The purpose of this study is to investigate the safety and effects of IMM 101 in combination with a single targeted dose of radiation in patients with metastatic colorectal cancer in whom chemotherapy or other treatment has not been effective. Administration of radiation (using the CyberKnife) to the target tumour growth in the liver results in the release of tumour material. IMM-101 may help the immune system to react to the tumour material released from the damaged tumour, and so have a beneficial effect in slowing down the rate of growth of other tumour growths in the liver and other organs.

Radiotherapy given in standard fractionation regimes leads to cell death by causing double stranded DNA breaks via production of oxygen free radicals. At the very high doses of stereotactic body radiotherapy (SBRT) administered with extreme accuracy in a single fraction by the CyberKnife system, there is induction of tumour necrosis due to endothelial cell damage and vascular collapse, cell membrane breakdown, and the release of cellular material and tumour antigens into the circulation, in addition to DNA strand breaks. It is hypothesised that the combination of modulation of the body's immune responses in the presence of an increased exposure to tumour antigen will provide sufficient induction of the immune system to suppress tumour growth.

Inclusion criteria:

Male or female; aged ≥ 18 years. Histologically confirmed colorectal adenocarcinoma. Documented evidence of disease progression following at least one line of chemotherapy.

No further standard chemotherapy options available have refused further chemotherapy.

Metastatic lesions in at least two sites in the liver (+/- other sites) suitable for bidimensional and volumetric evaluation by CT scan.

World Health Organization (WHO) performance status of 0-2. Cockcroft calculated Glomerular Filtration Rate of > 40mL/min at screening. Life expectancy, in the opinion of the Investigator, of > 3 months from screening.

Exclusion Criteria:

Evidence of central nervous system metastasis. Severe, active uncontrolled infection requiring systemic antibiotics, antiviral or antifungal treatments.

Any previous or concurrent malignancy, except adequately treated carcinoma in situ of the cervix, basal cell carcinoma of the skin and/or non-melanoma skin cancer, or if previous malignancy was more than 5 years earlier and there are no signs of recurrence.

Serum albumin < 30 g/L at screening. C-reactive protein (CRP) > 70 mg/L at screening. Transaminases (ALT or AST) > 5 X Upper Limit of Normal at screening. Bilirubin level > 2 X Upper Limit of Normal at screening. Radiotherapy in the 12 weeks before screening. Depot corticosteroid use in the 6 weeks before screening. Chronic use of any systemic corticosteroids (> 10 mg per day of prednisolone or equivalent for a period of 2 weeks or more) and/or immunosuppressant drugs (such as azathioprine, tacrolimus, cyclosporin) within the 2-week period before the first administration of study drug.

Woman of child-bearing potential who is not using an approved method of birth control Any investigational product administration in the 3 months before screening. Contraindication to CT scan, e.g., allergy to iodine based contrast medium. A surgical or medical condition which, in the judgement of the Investigator, might interfere with the activity of IMM-101, or with the performance of this study.

Any uncontrolled concomitant disease which, in the judgement of the Investigator, might interfere with the activity of IMM-101, or with the performance of this study.

History of serious adverse reaction or serious hypersensitivity to any drug that in the opinion of the Investigator may raise a safety concern.

Any previous treatment with IMM-101 or related mycobacterial immunotherapy (prior bacillus Calmette-Guerin (BCG) vaccination against Tuberculosis is allowed).

Known history of human immunodeficiency virus (HIV) or syphilis, current symptomatic Hepatitis B or C.

Unable or unwilling to comply with the protocol.

From screening until end of study (up to 54 weeks)

It was the responsibility of the investigator to report any directly observed AEs and AEs reported spontaneously by the patient, throughout the study after patient consent, and for IMM-101-related AEs, up to 30 days after the last study visit.

The success criteria for the study as a whole, including progression to the second stage, were challenging. With hindsight, a larger sample size facilitating analysis of a less demanding, but still clinically meaningful, treatment effect might have been more appropriate and would be recommended for any future similar investigations.