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Locally Advanced Gastric AdenocarcinomaPhase 2ZODIACNCT06250036

Zimberelimab Anti-PD1 +/- Domvanalimab in Resectable Mmrd Gastric Cancer

A Phase 2 study testing Single agent zimberelimab and Combination zimberelimab + domvanalimab in people with Locally Advanced Gastric Adenocarcinoma and MSI-H/dMMR Gastric Cancer, run by Royal Marsden NHS Foundation Trust at 10 sites in United Kingdom.

Suspended

Paused. Enrolment is on hold for now and may resume.

Official record
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Trial summary

A phase II study of peri-operative anti-PD1 (Zimberelimab) +/- anti-TIGIT (Domvanalimab) in resectable mismatch repair deficient (MMRd)/ high micro-satellite instability (MSI-H) gastric/gastro-oesophageal junctional (GOJ) adenocarcinoma (AC) Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Single agent zimberelimab and Combination zimberelimab + domvanalimab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
10 sitesUnited Kingdom
Study dates
20 Feb 2025to 1 Sep 2031
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age: ≥18 years
  • Histologically confirmed gastric or gastro-oesophageal junctional (GOJ) adenocarcinoma (inclusive of Siewert-stein classification type I-III (62))
  • MMRd/MSI-H. There are three different methods validated for detection (63) :
  • Immunohistochemistry (IHC) staining for expression of MMR proteins (MLH1, MSH2, PMS2 and MSH6), MMRd defined as loss of function or one or more of these proteins.
  • Polymerase chain reaction (PCR) amplification of microsatellite sequences
  • Next-generation sequencing (NGS) for detection of MSI
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  • Stage II-IIIB: TNM T2-T4, N0-N3, M0
  • Absence of distant metastatic disease on CT scan + PET CT + staging laparoscopy prior to study entry.
  • MDT determined suitable for surgery and MDT believes an R0 resection is achievable after neo-adjuvant therapy (resectable disease)
  • No prior anti-cancer therapy for gastric / GOJ adenocarcinoma
  • ECOG performance status 0-2
  • Laboratory parameters
  • Adequate haematologic and end-organ function defined by the following laboratory test results: Haematology: Absolute neutrophil count > 1.5 x 109/L Platelets > 100 x 109/L Haemoglobin > 90 x 109/L (can be post-transfusion) Biochemistry: Serum Creatinine Clearance >50ml/min (calculated using Cockcroft-Gault formula Appendix X)
  • Liver function: Bilirubin within normal limits ALT/AST ≤2.5x ULN
  • Coagulation profile (for patients not receiving therapeutic anticoagulation):
  • International Normalised Ratio (INR) < 1.5 Activated Prothrombin Time (APTT) < 1.5xULN
  • Before patient registration/randomisation, written informed consent must be given according to ICH/GCP, and national/local regulations
  • Patient is fit to undergo all protocol investigations and receive all protocol treatment based on the assessment in the surgical / oncology clinic
  • Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrolment
  • Willingness and ability to comply with the protocol for the duration of the study including scheduled visits, examinations, investigations and treatment plans

Who cannot join

  • Patients are not eligible for the trial if any of the exclusion criteria below are met:
  • Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3CTCAE v5.0, any history of anaphylaxis
  • Any prior treatment with cancer immunotherapy including anti-PD-1, anti-TIGIT, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
  • Treatment with systemic immunosuppressive medications, including but not limited to: corticosteroids (dose of > 10mg/day prednisone equivalent) cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1 Day 1
  • Prior malignancy active within the previous 2 years except for:
  • locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix
Show all 42Show fewer
  • localised prostate cancer
  • breast cancer diagnosed >2 years ago, now on adjuvant endocrine therapy (no known active disease)
  • Patients recommended to have radiotherapy as part of routine management for their gastric/GOJ AC are ineligible
  • QTc ≥480 msec using Fredericia QT correction formula
  • Metastatic disease on imaging or staging laparoscopy - visualisation of peritoneal disease on staging laparoscopy is an exclusionPrior organ transplantation, including allogeneic stem-cell transplantation
  • Any active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or is expected to deteriorate when receiving immunotherapy, with the following exceptions:
  • Patients with autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
  • Patients only receiving hormone replacement therapy e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy (doses ≤10mg - or equivalent - of prednisolone per day) for adrenal or pituitary insufficiency) are eligible
  • Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only not requiring immunosuppressive treatment are eligible, providing they meet the following conditions
  • Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
  • Rash mush cover less than 10% of body surface area
  • Disease is well controlled at baseline and only requiring low-potency topical steroids
  • No acute exacerbations of underlying condition within the last 12 months
  • Patients with controlled type 1 diabetes mellitus on a stable dose of insulin regimen are eligible
  • Patients requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement
  • Administration of steroids through a route known to result in minimal systemic exposure (topical, intranasal intra-ocular, or inhalation) are acceptable. Steroids as pre-medication for hypersensitivity reactions e.g., CT contrast are also acceptable
  • History of inflammatory bowel disease with the following exception:
  • Patients with a history of ulcerative colitis who have had a colectomy are eligible
  • Patients with a history of interstitial lung disease or radiological evidence of pulmonary fibrosis
  • Cerebrovascular disease (including transient ischaemic attacks (TIA) and strokes) within the 6 months prior to Cycle 1 Day 1
  • Cardiovascular diseases as follows:
  • Myocardial infarction within the previous year
  • Serious cardiac arrhythmia requiring medication (for example, ventricular tachycardia, supraventricular tachycardia or atrial fibrillation with a resting heart rate > 110bpm)
  • Unstable angina
  • Congestive cardiac failure (New York Heart Association Classification Class III or IV), EF <50%
  • Active infection requiring systemic therapy, non-healing wound, ulcer or bone fracture requiring therapy
  • Major surgery, major trauma within 28 days prior to registration (not including staging laparoscopy)
  • Current signs or symptoms of any other severe progressive or uncontrolled hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease other than directly related to gastric/GOJ adenocarcinoma, which in the opinion of the investigator, might impair the subject's tolerance of trial treatment or procedures
  • Other severe acute or chronic medical conditions or psychiatric conditions including recent (within the past year) active suicidal ideation or behaviour
  • Active/ uncontrolled Hepatitis A, B or C infection, for hepatitis B known positive HBV surface antigen (HBsAg) result, patients with past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are only eligible if polymerase chain reaction is negative for HCV RNA.
  • Uncontrolled human immunodeficiency virus (HIV) infection
  • If known HIV diagnosis and well controlled on anti-retrovirals (CD4 count ≥350cells/ul and undetectable viral load) patient is eligible, ensure HIV team involvement for management and monitoring whilst on treatment
  • Use of live attenuated vaccine within 28 days of initiation of study therapy, or anticipation that a live attenuated vaccine will be required during the study
  • Pregnancy must be excluded with a negative serum pregnancy test, within 3 days before initiation of therapy, if the risk of conception exists. Sexually active female patients must be surgically sterile or be postmenopausal or must agree to use highly effective contraception. Sexually active male patients must be surgically sterile or must agree to use highly effective contraception, i.e. methods with a failure rate of <1% per year (see section 5.4 for full definition and examples of highly effective contraception)
  • Lactation-breast-feeding is contraindicated and must be discontinued for the duration of the study period and for the required duration of the contraception use after the last dose of the study drug.
  • Any patient specific factors which are likely to interfere with compliance of trial specific procedures or treatment, including any medical or psychiatric conditions that in the investigator's or sponsor's opinion poses an undue risk to the participant's participation in the study or may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.

Trial locations and contacts

10 sites in 1 country.

10 sites in 1 country

United Kingdom10 sites

  • Addenbrooke's Hospital

    Cambridge, Cambridgeshire, CB2 0QQ

  • Kent & Canterbury Hospital

    Canterbury, Kent, CT1 3NG

  • Ninewells hospital and Medical School

    Dundee, DD1 9SY

  • Royal Devon University Healthcare Foundation Trust

    Exeter, Devon, EX2 5DW

  • St James's University hospital

    Leeds, Yorkshire, LS9 7TF

  • St Bartholomew's Hospital

    London, EC1A 7BE

  • University College London Hospital NHS Foundation Trust

    London, N15 6UL

  • The Royal Free NHS Foundation Trust

    London, NW32QG

  • Guy's and St Thomas' NHS Foundation Trust

    London, SE1 9RT

  • The Royal Marsden NHSFT

    London, SW3 6JJ

Other trials in United Kingdom

About this study

Official title: A Randomised Phase II Study of Zimberelimab Anti-PD1 immunOtherapy +/- Domvanalimab Anti-TIGIT Immunotherapy in Resectable Mismatch Repair Deficient Gastric and Gastro-oesophageal Junctional AdenoCarcinoma

A phase II study of peri-operative anti-PD1 (Zimberelimab) +/- anti-TIGIT (Domvanalimab) in resectable mismatch repair deficient (MMRd)/ high micro-satellite instability (MSI-H) gastric/gastro-oesophageal junctional (GOJ) adenocarcinoma (AC)

Read the detailed description

Primary objective The primary objective of the trial is to evaluate the efficacy of zimberelimab +/- domvanalimab as peri-operative treatment in resectable MMRd/MSI-H gastric/GOJ adenoca. A chemotherapy-sparing approach. The primary endpoint is pathological complete response rate at surgery, and to identify which is the most promising experimental arm (zimberelimab alone vs zimberelimab in combination with domvanalimab).

Secondary objectives

  • To assess the safety and tolerability of zimberelimab+/- domvanalimab in this disease setting
  • To further assess the efficacy of zimberelimab+/- domvanalimab in terms of radiological response rate, R0 resection rate, progression free survival (PFS) and overall survival (OS)
  • To evaluate surgical outcomes following treatment with zimberelimab +/- domvanalimab

Translational analyses on tissue and blood biomarkers aimed at identifying those who derive the most benefit from this immunotherapy combination, and those who are non/poor responders.

Being tested
Single agent zimberelimab, Combination zimberelimab + domvanalimab
Keywords
dMMR, MMRd, MSI-H, gastric adenocarcinoma, GEJ adenocarcinoma, Gastroesophageal-junction adenocarcinoma, Peri-operative, MMRd/MSI-H operable gastric/GEJ adenocarcinoma, domvanalimab, zimberelimab, ZODIAC

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Single agent zimberelimabDrug

    Single agent zimberelimab (PD-1 inhibitor) Q3W

  • Combination zimberelimab + domvanalimabDrug

    Combination zimberelimab + domvanalimab (TIGIT inhibitor) Q3W

Study groups in NCT06250036
Study groupRoleWhat they receive
Single agent zimberelimabExperimentalSingle agent zimberelimab (PD-1 inhibitor) Q3W
Receives: Drug: Single agent zimberelimab
Combination zimberelimab + domvanalimabExperimentalCombination zimberelimab + domvanalimab (anti-TIGIT) Q3W
Receives: Drug: Combination zimberelimab + domvanalimab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Efficacy of zimberelimab +/- domvanalimab in patients with resectable MMRd/MSI-H gastric/GOJ adenocarcinoma who proceed to surgery

    Complete pathological response (pCR) rate, to be assessed following surgery by pathological review pCR defined as complete disappearance of tumour cells in the primary tumour surgical specimen and lymph nodes, pCR graded using Mandard TRG grading system

    Measured: 5 years

Secondary outcomes (3)

  1. Efficacy of zimberelimab +/- domvanalimab in patients with resectable MMRd/MSI-H gastric/GOJ adenocarcinoma (all patients treated with study drug(s))

    Clinical complete response rate (cCR), defined as either pCR in patients who have completed surgery, or a complete response on pre-operative imaging in patients who do not have surgery

    Measured: 5 years

  2. Assess the safety of zimberelimab+/- domvanalimab with the incidence of TEAEs, SAEs, AEs leading to discontinuation or delays, irAEs, deaths and laboratory abnormalities per CTCAEv5 grade

    Incidence of TEAEs, SAEs, AEs leading to discontinuation or delays, irAEs, deaths and laboratory abnormalities per CTCAEv5 grade

    Measured: 5 years

  3. Further assess the anti-tumour effect of zimberelimab +/- domvanalimab and any additional benefit of domvanalimab with radiological response, R0 resection rate, and major surgical complications and survival

    EFS,OS, Overall response rate (ORR) by RECIST v1.1, R0 resection rate, length of hospital stay, major surgical complications

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Feb 2024
  2. Study start20 Feb 2025
  3. Primary completion20 Mar 2027 (estimated)
  4. Study completion1 Sep 2031 (estimated)

Why it stopped: Gilead's ongoing evaluation of the wider Zimberelimab and Domvanalimab programme, following the outcomes of the STAR-221 study and the discontinuation of EDGE-Gastric studies. No safety concerns have been identified in relation to ZODIAC.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
A UK multicentre, prospective, randomised open label phase II proof of concept study with screen selection design. There will be two cohorts with a 1:1 randomisation
Masking
None (open label)
Enrolment
50 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06250036
Sponsor's protocol ID
CCR5924
Acronym
ZODIAC
Status last verified
Aug 2026
First submitted
11 Dec 2023
Last updated
21 Aug 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Single agent zimberelimab and Combination zimberelimab + domvanalimab in people with Locally Advanced Gastric Adenocarcinoma and MSI-H/dMMR Gastric Cancer, run by Royal Marsden NHS Foundation Trust at 10 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: paused, as of the sponsor's last update on 21 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy of zimberelimab +/- domvanalimab in patients with resectable MMRd/MSI-H gastric/GOJ adenocarcinoma who proceed to surgery (time frame: 5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06250036.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2026.

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