| Eligibility |
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 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
- 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.
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