A phase II trial to find the durable clinical benefit of nivolumab in class II expressing microsatellite colorectal cancer

ISRCTN	ISRCTN40245896
DOI	https://doi.org/10.1186/ISRCTN40245896
EudraCT/CTIS number	2018-000318-39
IRAS number	237804
ClinicalTrials.gov number	NCT03981146
Secondary identifying numbers	CPMS 37422, IRAS 237804

Submission date: 01/04/2019
Registration date: 04/04/2019
Last edited: 12/12/2023

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-nivolumab-for-advanced-bowel-cancer-anicca-class-ii

Study website

Contact information

Dr Joshua Savage
Scientific

Cancer Research UK Clinical Trials Unit
University of Birmingham
Vincent Drive
Edgbaston
Birmingham
B15 2TT
United Kingdom

ORCID ID	0000-0003-0599-0245
Phone	+44 (0)121 414 6754
Email	Anicca-classii@trials.bham.ac.uk

Prof Gary Middleton
Scientific

University of Birmingham
Institute of Cancer & Genomic Sciences
Vincent Drive
Birmingham
B15 2TT
United Kingdom

ORCID ID	0000-0001-5695-3474
Phone	+44 (0)1214158237
Email	g.middleton@bham.ac.uk

Study information

Study design	Non-randomised; Interventional; Design type: Treatment, Screening, Immunotherapy
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	A phase II trial assessing nivolumab in class II expressing microsatellite stable colorectal cancer
Study acronym	ANICCA-Class II
Study objectives	The primary objective of this trial is to detect the rate of durable clinical benefit in patients with class II expressing microsatellite stable colorectal cancer treated with single-agent nivolumab, to justify further investigation in subsequent studies. The secondary objectives will be to evaluate the benefit to patients in terms of other clinical outcomes, to include: 1. Objective response rate 2. Best percentage change in sum of target lesion diameters 3. Time to maximal response 4. Progression-free survival time 5. Overall survival time
Ethics approval(s)	Approved 11/06/2019, South Central – Oxford B Research Ethics Committee (Whitefriars, Level 3, Block B, Lewins Mead, Bristol, BS1 2NT, United Kingdom; +44 (0)20 7104 8049; nrescommittee.southcentral-oxfordb@nhs.net), ref: 19/SC/0107
Health condition(s) or problem(s) studied	Colorectal cancer
Intervention	Informed consent: Patients potentially suitable for the trial will be identified at an oncology clinic, and will be approached about the trial with the aid of the patient information sheet. After discussion about the trial and sufficient time to consider whether they wish to take part (usually at least 24 hours), the patient will be asked to sign an informed consent form in the presence of the research doctor. They will initially be provided with an information sheet explaining the purpose of the biopsy screening assessment and provide consent for this to be done. If MSS CRC with class II levels are demonstrated they will then be provided with the information sheet for the main trial and provide further consent to take part. Screening investigations: Following the informed consent process, the patient will undergo screening assessments. These will include: Full medical history - To include smoking and alcohol history, any relevant significant medical conditions (other than colorectal cancer) and autoimmune conditions, history of treatment for the primary diagnosis, including prior systemic treatment, radiation treatment and surgical treatment including best response to prior treatments where applicable. Date of last prior cancer treatment must be documented. Radiographic studies performed prior to trial entry may also be requested for review. 1. Coagulation parameters: Prothrombin (PT) / International Normalised Ratio (INR) and partial thromboplastin (aPTT) 2. CT scan with contrast – chest, abdomen and pelvis within 28 days of planned treatment date (RECIST v1.1 reporting). 3. Hepatitis C Virus (HCV) RNA (qualitative), Hepatitis B Surface Antigen and Human Immunodeficiency Virus (HIV) 1 / 2 antibodies. The following screening tests should be undertaken locally up to 7 days prior to trial registration: 1. Physical examination including height and weight 2. Vital signs - temperature, pulse, respiratory rate and blood pressure (average of 3 BP readings) 3. ECOG performance status 4. Adverse events - Adverse Events (AEs) and laboratory safety measurements will be graded per NCI Common Terminology Criteria for Adverse Events (CTCAE) version v4.03 . All adverse events, whether gradable by CTCAE or not, will also be evaluated for seriousness 5. Concomitant medications – taken within four weeks prior to registration. 6. Full blood count (FBC) to include: white blood cells, haematocrit, haemoglobin, platelets, neutrophils, lymphocytes, red blood cells, monocytes, basophils, eosinophils, absolute neutrophil count 7. Urinalysis 8. Pregnancy test if applicable (urine or serum β-HCG) 9. Comprehensive serum chemistry panel to include: sodium, potassium, urea, nitrogen, creatinine, magnesium, calcium (total), bilirubin (total), direct bilirubin, albumin, alkaline phosphatase (ALP), aspartate transferase (AST), alanine transferase (ALT), glucose, lactate dehydrogenase (LDH), phosphate, total protein, C reactive protein (CRP), Carcinoembryonic antigen (CEA) 10. Renal function - Patients must have adequate renal function as defined by Creatinine clearance <1.5 x ULN concurrent with creatinine clearance >50 ml/min (calculated as per institutional standard) 11. Thyroid function and cortisol - analysis of cortisol, T3, T4 and Thyroid Stimulating Hormone (TSH) Up to 24 hours to first treatment: 1. Urine pregnancy test, if cannot be confirmed as negative a serum test will be required Treatment: Nivolumab will be administered as a 60 minute IV infusion, with a window of -5 and +10 minutes, at a dose of 3 mg/kg on day 1 every 2 weeks. Patients will receive nivolumab for a maximum of 2 years and enter then enter the follow-up period. Updated 05/08/2020: Treatment: Nivolumab will be administered as a 60 minute IV infusion, with a window of -5 and +10 minutes, at a dose of 480 mg every 28 days (4 weeks). Patients will receive nivolumab for a maximum of 2 years and enter then enter the follow-up period. Routine and safety tests: 1. Physical examination including vital signs and measure of ECOG performance status 2. Routine blood samples for the analysis of haematology, biochemistry, thyroid function and cortisol 3. A CT scan of the chest, pelvis and abdomen 4. Adverse event review 5. Concomitant medication review Research procedures: 1. A DNA sample (at baseline only) 2. ctDNA blood samples (at baseline, every 8 weeks and end of treatment) 3. Cytokine/chemokine and proteomics blood samples (at baseline, every 8 weeks and end of treatment) Treatment discontinuation: When a patient completes (or discontinues early) trial therapy, they will undergo the same tests performed throughout treatment at their end of treatment visit. The timing of all investigations and sampling are detailed in the protocol and the relevant Patient Information Sheet. Follow up: A mandatory Safety Follow-Up Visit should be performed approximately 28 days after the last infusion of study medication, and include: 1. Physical examination including vital signs and measure of ECOG performance status 2. Routine blood samples for the analysis of haematology, biochemistry, thyroid function and cortisol 3. Renal function by calculation in the first instance, and measurement is permitted if required 4. Adverse event review 5. Concomitant medication review For patients who begin another cancer therapy before 28 days after discontinuation of study therapy, the Safety Follow-Up Visit should occur prior to the patient receiving another cancer therapy. Follow up data will be provided every 4 weeks up to 6 months post treatment discontinuation then every 12 weeks up to five years to obtain disease progression details (if patient discontinued for non-progression reasons), record treatment after progression and death date if applicable.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Nivolumab
Primary outcome measure	Durable clinical benefit (DCB) defined as the occurrence of complete response (CR), partial response (PR) or stable disease (SD) for 27 weeks or greater
Secondary outcome measures	1. Objective response: overall tumour burden assessed using RECIST version at CT scans every 9 weeks from trial entry up to 45 weeks, then every 12 weeks, until disease progression 2. Best percentage change in sum of target lesion diameters - 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. 3. Time to maximal response, defined as the time from commencement of trial treatment to the date of CT scan that first records the best objective response as per RECIST 4. Progression-free survival time, 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 5, Overall survival time, defined as the time from commencement of trial treatment to the date of death
Overall study start date	01/12/2017
Completion date	01/12/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 36; UK Sample Size: 36
Key inclusion criteria	Current inclusion criteria as of 05/08/2020: 1. Histologically confirmed locally advanced or metastatic MSS CRC with class II expression (greater than 1% cancer cell positivity for class II expression on immunohistochemistry) 2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 3. Age > = 18 years 4. 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 5. CT scan of chest, abdomen, pelvis within 28 days of registration demonstrating uni-dimensionally measurable disease as per RECIST version 1.1 6. Demonstrate adequate haematological function: 6.1. Platelet count > = 100 x 109 /L 6.2. Neutrophils > = 1.5 x 109/L 6.3. Haemoglobin > = 90 g/L 7. Demonstrate adequate hepatic function: 7.1. Serum bilirubin < = 1.5 x upper limit of normal (ULN) 7.2. Serum AST or ALT < = 2.5 x ULN or < 5 x ULN in the presence of liver metastases 8. Demonstrate adequate renal function: 8.1. Creatinine clearance < 1.5 times ULN and > 30ml/min (as per institutional standard) 9. Provision of signed and dated, written informed consent prior to any trial-specific procedures, sampling and analyses. 10. Negative pregnancy test (female patients of reproductive potential) 11. Patients must agree to the use of contraception Previous inclusion criteria: 1. Histologically confirmed locally advanced or metastatic MSS CRC with strong class II expression (greater than 50% cancer cell positivity for class II expression on immunohistochemistry) 2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 3. Age > = 18 years 4. 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 5. CT scan of chest, abdomen, pelvis within 28 days of registration demonstrating uni-dimensionally measurable disease as per RECIST version 1.1 6. Demonstrate adequate haematological function: 6.1. Platelet count > = 100 x 109 /L 6.2. Neutrophils > = 1.5 x 109/L 6.3. Haemoglobin > = 90 g/L 7. Demonstrate adequate hepatic function: 7.1. Serum bilirubin < = 1.5 x upper limit of normal (ULN) 7.2. Serum AST or ALT < = 2.5 x ULN or < 5 x ULN in the presence of liver metastases 8. Demonstrate adequate renal function: 8.1. Creatinine clearance < 1.5 times ULN and > 30ml/min (as per institutional standard) 9. Provision of signed and dated, written informed consent prior to any trial-specific procedures, sampling and analyses. 10. Negative pregnancy test (female patients of reproductive potential) 11. Patients must agree to the use of contraception
Key exclusion criteria	1. Previous treatment with PD1/PDL1 inhibitors 2. Untreated symptomatic brain or leptomeningeal metastatic disease 3. Medical or psychiatric conditions compromising informed consent 4. 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 5. Administration of chemotherapy, radioactive or biological cancer therapy within 4 weeks prior to the first dose of trial therapy 6. 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 7. 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 8. 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 9. 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) 10. 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 11. Has a history of non-infectious pneumonitis requiring steroids or has active pneumonitis or significantly reduced transfer coefficient (KCO) 12. Female patients that are either pregnant or breastfeeding 13. Male and female patients (of childbearing age) not willing to use adequate contraception 14. Patient previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody 15. 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 16. Known history of tuberculosis 17. Patient has an active infection requiring therapy 18. Has received a live vaccine within 30 days prior to the first dose of trial treatment 19. 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)
Date of first enrolment	28/08/2019
Date of final enrolment	06/09/2021

Locations

Countries of recruitment

England
Northern Ireland
Scotland
United Kingdom

Study participating centres

University Hospitals Birmingham NHS Foundation Trust

Address Trust HQ
PO Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom

NHS Greater Glasgow and Clyde

J B Russell House
Gartnavel Royal Hospital
1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

The Christie NHS Foundation Trust

550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom

University College London Hospitals NHS Foundation Trust

250 Euston Road
London
NW1 2PG
United Kingdom

Guy's and St Thomas' NHS Foundation Trust

Trust Offices
Guy's Hospital
Great Maze Pond
London
SE1 9RT
United Kingdom

Belfast Health & Social Care Trust

Knockbracken Healthcare Park
Saintfield Road
Belfast
BT8 8BH
United Kingdom

The Royal Marsden NHS Foundation Trust

Fulham Road
London
SW3 6JJ
United Kingdom

Leeds Teaching Hospitals NHS Trust

St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

University Hospitals of Leicester NHS Trust

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

Western General Hospital

Crewe Rd S
Edinburgh
EH4 2XU
United Kingdom

Freemans Hospital

Freeman Rd
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Clatterbridge Cancer Centre

Clatterbridge Rd
Birkenhead
Wirral
CH63 4JY
United Kingdom

Sponsor information

University of Birmingham
University/education

Research Support Group
Aston Webb Building (B Block)
Birmingham
B15 2TT
England
United Kingdom

Phone	+44 (0)121 415 8011
Email	researchgovernance@Contacts.bham.ac.uk
"ROR"	https://ror.org/03angcq70

Funders

Funder type

Industry

Bristol-Myers Squibb
Government organisation / For-profit companies (industry)

Alternative name(s): Bristol-Myers Squibb Company, BMS
Location: United States of America

Results and Publications

Intention to publish date	01/12/2024
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	1. Peer reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website
IPD sharing plan	Current IPD sharing plan as of 12/12/2023: For ANICCA-Class II data, scientifically sound proposals from appropriately qualified Research Groups will be considered for data sharing. Requests should be made by returning a completed Data Sharing Request Form and curriculum vitae of the lead applicant and statistician to newbusiness@trials.bham.ac.uk. The Data Sharing Request Form captures information on the specific requirements of the research, the statistical analysis plan, and the intended publication schedule. The request will be reviewed independently by the Cancer Research UK Clinical Trials Unit (CRCTU) Directors at the University of Birmingham in discussion with the Chief Investigator, relevant Trial Management Group and independent Trial Steering Committee. In making their decision the Director’s Committee will consider the scientific validity of the request, the qualifications of the Research Group, the views of the Chief Investigator, Trial Management Group and Trial Steering Committee, consent arrangements, the practicality of anonymizing the requested data and contractual obligations. Where the CRCTU Directors and appropriate Trial Committees are supportive of the request, and where not already obtained, consent for data transfer will be sought from the Sponsor of the trial before notifying the applicant of the outcome of their request. It is anticipated that applicants will be notified of a decision within 3 months of receipt of the original request. Previous IPD sharing plan as of 07/12/2023 to 12/12/2023: The datasets generated during and/or analysed during the current study are/will be available upon request. Previous IPD sharing plan: The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Abstract results		13/09/2022	07/12/2023	No	No

Editorial Notes

12/12/2023: The following changes were made:
1. ORCID IDs were added.
2. The public contact was changed.
3. The IRAS number was added.
4. The individual participant data (IPD) sharing plan and summary were updated.
07/12/2023: The following changes were made:
1. Abstract uploaded.
2. The intention to publish date was changed from 01/12/2026 to 01/12/2024.
3. The individual participant data (IPD) sharing plan and summary were changed.
09/09/2021: The recruitment end date has been changed from 01/12/2021 to 06/09/2021.
02/12/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/12/2020 to 01/12/2021.
2. The overall trial end date was changed from 01/12/2027 to 01/12/2025.
3. The intention to publish date was changed from 01/12/2028 to 01/12/2026.
06/08/2020: Internal review.
05/08/2020: The following changes were made to the trial record:
1. "Strong class II" and "high class II" were changed to "class II" throughout the trial record.
2. The inclusion criteria and interventions were updated.
3. Contact details updated.
4. Recruitment has resumed at “The Christie NHS Foundation Trust” and “University College London Hospitals NHS Foundation Trust”, and remains paused at “The Royal Marsden NHS Foundation Trust”.
18/06/2020: Trial website added.
27/04/2020: Due to current public health guidance, recruitment for this study has been paused at “The Christie NHS Foundation Trust”, “University College London Hospitals NHS Foundation Trust”, and “The Royal Marsden NHS Foundation Trust”. The trial participating centres "Western General Hospital", "Freemans Hospital", and "Clatterbridge Cancer Centre" have been added.
08/11/2019: Internal review.
28/10/2019: The recruitment start date was changed from 01/05/2019 to 28/08/2019, ClinicalTrials.gov number and ethics approval date added.
11/10/2019: Cancer Research UK lay summary link added to plain English summary field.
05/08/2019: Internal review.
21/06/2019: Internal review.
04/04/2019: Trial's existence confirmed by the NIHR.