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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Nivolumab

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab; Patients will receive 480mg of Nivolumab on a four weekly cycle for a maximum of two years.	Drug: Nivolumab; 60 Minute IV Infusion; Other Names: Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Beginning of trial treatment to free of disease progression (104 weeks maximum)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response	Objective response is the occurrence of CR or PR as the best overall response	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.	Trial Treatment to disease progression (104 weeks maximum)
Time to Maximal Response	This is 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 version 1.1.	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 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.	Trial Treatment to date of death.

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Gary Middleton, MB,BS,FRCP, University of Birmingham

Publications and helpful links

Helpful Links

• Trial Website

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2019
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: May 9, 2019
• First Submitted That Met QC Criteria: June 7, 2019
• First Posted (Actual): June 10, 2019

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 9, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Class II Microsatellite Status
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: RG_17-215; 2018-000318-39 (EudraCT Number); 40245896 (Registry Identifier: ISRCTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No