CompletedNCT03981146ANICCAUpdated Apr 22, 2026Results posted

A Phase II Trial Assessing Nivolumab in Class II Expressing Microsatellite Stable Colorectal Cancer

A Phase 2 interventional study of Nivolumab in Colorectal Cancer, sponsored by University of Birmingham. Completed at 14 sites in United Kingdom. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-04-22.

Sponsored by University of Birmingham · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 35
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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.

Conditions studied

Colorectal Cancer

Browse trials for

Colorectal Neoplasms 5,599

Keywords

Class II Microsatellite Status

In context

Colorectal Neoplasms

5,599 studies on the registry are indexed under Colorectal Neoplasms; 1,459 are open to participants now.

This study's enrollment of 35 is below the median of 77 across 4,123 interventional studies indexed under Colorectal Neoplasms.

Browse Colorectal Neoplasms studies →

Lead sponsor

University of Birmingham is the lead sponsor of 179 studies on the registry; 30 are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

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

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).

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 35 participants (actual)

Study arms

Experimental
Nivolumab
Patients will receive 480mg of Nivolumab on a four weekly cycle for a maximum of two years.
Drug: Nivolumab

Interventions

DrugNivolumab
60 Minute IV Infusion
Also known as: Opdivo

What researchers measure

Primary outcomes

Durable Clinical Benefit
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
Time frame: Beginning of trial treatment to free of disease progression (104 weeks maximum)

Secondary outcomes

Objective Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) assessed by CT scan, objective response is the occurrence of Complete Response (CR) or Partial Response (PR) as the best overall response. Best overall response is the combined evaluation of target and non-target lesions, as provided in the protocol appendix 3. Target lesions are evaluated as Complete Response (CR; disappearance of all target lesions), Partial Response (PR; \>=30% decrease in the sum of the longest diameter), Progressive Disease (PD; \>=20% increase in the sum of the longest diameter) or Stable Disease (SD; insufficient shrinkage for PR or insufficient increase for PD). Non-target lesions are evaluated as Complete Response (CR; disappearance of all non-target lesions), Incomplete Response/Stable Disease (SD; persistence of non-target lesions) or Progressive Disease (PD; new lesions and/or progression of existing non-target lesions).
Time frame: Trial treatment until disease progression (104 weeks maximum)
Best Percentage Change in Sum of Target Lesions
At each evaluation, the longest diameters of all selected target lesions will be measured and summed and the percentage change from the baseline measurement will be calculated. The best percentage change is the one that reflects either the greatest decrease or the least increase over the whole period of assessment.
Time frame: Trial Treatment to disease progression (104 weeks maximum)
Time to Maximal Response
Time to maximal response was defined to be the time from commencement of trial treatment to the date of CT/MRI that first records objective response as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) version 1.1. Objective response is the occurrence of Complete Response (CR) or Partial Response (PR) as patient's best overall response (see Secondary Outcome: Objective Response).
Time frame: Occurrence of CR or PR during the trial (104 weeks maximum)
Progression Free Survival Time
This is defined as the time from commencement of trial treatment to the date of CT scan when progressive disease first recorded or date of death without previously recorded progression.first records the best objective response as per RECIST version 1.1.
Time frame: time from commencement of trial treatment to the date of CT scan when progressive disease first recorded (104 weeks maximum)
Overall Survival Time
This is defined as the time from commencement of trial treatment to the date of death from any cause.
Time frame: 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.

Results

Posted Apr 22, 2026

Participant flow

Participant flow — Overall Study
Milestone	Nivolumab
Started	35
Completed	35
Not completed	0

Outcome measures

PrimaryDurable Clinical Benefit

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

Time frame:: Beginning of trial treatment to free of disease progression (104 weeks maximum)
Reported as:: Count of participants · Participants

Durable Clinical Benefit
Participants	Nivolumab
DCB	3
Non-DCB	32

SecondaryObjective Response

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) assessed by CT scan, objective response is the occurrence of Complete Response (CR) or Partial Response (PR) as the best overall response. Best overall response is the combined evaluation of target and non-target lesions, as provided in the protocol appendix 3. Target lesions are evaluated as Complete Response (CR; disappearance of all target lesions), Partial Response (PR; \>=30% decrease in the sum of the longest diameter), Progressive Disease (PD; \>=20% increase in the sum of the longest diameter) or Stable Disease (SD; insufficient shrinkage for PR or insufficient increase for PD). Non-target lesions are evaluated as Complete Response (CR; disappearance of all non-target lesions), Incomplete Response/Stable Disease (SD; persistence of non-target lesions) or Progressive Disease (PD; new lesions and/or progression of existing non-target lesions).

Time frame:: Trial treatment until disease progression (104 weeks maximum)
Reported as:: Count of participants · Participants

Objective Response
Participants	Nivolumab
Objective Response Not Achieved	35
Objective Response Achieved	0

SecondaryBest Percentage Change in Sum of Target Lesions

At each evaluation, the longest diameters of all selected target lesions will be measured and summed and the percentage change from the baseline measurement will be calculated. The best percentage change is the one that reflects either the greatest decrease or the least increase over the whole period of assessment.

Time frame:: Trial Treatment to disease progression (104 weeks maximum)
Reported as:: Mean · % change

Best Percentage Change in Sum of Target Lesions
% change	Nivolumab
Best Percentage Change in Sum of Target Lesions	21.1 ± 18.0

SecondaryTime to Maximal Response

Time to maximal response was defined to be the time from commencement of trial treatment to the date of CT/MRI that first records objective response as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) version 1.1. Objective response is the occurrence of Complete Response (CR) or Partial Response (PR) as patient's best overall response (see Secondary Outcome: Objective Response).

Time frame:: Occurrence of CR or PR during the trial (104 weeks maximum)

No measurements were reported for this outcome.

SecondaryProgression Free Survival Time

This is defined as the time from commencement of trial treatment to the date of CT scan when progressive disease first recorded or date of death without previously recorded progression.first records the best objective response as per RECIST version 1.1.

Time frame:: time from commencement of trial treatment to the date of CT scan when progressive disease first recorded (104 weeks maximum)
Reported as:: Mean · Weeks

Progression Free Survival Time
Weeks	Nivolumab
Progression Free Survival Time	9.0 (8.7 to 9.7)

SecondaryOverall Survival Time

This is defined as the time from commencement of trial treatment to the date of death from any cause.

Time frame:: 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.
Reported as:: Mean · Months

Overall Survival Time
Months	Nivolumab
Overall Survival Time	7.2 (4.0 to 11.9)

Adverse events

Collected over From the date of trial consent until 6 months after treatment discontinuation. If at the 6 month review time-point, any toxicities at grade 2 or higher related to trial treatment were still occurring, these were to be followed up until resolution or grade reduction to grade 1, for a minimum of 18 months post-registration, if trial treatment was discontinued early, or up to 24 months post-registration for those completing trial treatment.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Nivolumab	29/35 (82.9%)	25/35 (71.4%)	35/35 (100%)

Most frequent serious events

Showing 10 of 29

Most frequent serious events
Event	Nivolumab
Abdominal painGastrointestinal disorders	6/35
FeverGeneral disorders	4/35
AscitesGastrointestinal disorders	2/35
Colonic obstructionGastrointestinal disorders	2/35
Upper gastrointestinal hemorrhageGastrointestinal disorders	2/35
VomitingGastrointestinal disorders	2/35
FatigueGeneral disorders	2/35
Urinary tract infectionInfections and infestations	2/35
Blood bilirubin increasedInvestigations	2/35
Febrile neutropeniaBlood and lymphatic system disorders	1/35

Most frequent other events

Showing 10 of 58

Most frequent other events
Event	Nivolumab
FatigueGeneral disorders	21/35
AnorexiaMetabolism and nutrition disorders	16/35
NauseaGastrointestinal disorders	14/35
Abdominal PainGastrointestinal disorders	13/35
ConstipationGastrointestinal disorders	12/35
DiarrheaGastrointestinal disorders	11/35
VomitingGastrointestinal disorders	10/35
Back PainMusculoskeletal and connective tissue disorders	10/35
DyspneaRespiratory, thoracic and mediastinal disorders	9/35
Urinary Tract InfectionInfections and infestations	8/35

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Nivolumab
Median	63 (37 to 81)

Sex: Female, Male
Sex: Female, Male(Participants)	Nivolumab
Female	16
Male	19

Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)	Nivolumab

Primary Cancer Stage
Primary Cancer Stage(Participants)	Nivolumab
Ascending colon	4
Descending colon	3
Transverse colon	2
Sigmoid colon	14
Rectum	12

Primary Resection Performed
Primary Resection Performed(Participants)	Nivolumab
No	7
Yes	28

RAS Mutations
RAS Mutations(Participants)	Nivolumab
KRAS	16
NRAS	3
BRAF	1
Not Known	15

Previous Lines of Therapy
Previous Lines of Therapy(Number of Lines of Therapy)	Nivolumab
Median	6 (1 to 16)

ECOG Performance Status
ECOG Performance Status(Participants)	Nivolumab
0	11
1	23
Not Known	1

3 further baseline measures are reported on the registry.

Study locations

14 sites

Belfast City Hospital
Belfast, United Kingdom
Queen Elizabeth Hospital
Birmingham, United Kingdom
Velindre Cancer Centre
Cardiff, United Kingdom
Western General Hospital
Edinburgh, United Kingdom
St James Leeds
Leeds, LS9 7TF, United Kingdom
Leicester Royal Infirmary
Leicester, LE1 5WW, United Kingdom
Clatterbridge Cancer Centre
Liverpool, United Kingdom
The Royal Free Hospital
London, NW3 2QG, United Kingdom
Guys Hospital
London, United Kingdom
The Royal Marsden NHS Foundation Trust
London, United Kingdom
University College Hospital
London, United Kingdom
The Christie Hospital, The Christie NHS Foundation Trust
Manchester, United Kingdom
Freemans Hospital
Newcastle upon Tyne, United Kingdom
Weston Park
Sheffield, S10 2SJ, United Kingdom

References and documents

Publications

Middleton G, Gaskell C, Savage J, Bridgewater J, Ross P, Saunders M, Palmer D, Plummer R, Clive S, Coyle V, Thomas A, Cunningham D, Taniere P, Billingham L. Final results of ANICCA-Class II, a single arm, open-label phase II trial assessing nivolumab in tissue-specific class II expressing metastatic microsatellite stable colorectal cancer, with a parallel assessment of the immunoscore-immune checkpoint as a predictive biomarker for single-agent anti-PD-1. J Immunother Cancer. 2025 Dec 17;13(12):e012749. doi: 10.1136/jitc-2025-012749. PubMed 41407398 ↗

Study documents

Study protocol · Nov 1, 2021
Statistical analysis plan · Dec 2, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Apr 22, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03981146
Lead sponsor: University of Birmingham
Collaborators: Bristol-Myers Squibb
Responsible party: Sponsor
First posted: Jun 10, 2019
Start date: Aug 28, 2019
Primary completion: Nov 26, 2024
Completion: Nov 26, 2024
Results posted: Apr 22, 2026
Last update: Apr 22, 2026

Study contacts

Gary Middleton, MB,BS,FRCP

principal investigator · University of Birmingham

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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