Combination Immunotherapy + Chemotherapy for Gastric Cancer

(STAR-221 Trial)

Not currently recruiting at 358 trial locations

Overseen By Medical Director

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Arcus Biosciences, Inc.

Disqualifiers: Cardiovascular disease, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 12-24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new combinations of immunotherapy and chemotherapy to evaluate their effectiveness for certain types of stomach cancer that cannot be surgically removed or have spread. Participants will receive either a combination of two new antibodies (proteins that help the immune system attack cancer) with chemotherapy or a different antibody with chemotherapy, to determine which is more effective. Individuals with stomach, gastroesophageal junction, or esophageal cancer that cannot be surgically removed or has spread might be suitable, especially if they have at least one measurable cancer spot. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking cancer treatments.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining the drugs domvanalimab and zimberelimab with chemotherapy has produced promising results in previous studies. This combination was associated with patients with advanced gastroesophageal adenocarcinomas living for a median of 26.7 months, a significant improvement over usual treatments.

While these results are encouraging, the studies also examined safety. The treatment was generally well-tolerated, with most patients not experiencing severe side effects. However, all treatments can have side effects, which may vary from person to person.

Prospective trial participants should discuss any concerns with their healthcare provider to understand potential side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Domvanalimab and Zimberelimab with chemotherapy for gastric cancer because it introduces a novel approach to enhancing the immune system's response against cancer cells. Unlike standard treatments that primarily rely on chemotherapy, this combination leverages immune checkpoint inhibitors, Domvanalimab and Zimberelimab, to potentially improve treatment effectiveness by blocking specific proteins that inhibit immune response. This dual immunotherapy targets the TIGIT and PD-1 pathways, which are not typically addressed by existing therapies, offering a new mechanism to enhance the body's ability to fight cancer. Additionally, the flexibility in dosing schedules with options like FOLFOX or CAPOX allows for personalized treatment approaches based on patient and physician choice.

What evidence suggests that this trial's treatments could be effective for gastric cancer?

In this trial, participants will receive different treatment combinations. One arm will study the combination of domvanalimab and zimberelimab with chemotherapy, which research has shown to be promising for treating advanced stomach and esophagus cancers. Specifically, studies found that this treatment helped patients live for an average of 26.7 months, with 59% experiencing a noticeable reduction in tumor size. The side effects resemble those of other treatments and can be managed. This suggests that the domvanalimab-zimberelimab combination could serve as an effective first choice for treating these advanced cancers. ^{1 3 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Arcus Biosciences

Are You a Good Fit for This Trial?

This trial is for adults with advanced gastric, GEJ, or esophageal adenocarcinoma that can't be surgically removed and has spread. Participants must have a good performance status (able to carry out daily activities), at least one measurable lesion, and no prior treatments for this cancer stage.

Inclusion Criteria

At least one measurable target lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

My cancer is in the stomach, GEJ, or esophagus and cannot be surgically removed.

I am fully active or can carry out light work.

Exclusion Criteria

I do not have any health conditions that would make the study treatment dangerous for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Domvanalimab, Zimberelimab, and chemotherapy or Nivolumab and chemotherapy

12-24 weeks

Visits every 2-4 weeks depending on treatment regimen

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• Domvanalimab
• Fluorouracil
• Leucovorin
• Oxaliplatin
• Zimberelimab

Trial Overview The study tests new drugs Domvanalimab (TIGIT inhibitor) and Zimberelimab (PD-1 inhibitor) with chemotherapy against Nivolumab (another PD-1 inhibitor) with chemo in first-line treatment. It's randomized, meaning patients are assigned to groups by chance.

How Is the Trial Designed?

Group I: Domvanalimab + Zimberelimab + FOLFOX/CAPOX (PI Choice) Experimental Treatment 6 Interventions

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.

Group II: Nivolumab + FOLFOX/CAPOX (PI Choice) Active Control 5 Interventions

Participants in this arm will receive Nivolumab Q2W and FOLFOX Q2W or Nivolumab Q3W + CAPOX Q3W.

Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

Arcus Biosciences, Inc.

Lead Sponsor

Trials

44

Recruited

7,500+

Taiho Pharmaceutical Co., Ltd.

Industry Sponsor

Trials

67

Recruited

18,600+

Masayuki Kobayashi

Taiho Pharmaceutical Co., Ltd.

Chief Executive Officer since 2012

Background in political and law studies

Harold Keer

Taiho Pharmaceutical Co., Ltd.

Chief Medical Officer since 2024

MD

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Published Research Related to This Trial

The XELOX regimen, combining oxaliplatin and capecitabine, demonstrated a 41.5% overall response rate in 41 patients with advanced or recurrent gastric cancer, indicating its efficacy in this challenging condition.

The treatment was associated with manageable toxicity, with only a few patients experiencing severe side effects, such as grade 3-4 neural toxicity and hematological issues, suggesting it is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preliminary study of XELOX regimen as the first-line chemotherapy in advanced or recurrent gastric cancer]. Min, N., He, BF., Zhang, LS., et al.[2020]

In a study of 44 previously untreated patients with advanced gastric cancer, the combination of cetuximab and XELOX chemotherapy resulted in a significant overall response rate of 52.3%, with median progression-free survival of 6.5 months and overall survival of 11.8 months.

The treatment was generally safe, with most side effects being mild to moderate (grade 1 or 2), such as anemia and asthenia, and serious hematologic toxicities were rare, indicating that cetuximab combined with XELOX is a viable first-line option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Kim, C., Lee, JL., Ryu, MH., et al.[2021]

The study compared the efficacy and safety of two chemotherapy regimens, XELOX and FOLFOXs, in 1585 patients with advanced gastric cancer, but found no significant difference in overall response rate or clinical benefit rate between the two treatments.

XELOX was associated with lower risks of nausea, stomatitis, diarrhea, and alopecia compared to FOLFOXs, but had a higher risk of hand-foot syndrome, suggesting it may be a safer option despite similar efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine plus oxaliplatin (XELOX) compared with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in advanced gastric cancer: meta-analysis of randomized controlled trials. Xu, HB., Huang, F., Su, R., et al.[2022]

In a phase II trial involving 63 patients with advanced gastric cancer, the combination of oxaliplatin, irinotecan, and fluorouracil/folinic acid showed a response rate of 33%, indicating it is an effective treatment option for this condition.

The treatment was generally well-tolerated, with manageable side effects; however, significant toxicities included neutropenia in 59% of patients and neurotoxicity in 33%, highlighting the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group. Comella, P., Lorusso, V., Maiorino, L., et al.[2018]

S-1, an oral chemotherapy drug combining tegafur with modulators, has shown advantages over standard 5-FU-based treatments for gastric cancer in large Phase III studies, making it a recommended option in treatment guidelines.

S-1, either alone or in combination with cisplatin, is non-inferior to traditional 5-FU regimens while offering greater convenience and reduced toxicity, highlighting its potential for higher efficacy in treating gastrointestinal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 for the treatment of gastrointestinal cancer. Satoh, T., Sakata, Y.[2022]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

In Korea, patients with advanced gastric cancer who undergo D2 resection benefit from postoperative adjuvant chemotherapy with S-1 or capecitabine plus oxaliplatin, indicating a potential effective treatment strategy in this population.

Trastuzumab is now part of the standard chemotherapy for gastric cancers that overexpress the HER2 protein, highlighting the importance of targeted therapies in improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for advanced gastric cancer: review and update of current practices. Park, SC., Chun, HJ.[2023]

Citations

1. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Anti-TIGIT-Domvanalimab-Plus-Anti-PD-1-Zimberelimab-and-Chemotherapy-Showed-26-7-Months-of-Median-Overall-Survival-as-First-Line-Treatment-of-Unresectable-or-Advanced-Gastroesophageal-Adenocarcinomas-in-the-Phase-2-EDGE-Gastric-Study/default.aspx

Anti-TIGIT Domvanalimab Plus Anti-PD-1 Zimberelimab and ... Anti-TIGIT Domvanalimab Plus Anti-PD-1 Zimberelimab and Chemotherapy Showed 26.7 Months of Median Overall Survival as First-Line Treatment of ...

2. onclive.com onclive.com/view/domvanalimab-plus-zimberelimab-and-chemo-set-for-phase-3-study-after-showing-efficacy-in-untreated-upper-gi-cancers

Domvanalimab Plus Zimberelimab and Chemo Set for ... Domvanalimab and zimberelimab, combined with FOLFOX, showed promising efficacy in advanced gastric and esophageal adenocarcinoma, with a 59% ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT411272

STAR-221: A randomized, open-label, multicenter, phase 3 ... STAR-221: A randomized, open-label, multicenter, phase 3 trial of domvanalimab, zimberelimab, and chemotherapy versus nivolumab and chemotherapy in previously ...

4. finance.yahoo.com finance.yahoo.com/news/anti-tigit-domvanalimab-plus-anti-220500438.html

Anti-TIGIT Domvanalimab Plus Anti-PD-1 Zimberelimab ... Anti-TIGIT Domvanalimab Plus Anti-PD-1 Zimberelimab and Chemotherapy Showed 26.7 Months of Median Overall Survival as First-Line Treatment of ...

5. researchgate.net researchgate.net/publication/396658661_Domvanalimab_and_zimberelimab_in_advanced_gastric_gastroesophageal_junction_or_esophageal_cancer_a_phase_2_trial

Domvanalimab and zimberelimab in advanced gastric ... Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum ...

6. nature.com nature.com/articles/s41571-025-01097-9

Domvanalimab plus zimberelimab shows promise in upper ... Domvanalimab plus zimberelimab shows promise in upper-tract cancers. Peter Sidaway. Nature Reviews Clinical Oncology (2025)Cite this article.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05329766

NCT05329766 | A Safety and Efficacy Study of Treatment ... The purpose of this study is to evaluate the safety and preliminary clinical activity of treatment combinations with and without chemotherapy in participants

8. nature.com nature.com/articles/s41591-025-04022-w

Domvanalimab and zimberelimab in advanced gastric ... Building on this rationale, we report results from arm A1 of the phase 2 EDGE-Gastric study (NCT05329766) of domvanalimab and zimberelimab in ...