Metastatic Colorectal Cancer
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALMycobacterium obuense
IMM-101 is a suspension of heat-killed whole cell M. obuense in borate-buffered saline.
RADIATIONSBRT
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.
Sponsors
Immodulon Therapeutics Ltd
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Stabilisation Rate | 24 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 12, 24, 36 and 48 weeks | Patients with an objective response were those who had a complete (CR) or partial response (PR), or stable disease(SD) based on CT scan findings, absence of clinical signs and symptoms of progression, did not withdraw due to disease progression prior to/at the Week 12/ 24 /36 / 48 assessment and were alive at the relevant assessment point |
| Disease Stabilisation Rate | 12, 36 and 48 weeks | Patients with disease stabilisation were those who had CR, PR, or SD based on CT scan findings, absence of clinical signs and symptoms of progression, did not withdraw due to disease progression prior to/at the Week 24, 36 or 48 assessment and were alive at the respective assessment. |
| Safety and Tolerability Profiles | 48 weeks | 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 are be monitored through the study by a Data Monitoring Committee (DMC) |
| Overall Response Rate | 12, 24, 36 and 48 weeks. | The overall response rate will be recorded as the percentage of patients with a CR or PR as best overall response. |
| Survival | 12, 24, 36 and 48 weeks | The number of patients alive at 12, 24, 36 & 48 weeks. Patients without a date of death were to be censored at the date the patient was last known to be alive. The protocol made provision for patients to continue to be followed up and data to be collected, post study withdrawal. |
| Overall Disease Stabilisation Rate | 12, 36 and 48 weeks. | The overall disease stabilisation rate was recorded as the percentage of patients with a CR, PR or SD as best overall response and was to be assessed at 12, 24 (primary time point), 36 and 48 weeks and overall. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IMM-101 Plus SBRT 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
Mycobacterium obuense: IMM-101 is a suspension of heat-killed whole cell M. obuense in borate-buffered saline.
SBRT: 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. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | IMM-101 Plus SBRT |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
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.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMM-101 Plus SBRT | Disease Stabilisation Rate | 0 Participants |
Secondary
Disease Stabilisation Rate
Patients with disease stabilisation were those who had CR, PR, or SD based on CT scan findings, absence of clinical signs and symptoms of progression, did not withdraw due to disease progression prior to/at the Week 24, 36 or 48 assessment and were alive at the respective assessment.
Time frame: 12, 36 and 48 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 Plus SBRT | Disease Stabilisation Rate | Number of patients with disease stabilisation at Week 12 | 0 Participants |
| IMM-101 Plus SBRT | Disease Stabilisation Rate | Number of patients with disease stabilisation at Week 36 | 0 Participants |
| IMM-101 Plus SBRT | Disease Stabilisation Rate | Number of patients with disease stabilisation at Week 48 | 0 Participants |
Secondary
Objective Response Rate
Patients with an objective response were those who had a complete (CR) or partial response (PR), or stable disease(SD) based on CT scan findings, absence of clinical signs and symptoms of progression, did not withdraw due to disease progression prior to/at the Week 12/ 24 /36 / 48 assessment and were alive at the relevant assessment point
Time frame: 12, 24, 36 and 48 weeks
Population: All enrolled patients who were still in follow up at each timepoint
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 Plus SBRT | Objective Response Rate | Number of patients with objective response at Week 12 | 0 Participants |
| IMM-101 Plus SBRT | Objective Response Rate | Number of patients with objective response at Week 24 | 0 Participants |
| IMM-101 Plus SBRT | Objective Response Rate | Number of patients with objective response at Week 36 | 0 Participants |
| IMM-101 Plus SBRT | Objective Response Rate | Number of patients with objective response at Week 48 | 0 Participants |
Secondary
Overall Disease Stabilisation Rate
The overall disease stabilisation rate was recorded as the percentage of patients with a CR, PR or SD as best overall response and was to be assessed at 12, 24 (primary time point), 36 and 48 weeks and overall.
Time frame: 12, 36 and 48 weeks.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 Plus SBRT | Overall Disease Stabilisation Rate | Overall disease stabilisation rate at Week 12 | 0 Participants |
| IMM-101 Plus SBRT | Overall Disease Stabilisation Rate | Overall disease stabilisation rate at Week 36 | 0 Participants |
| IMM-101 Plus SBRT | Overall Disease Stabilisation Rate | Overall disease stabilisation rate at Week 48 | 0 Participants |
Secondary
Overall Response Rate
The overall response rate will be recorded as the percentage of patients with a CR or PR as best overall response.
Time frame: 12, 24, 36 and 48 weeks.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 Plus SBRT | Overall Response Rate | Overall response rate at Week 12 | 0 Participants |
| IMM-101 Plus SBRT | Overall Response Rate | Overall response rate at Week 24 | 0 Participants |
| IMM-101 Plus SBRT | Overall Response Rate | Overall response rate at Week 36 | 0 Participants |
| IMM-101 Plus SBRT | Overall Response Rate | Overall response rate at Week 48 | 0 Participants |
Secondary
Safety and Tolerability Profiles
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 are be monitored through the study by a Data Monitoring Committee (DMC)
Time frame: 48 weeks
Population: All enrolled patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMM-101 Plus SBRT | Safety and Tolerability Profiles | Serious adverse events (SAE) reported | 0 Adverse event |
| IMM-101 Plus SBRT | Safety and Tolerability Profiles | Adverse events (AE) reported | 156 Adverse event |
Secondary
Survival
The number of patients alive at 12, 24, 36 & 48 weeks. Patients without a date of death were to be censored at the date the patient was last known to be alive. The protocol made provision for patients to continue to be followed up and data to be collected, post study withdrawal.
Time frame: 12, 24, 36 and 48 weeks
Population: One patient died during the study due to the AE of Jaundice (unrelated to IMM-101). The remaining 11 patients died after withdrawal from the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 Plus SBRT | Survival | Number of patients alive at 12 weeks | 10 Participants |
| IMM-101 Plus SBRT | Survival | Number of patients alive at 24 weeks | 6 Participants |
| IMM-101 Plus SBRT | Survival | Number of patients alive at 36 weeks | 3 Participants |
| IMM-101 Plus SBRT | Survival | Number of patients alive at 48 weeks | 2 Participants |