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)
Age: ≥18 years
Histologically confirmed gastric or gastro-oesophageal junctional (GOJ) adenocarcinoma (inclusive of Siewert-stein classification type I-III (62))
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
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
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
Parallel
Single agent zimberelimab
DrugSingle agent zimberelimab (PD-1 inhibitor) Q3W
Combination zimberelimab + domvanalimab
DrugCombination zimberelimab + domvanalimab (TIGIT inhibitor) Q3W
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
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
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
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
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 changes, mIF IHC, and assessment of tumour immune environment including PDL1 status, TMB, genomic changes by whole exome sequencing (WES) and RNA sequencing, immune surveillance by TCR sequencing, HRD testing
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Royal Marsden NHS Foundation Trust
Lead sponsor
Gilead Sciences
Collaborator
