| Eligibility |
Inclusion Criteria
1. Male or female patients aged =18 years
2. Patients with histologically confirmed advanced/metastatic RAS/RAF wild type colon or
rectal adenocarcinoma who had a prior radiological response to EGFR blockade as a
single agent or in combination with chemotherapy but have subsequently progressed/
become refractory to this treatment based on physician judgment. Patients should not
have received any other systemic anti-cancer therapy between the end of treatment with
EGFR inhibitors as a single agents or in combination with chemotherapy and screening
for the iSCORE study
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4. Estimated life expectancy of at least 3 months at the time of informed consent per
Investigator assessment
5. Adequate organ functioning as defined by the following:
i. Absolute neutrophil count (ANC) = 1.5 × 109/L (stable off any growth factor within
4 weeks prior to first study drug administration) ii. Platelet count = 100 × 109/L
(Transfusion to achieve this level is not permitted within 2 weeks of first study drug
administration) iii. Haemoglobin = 8.5 g/dL (Transfusion to achieve this level is not
permitted within 2 weeks of first study drug administration) iv. Creatinine < 1.5 X
ULN or creatinine clearance = 40 mL/min (Cockcroft-Gault formula) v. AST and ALT
levels = 3 × ULN vi. Lipase and amylase < 1.5 ULN vii. Total bilirubin level = 1.5 ULN
(except patients with Gilbert's Syndrome who must have a normal direct bilirubin)
viii. Normal thyroid function or on stable hormone supplementation per investigator
assessment ix. Albumin >28 g/dL x. LVEF assessment with documented LVEF = 50% by TTE
within 6 months from first study drug administration
6. Negative serum or urine pregnancy test at screening for women of childbearing
potential**
7. Highly effective contraception for both male and female patients throughout the study
and for at least 165 days for women 225 days for males after the last treatment
administration if the risk of conception exists. Please refer to Section 9.15 -
Pregnancy reporting for details of acceptable and unacceptable methods of
contraception.
8. Patient must consent and be eligible to undergo mandatory baseline and sequential
biopsies; in such case as a specimen cannot be obtained at acceptable clinical risk as
judged by the Investigator then patients may still be included in the study. Patients
must not be anti-coagulated at the time of biopsy or on aspirin/clopidogrel for 7 days
pre-biopsy
9. Resolved acute effects of prior therapy to baseline severity or =Grade 1 except for
AEs not constituting a safety risk by investigator judgement
10. Signed and dated informed consent
11. Patients willing and able to comply with scheduled visits, treatment plans, laboratory
tests, and other procedures. Prisoners and patients who are involuntarily incarcerated
are excluded
12. Presence of measurable disease as defined by RECIST v 1.1 criteria for response
assessment ** Defined as a pre-menopausal female capable of becoming pregnant. This
includes women on oral, injectable or mechanical contraception
Exclusion Criteria
Patients are not eligible for the trial if any of the exclusion criteria below are met:
1. Systemic therapy within 4 weeks prior to the planned administration of the first study
treatment dose
2. Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry.
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has
been completed 48 hours prior to study entry and there is at least one measurable
lesion that has not been irradiated
3. Participation in other studies involving investigational drug(s) within 4 weeks prior
to study entry and/or during study participation
4. Previous exposure to immune checkpoint inhibitors or immune co-stimulatory drugs such
as but not limited to anti-CTLA-4, anti-PD-1, anti-PDL1, anti-PD-2, anti-KIR,
anti-CD137, anti-LAG-3, anti-OX40 antibodies or IDO or CXCR2 targeted agents
5. Known severe hypersensitivity reactions (Grade = 3 NCI CTCAE v 5.0) to monoclonal
antibodies or related compounds or any of their components (e.g. history of severe
hypersensitivity reactions to drugs formulated with polysorbate 80), any history of
anaphylaxis or uncontrolled asthma (defined a 3 or more features of partially
controlled asthma)
6. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
inhaled, topical steroids, or local steroid injection (e.g., intra-articular
injection); b. Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone
or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT
scan premedication)
7. Active infection requiring systemic therapy
8. Any active malignancy, with the exception of adequately treated cervical carcinoma in
situ, localized non-melanoma skin cancer or other locally curable cancers including
superficial bladder cancer, carcinoma in situ of the prostate, cervix or breast
9. Significant acute or chronic infections including, among others:
- Known history of testing positive test for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS)
- Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV
antibody tested positive)
10. All patients with brain metastases, except those meeting the following criteria:
- Brain metastases that have been treated locally and are clinically stable for at
least 2 weeks prior to enrolment
- 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)
- Patients must be either off steroids or on a stable or decreasing dose of <10mg
daily prednisone (or equivalent)
11. Prior organ transplantation, including allogeneic stem cell transplantation
12. Any active autoimmune disease that has required systemic treatment in past 2 years
(i.e, with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment and is allowed.
13. Uncontrolled or significant cardiovascular disease including, but not limited to, any
of the following:
1. Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6
months prior to consent
2. Uncontrolled angina within the 3 months prior to consent
3. Any history of clinically significant arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled
atrial fibrillation)
4. QTc prolongation > 480 msec
5. History of other clinically significant cardiovascular disease (i.e.,
cardiomyopathy, congestive heart failure with New York Heart Association [NYHA]
functional classification III-IV, pericarditis, significant pericardial effusion,
significant coronary stent occlusion, poorly controlled deep venous thrombosis,
etc )
6. Cardiovascular disease-related requirement for daily supplemental oxygen
7. History of two or more MIs OR two or more coronary revascularization procedures
8. Patients with history of myocarditis, regardless of aetiology
14. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Patients with TnT or TnI levels
between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are =1 x
ULN. If TnT or TnI levels are >1 to 2 × ULN within 24 hours, the patient may undergo a
cardiac evaluation and be considered for treatment based on the discretion of the PI.
When repeat levels within 24 hours are not available, a repeat test should be
conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x
ULN, the patient may undergo a cardiac evaluation and be considered for treatment,
based on the discretion of the CI
15. Patients with a history of interstitial lung disease or radiological evidence of
pulmonary fibrosis
16. Persisting toxicity related to prior therapy (NCI CTCAE v. 5.0 Grade > 1) except
alopecia, sensory neuropathy Grade = 2, or other Grade = 2 not constituting a safety
risk based on investigator's judgment are acceptable
17. Pregnancy or lactation (females of childbearing potential must have a negative
pregnancy test within 3 days prior to treatment initiation and every month during
treatment
18. Known alcohol or drug abuse
19. Other severe acute or chronic medical conditions including colitis, inflammatory bowel
disease, pneumonitis, pulmonary fibrosis 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
20. Any psychiatric condition that would prohibit the understanding or rendering of
informed consent
21. Vaccination within 4 weeks of the first dose of study drugs and while on trial is
prohibited except for administration of inactivated vaccines
22. A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year
prior to informed consent
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