Inclusion Criteria
i. Male/female patients aged ≥18 years ii. Histologically confirmed gastric,
gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as oesophagogastric
adenocarcinoma (OGA) in this protocol) or colorectal adenocarcinoma (referred to as CRC in
this protocol) iii. Agrees to undergo biopsies for translational endpoints iv. Tumour must
be mismatch repair proficient assessed using a validated test such as immunohistochemistry
for mismatch repair proteins or microsatellite instability testing v. Tumours should be
advanced and inoperable or metastatic vi. Patients must have received at least one prior
chemotherapy treatment for their cancer, have no established treatment option, or decides
against an established treatment option.
vii. Adequate bone marrow function:
1. Absolute neutrophil count (ANC) ≥1.5 x109/L
2. White blood count >3x109/L
3. Platelets ≥100x109/L
4. Haemoglobin (Hb) ≥9g/dl (can be post-transfusion) viii. Adequate renal function:
Creatinine Clearance o ≥30ml/min is required. This may be calculated as per local
practice, if calculated CrCl is <60ml/min then EDTA is required to demonstrate CrCl of
≥30ml/min If available, the EDTA clearance should always take precedence over the
creatinine clearance.
ix. Adequate liver function
a. Serum bilirubin ≤1.5x ULN b. ALT/AST ≤2.5x ULN or ALT/AST ≤5x ULN if metastatic disease
to liver x. Adequate coagulation profile
1. International Normalised Ratio (INR) < 1.5
2. Activated Prothrombin Time (APTT) < 1.5xULN xi. Patients on oral anticoagulation are
advised to change to low molecular weight heparin prior to study entry to be eligible
xii. ECOG performance status 0-1 xiii. Patient is fit to undergo all protocol
investigations and receive all protocol treatment based on the assessment oncology
clinics xiv. 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.
xv. Willingness and ability to comply with the protocol for the duration of the study
including scheduled visits, examinations, investigations and treatment plans xvi. Pregnancy
must be excluded with a negative serum pregnancy test, within 7 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
which must be used for 10 days before the negative pregnancy test. 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 6.4 for full definition and
examples of highly effective contraception). Highly effective contraception must be agreed
to be used throughout the study and for 30 days after last avelumab treatment if risk of
conception exists. Female patients of child-bearing potential should be strictly advised to
use a highly effective contraceptive measure, from the time of screening to 30 days after
the last dose of trial treatment. If the patient uses a hormonal contraceptive method, the
patient's partner should additionally use a condom. Male patients with partners of child
bearing potential should be strictly advised to use barrier contraception in addition to
having their partner use another method of contraception during the trial and for three
months after the last dose. Male patients should also be advised to abstain from sexual
intercourse with pregnant or lactating women, or to use condoms.
Exclusion Criteria
i. Any contraindication or known hypersensitivity reaction to any of the study drugs ii.
Persisting toxicity relating to prior therapy of >grade 1 CTCAE version 4.03 except
alopecia of any grade and neuropathy ≤ grade 2, or other grade ≤2 not constituting a safety
risk based on investigators judgement iii. Any prior treatment with immunotherapy including
anti-PD-1or PD-L1 therapy or other immunomodulatory drugs.
iv. All subjects with brain metastases, except those meeting the following criteria:
1. Brain metastases that have been treated locally and are clinically stable for at least
2 weeks prior to enrolment
2. No ongoing neurological symptoms that are related to the brain localization of the
disease (sequelae that are a consequence of the treatment of the brain metastases are
acceptable)
3. Subjects must be either off steroids or on a stable or decreasing dose of <10mg daily
prednisone (or equivalent)
v. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v
4.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of
partially controlled asthma) vi. Patients who have received chemotherapy or radiotherapy
for a previous malignancy in the past 3 years.
vii. Any immunodeficiency disorder viii. Any active, known or suspected autoimmune disease
that might deteriorate when receiving immunostimulatory agent, with the following
exceptions:
1. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not
requiring immunosuppressive treatment are eligible
2. Patients requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at doses
≤10mg (or equivalent) of prednisolone per day
3. Administration of steroids through a route known to result in minimal systemic
exposure (topical, intranasal, intra-ocular, intra-articular or inhalation) are
acceptable. Steroids as pre-medication for hypersensitivity reactions e.g. CT contrast
are also acceptable.
ix. Prior organ transplantation, including allogeneic stem-cell transplantation x. Active
infection requiring systemic therapy xi. History of inflammatory bowel disease xii.
Patients with a history of interstitial lung disease or radiological evidence of pulmonary
fibrosis xiii. Cerebrovascular disease (including transient ischaemic attacks (TIA) and
strokes) within the previous 6 months xiv. Cardiovascular diseases as follows:
1. Myocardial infarction within the previous 6 months
2. Unstable angina
3. Congestive heart failure ≥NYHA Classification Class II
4. Serious cardiac arrhythmia requiring medication (for example, ventricular tachycardia,
supraventricular tachycardia or atrial fibrillation with a resting heart rate >
110bpm) xv. Current signs or symptoms of any other severe progressive or uncontrolled
hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease,
which in the opinion of the investigator, might impair the subject's tolerance of
trial treatment or procedures.
xvi. Major surgery, major trauma or open biopsy within 28 days prior to registration (not
including staging laparoscopy) xvii. Evidence of bleeding diathesis or coagulopathy xviii.
Active non-healing wound, ulcer or bone fracture requiring therapy xix. Known positive
tests for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency
syndrome, hepatitis A or C virus, acute or chronic active hepatitis B infection xx. 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 xxi. Current lactation
(patients that discontinue breastfeeding may be eligible) xxii. Other severe acute or
chronic medical conditions or psychiatric conditions including recent (within the past
year) or active suicidal ideation or behaviour; or laboratory abnormalities that may
increase the risk associated with study participation or study treatment administration or
may interfere with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for entry into this study.
