximately 15 months)
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	From on or after the date of first dose of any study treatment to the date of last study treatment specific safety follow-up or date of initiation of subsequent systemic anti-cancer therapy, whichever occurs first (Approximately 15 months)
Time to first symptom deterioration in the FACT-Ga gastric cancer subscale.	From the date of randomization to change from baseline in subscale greater than or equal to the deterioration threshold, or death from any cause, whichever comes first (Approximately 15 months)

Collaborators and Investigators

• Sponsor: Arcus Biosciences, Inc.
• Collaborators: Gilead Sciences; Taiho Pharmaceutical Co., Ltd.
• Investigators: Study Director: Medical Director, Arcus Biosciences

Publications and helpful links

General Publications

• Yu J, Mehta R. Biomarker-Driven Approach to the Treatment of Metastatic Gastric or Gastroesophageal Adenocarcinoma. J Natl Compr Canc Netw. 2025 May;23(5):e257036. doi: 10.6004/jnccn.2025.7036.

Helpful Links

• STAR-221 Public Website

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 3, 2022
• First Posted (Actual): October 5, 2022

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Nivolumab; Gastric cancer; Esophageal adenocarcinoma; Gastroesophageal junction cancer; Gastric adenocarcinoma; Zimberelimab; Domvanalimab; Advanced upper gastrointestinal tract adenocarcinoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Adenocarcinoma Of Esophagus; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Enzymes and Coenzymes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Deoxyribonucleosides; Capecitabine; Oxaliplatin; Nivolumab; Fluorouracil; Leucovorin; zimberelimab
• Other Study ID Numbers: STAR-221; jRCT2051220179 (Registry Identifier: Japan Registry of Clinical Trials); MOH_2023-04-30_012590 (Registry Identifier: Israel Clinical Research Site - MyTrials); CTR20233469 (Registry Identifier: China: Drug Clinical Trial Registration and Information Disclosure Platform); CTR20233470 (Registry Identifier: China: Drug Clinical Trial Registration and Information Disclosure Platform); 2023-507522-16-00 (Other Identifier: EMA: Clinical Trials Information System (CTIS))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Arcus will provide access to individual de-identified participant data and related study documents [e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)] upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.

For more information, please visit our website.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No