Locally Advanced Gastric Adenocarcinoma, MSI-H/dMMR Gastric Cancer, MSI-H/dMMR Gastroesophageal-junction Cancer
Conditions
Keywords
dMMR, MMRd, MSI-H, gastric adenocarcinoma, GEJ adenocarcinoma, Gastroesophageal-junction adenocarcinoma, Peri-operative, MMRd/MSI-H operable gastric/GEJ adenocarcinoma, domvanalimab, zimberelimab, ZODIAC
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)
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.
Interventions
DRUGSingle agent zimberelimab
Single agent zimberelimab (PD-1 inhibitor) Q3W
DRUGCombination zimberelimab + domvanalimab
Combination zimberelimab + domvanalimab (TIGIT inhibitor) Q3W
Sponsors
Royal Marsden NHS Foundation Trust
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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): 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
Exclusion criteria
Patients are not eligible for the trial if any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of zimberelimab +/- domvanalimab in patients with resectable MMRd/MSI-H gastric/GOJ adenocarcinoma who proceed to surgery | 5 years | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of zimberelimab +/- domvanalimab in patients with resectable MMRd/MSI-H gastric/GOJ adenocarcinoma (all patients treated with study drug(s)) | 5 years | 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 | 5 years | 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 | 5 years | EFS,OS, Overall response rate (ORR) by RECIST v1.1, R0 resection rate, length of hospital stay, major surgical complications |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORNaureen Starling
The Royal Marsden NHSFT UK
Outcome results
None listed