An open-label, single-arm, phase II, multicentre clinical trial to determine the rate of durable clinical benefit of nivolumab in patients with class II expressing microsatellite stable colorectal cancer.

Immuno-oncology is transforming the care of certain patients with cancer. Not all patients respond to these therapies however, and in some common cancers checkpoint blockade has failed to make any real impact. In 2014 there were over 41,000 new cases of colorectal cancer (CRC) in the UK and nearly 16,000 deaths from the disease, making it the second commonest cause of cancer death (Cancer Research UK Cancer Statistics Key Facts). 15% of patients with CRC develop it as a result of deficient mismatch repair (microsatellite instability - MSI): this cohort of patients respond well to PD-1/PD-L1 blockade as these tumours harbour a very high number of mutations thus increasing the likelihood of the presence of immunogenic neo-epitopes which elicit an immune response1. The majority of CRC patients, particularly those with metastatic disease (around 95%), do not display this hyper-mutator phenotype (microsatellite stable (MSS) CRC) and in these patients the results of PD-1/PD-L1 blockade have been disappointing.

In summary, MSS CRC patients with a class II expression appear to represent immunologically a group of MSI-like MSS patients that may respond to usefully to the immunotherapy agent nivolumab as a single agent and thus a trial of nivolumab in patients with class II expression of their cancer cells appears to be highly justified.

Inclusion Criteria:

• Histologically confirmed locally advanced or metastatic MSS CRC with class II expression (greater than 1% cancer cell positivity for class II expression on immunohistochemistry).

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (APPENDIX 1)

• Age ≥ 18 years

• Patients must have completed all standard of care therapy that the treating oncologist deems appropriate. Trial treatment as first line therapy is permitted if the patient has declined standard of care therapy.

• CT scan of chest, abdomen, pelvis within 28 days of registration demonstrating unidimensionally measurable disease as per RECIST version 1.1 (APPENDIX 3).

• Demonstrate adequate haematological function:

  • Platelet count ≥100 x 109 /L
  • Neutrophils ≥1.5 x 109/L
  • Haemoglobin ≥ 90 g/L

• Demonstrate adequate hepatic function:

  • Serum bilirubin ≤1.5 x upper limit of normal (ULN)
  • Serum AST or ALT ≤2.5 x ULN or <5 x ULN in the presence of liver metastases

• Demonstrate adequate renal function

  o Creatinine clearance <1.5 times ULN and >30ml/min (as per institutional standard).

• Provision of signed and dated, written informed consent prior to any trial specific procedures, sampling and analyses.

• Negative pregnancy test (female patients of reproductive potential). (Serum Test must be negative)

• Patients must agree to the use of contraception as detailed in section 7.8

Exclusion Criteria:

• Previous treatment with PD1/PDL1 inhibitors.

  • Untreated symptomatic brain or leptomeningeal metastatic disease.
  • Medical or psychiatric conditions compromising informed consent.
  • Any medical condition which, in the opinion of the Investigator, would compromise the ability of the patient to participate in the trial or which would jeopardise compliance with the protocol.
  • Administration of chemotherapy, radioactive or biological cancer therapy within 4 weeks prior to the first dose of trial therapy Patient has not recovered to CTCAE grade 1 or better from the Adverse Event (AE) due to cancer therapeutics administered more than 4 weeks earlier.
  • 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, etc.) is not considered a form of systemic treatment.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patient has risk factors for bowel obstruction or bowel perforation (examples include but not limited to a history of acute diverticulitis, intra-abdominal abscess and abdominal carcinomatosis).
• Patient has a known history of other malignancy, unless the patient has undergone potentially curative therapy with no evidence of that disease for 3 years.
• Has a history of non-infectious pneumonitis requiring steroids or has active pneumonitis.
• Female patients that are either pregnant or breast feeding.
• Male and female patients (of childbearing age) not willing to use adequate contraception.
• Patient previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody.
• Patient is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected); patients with negative Hepatitis C antibody testing may not need RNA testing.
• Known history of tuberculosis.
• Patient has an active infection requiring therapy.
• Has received a live vaccine within 30 days prior to the first dose of trial treatment.
• Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).