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

NCT06250036 | Recruiting Phase 2 DMC

• 1 other identifier: CCR5924
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 9

Brief 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)

Conditions

Locally Advanced Gastric Adenocarcinoma; MSI-H/dMMR Gastric Cancer; MSI-H/dMMR Gastroesophageal-junction Cancer

Keywords

dMMR; MMRd; MSI-H; gastric adenocarcinoma; GEJ adenocarcinoma; Gastroesophageal-junction adenocarcinoma; Peri-operative; MMRd/MSI-H operable gastric/GEJ adenocarcinoma; domvanalimab; zimberelimab; ZODIAC

Outcome Measures

Primary Outcomes (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

  5 years

Secondary Outcomes (3)

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

  5 years

• 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

  5 years

• 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

  5 years

Other Outcomes (1)

• Exploratory - Translational analyses to exploring response to immunotherapy. To review immune surveillance, immune editing and immune association, and the role of T-cells in modulating disease and response, and the overall disease evolution

  Dynamic ctDNA tracking up to 2 years. The other exploratory translational analyses will be performed at specific time points - the archival biopsy and surgical resection

Study Arms (2)

Single agent zimberelimab

EXPERIMENTAL

Single agent zimberelimab (PD-1 inhibitor) Q3W

Drug: Single agent zimberelimab

Combination zimberelimab + domvanalimab

EXPERIMENTAL

Combination zimberelimab + domvanalimab (anti-TIGIT) Q3W

Drug: Combination zimberelimab + domvanalimab

Interventions

Single agent zimberelimab DRUG

Single agent zimberelimab (PD-1 inhibitor) Q3W

Single agent zimberelimab

Combination zimberelimab + domvanalimab DRUG

Combination zimberelimab + domvanalimab (TIGIT inhibitor) Q3W

Combination zimberelimab + domvanalimab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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):

You may not qualify if:

• 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
• 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
• 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

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Gilead Sciences: collaborator

Study Sites (9)

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

RECRUITING

Royal Devon University Healthcare Foundation Trust

Exeter, Devon, EX2 5DW, United Kingdom

RECRUITING

Ninewells hospital and Medical School

Dundee, Dundee, DD1 9SY, United Kingdom

RECRUITING

Kent & Canterbury Hospital

Canterbury, Kent, CT1 3NG, United Kingdom

RECRUITING

Guy's and St Thomas' NHS Foundation Trust

London, London, SE1 9RT, United Kingdom

RECRUITING

The Royal Marsden NHSFT

London, London, SW3 6JJ, United Kingdom

RECRUITING

St James's University hospital

Leeds, Yorkshire, LS9 7TF, United Kingdom

RECRUITING

St Bartholomew's Hospital

London, EC1A 7BE, United Kingdom

RECRUITING

University College London Hospital NHS Foundation Trust

London, N15 6UL, United Kingdom

RECRUITING

Study Officials

• Naureen Starling

  The Royal Marsden NHSFT UK

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Project Manager

CONTACT

02086613279; ZODIAC@rmh.nhs.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: December 11, 2023
• First Posted: February 8, 2024
• Study Start: February 20, 2025
• Primary Completion (Estimated): March 20, 2027
• Study Completion (Estimated): September 1, 2031
• Last Updated: August 21, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (9)