A Study of IMM-101 in Combination With Radiation Induced Tumour Necrosis in Colorectal Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II, Single Arm, Investigative Study of IMM-101 in Combination With Radiation Induced Tumour Necrosis in Patients With Previously Treated Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Biological: Mycobacterium obuense
* Radiation: SBRT


Participation Criteria
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Eligibility Criteria
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Patients are eligible to be included in the study if they: Are male or female; aged ≥ 18 years. Have a histologically confirmed colorectal adenocarcinoma. Have documented evidence of disease progression following at least one line of chemotherapy. Have no further standard chemotherapy options available have refused further chemotherapy. Have metastatic lesions in at least two sites in the liver (+/- other sites) suitable for bidimensional and volumetric evaluation by CT scan. Have WHO performance status of 0-2. Have a Cockcroft calculated Glomerular Filtration Rate of > 40mL/min at screening. Have a life expectancy, in the opinion of the Investigator, of > 3 months from screening. Patients are not eligible if one or more of the following statements are applicable: Patient has evidence of central nervous system metastasis. Patient has severe, active uncontrolled infection requiring systemic antibiotics, antiviral or antifungal treatments. Patient has 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. Patient has serum albumin < 30 g/L at screening. Patient has a C-reactive protein (CRP) > 70 mg/L at screening. Patient has transaminases (ALT or AST) > 5 X Upper Limit of Normal at screening. Patient has a bilirubin level > 2 X Upper Limit of Normal at screening. Patient has had radiotherapy in the 12 weeks before screening. Patient has used depot corticosteroids in the 6 weeks before screening. Patient has had 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. Patient of child-bearing potential who is not using an approved method of birth control (e.g., physical barrier [patient and partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device [IUD]). Those patients that utilise hormonal contraceptives must have used the same method for at least three months before study dosing. Patients of non-child-bearing potential are defined as having 12 month amenorrhoea or are surgically sterile. Patient who is pregnant, breast feeding or planning a pregnancy during the course of the study. Where appropriate, a pre-treatment serum pregnancy test measuring human chorionic gonadotrophin (hCG) must be negative. Patient has been administered any investigational product in the 3 months before screening. Contraindication to CT scan, e.g., allergy to iodine based contrast medium. Patient has 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. Patient has presence of any uncontrolled concomitant disease (e.g., unstable angina pectoris, congestive heart failure, myocardial infarction, cardiac arrhythmias, uncontrolled severe hypertension) which, in the judgement of the Investigator, might interfere with the activity of IMM-101, or with the performance of this study. Patient has a history of serious adverse reaction or serious hypersensitivity to any drug that in the opinion of the Investigator may raise a safety concern. Patient has had any previous treatment with IMM-101 or related mycobacterial immunotherapy (prior BCG vaccination against TB is allowed). Patient is known to have a history of human immunodeficiency virus (HIV) or syphilis, current symptomatic Hepatitis B or C. Patient is unable or unwilling to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMM-101 plus SBRT<br>The treatment regimen with IMM-101 (Mycobacterium obuense) will be every 2 weeks for the first three doses with the last of these doses being on the same day as the radiotherapy by CyberKnife treatment on a liver lesion targeted by the Principal Investigator. Following a rest of 4 weeks, patients will again receive IMM-101 every 2 weeks for the next 3 doses followed by a further 4 weeks rest. Thereafter, IMM-101 will be given at 4 week intervals for up to 12 months or until patient withdrawal for any reason | Biological: Mycobacterium obuense<br>* IMM-101 is a suspension of heat-killed whole cell M. obuense in borate-buffered saline.<br>* Other names: IMM-101;Radiation: SBRT<br>* The CyberKnife system is normally used for the treatment of cancerous tumours in cases where the type and position of the tumour and the condition of the patient indicate that treatment may be curative. In this study, the CyberKnife is being used in an experimental way to deliver a targeted dose of stereotactic body radiation with extreme accuracy in order to damage a single tumour growth (metastasis) in the liver.<br>* Other names: CyberKnife;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease stabilisation rate | The disease stabilisation rate at 24 weeks defined as the proportion of patients with a complete response, partial response or stable disease in accordance with immune-related response criteria. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and tolerability profiles | No clinically relevant deleterious effect of IMM-101 on safety and tolerability profiles as judged by: Local and systemic toxicities. Number, type and degree of toxicities as measured by the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) v4.0. Safety and tolerability will be monitored through the study by a Data Monitoring Committee (DMC) | 48 weeks | 
| Objective response rate |  | 12, 24, 36 and 48 weeks | 
| Disease stabilisation rate |  | 12, 36 and 48 weeks | 
| Overall disease stabilisation rate |  | End of study | 
| Overall response rate |  | End of study | 
| Progression-free survival |  | 12, 24, 36 and 48 weeks | 
| Survival |  | 12, 24, 36 and 48 weeks | 
| Tumour Markers |  | 12, 24, 36 and 48 weeks |