A Phase II Trial Assessing Nivolumab in Class II Expressing Microsatellite Stable Colorectal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Colorectal Cancer
- Sponsor
- University of Birmingham
- Enrollment
- 35
- Locations
- 19
- Primary Endpoint
- Durable Clinical Benefit
- Status
- Completed
- Last Updated
- 10 days ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
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:
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.
Arms & Interventions
Nivolumab
Patients will receive 480mg of Nivolumab on a four weekly cycle for a maximum of two years.
Intervention: Nivolumab
Outcomes
Primary Outcomes
Durable Clinical Benefit
Time Frame: Beginning of trial treatment to free of disease progression (104 weeks maximum)
patient will be defined as experiencing DCB if they remain free of disease progression at their third trial specific CT scan since treatment start date (i.e. at approximately 27 weeks) or at any CT scan after 27 weeks that shows the patient remains free of disease progression
Secondary Outcomes
- Progression Free Survival Time(time from commencement of trial treatment to the date of CT scan when progressive disease first recorded (104 weeks maximum))
- Best Percentage Change in Sum of Target Lesions(Trial Treatment to disease progression (104 weeks maximum))
- Objective response(trial treatment until disease progression (104 weeks maximum))
- Overall Survival Time(Trial Treatment to date of death.)
- Time to Maximal Response(Occurrence of CR or PR during the trial (104 weeks maximum))
- Objective Response(Trial treatment until disease progression (104 weeks maximum))
- Overall Survival Time(Commencement of trial treatment until date of death; minimum of 18 months post-registration, if trial treatment was discontinued early, or up to 24 months post-registration for those completing trial treatment.)