Checkpoint Inhibitor-induced Liver Injury

Recruiting

• Conditions: Immune-Mediated Hepatitis
• Interventions: Diagnostic Test: Obtaining biological samples

• Registration Number: NCT04476563
• Lead Sponsor: University of Nottingham

Brief Summary

In this multi-center prospective observational study, the investigators plan to identify the incidence and risk factors for checkpoint inhibitor-induced liver injury and characterize biochemical, genetic, immunological, and histological features associated with it.

Detailed Description

Checkpoint inhibitor-induced liver injury (ChILI) is a new incompletely understood category of hepatotoxicity which is distinct from other types of drug-induced liver injury (DILI) such as direct or idiosyncratic DILI. The data regarding the incidence and risk factors is lacking. Therefore, 'in-depth phenotyping' together with data from the control group exposed to checkpoint inhibitors (CPI) is necessary to develop refined algorithms incorporating CPI-related factors, host genetic and environmental risk factors that would enable pre-empting ChILI.

The aim of the study is to enroll two deeply phenotyped cohorts (patients who developed ChILI and patients who are starting checkpoint inhibitors) and obtain biological samples at multiple time points.

Study Timeline

• Study First Submitted: 2020-07-02
• Study First Submitted QC: 2020-07-14
• Study First Posted: 2020-07-20
• Study Start: 2020-10-13
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-01
• Last Update Posted: 2022-11-02
• Primary Completion: 2023-08
• Study Completion: 2023-08

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 160

Inclusion Criteria

Both patient groups and control group:

• Able to give written informed consent OR Potential participants who have developed encephalopathy related to ChILI as a response to checkpoint inhibitor therapy, who lack the capacity to give written informed consent and have a consultee (personal or nominated) - for ChILI patient group only

ChILI group:

Patients who developed checkpoint inhibitor-induced liver injury and meet the following criteria:

1. Meets one of the following analytical thresholds at enrolment (visit 1)

   • Alanine transaminase (ALT) exceeding 5 times the upper limit of normal (ULN) OR
   • ALT exceeding 3 times ULN plus bilirubin exceeding 2 times ULN OR
   • Alkaline phosphatase (ALP) exceeding 2 times ULN with accompanying elevations of gamma-glutamyl transferase in the absence of known bone metastases driving the rise in ALP level

2. Absence of other known causes of liver injury after detailed investigations

Patients who developed ChILI but did not meet the above criteria at enrolment or who were found to have a different cause for their liver injury after further investigations will be excluded from the analysis

Control group:

Consecutive patients with cancer who have a clinical indication to start checkpoint inhibitors. A small proportion of patients will develop ChILI following their checkpoint inhibitor treatment and will be classified as cases.

Exclusion Criteria

• Patients who are treated with cytotoxic chemotherapy concurrently with checkpoint inhibitors.
• On the judgment of chief investigator that the person has certain alternative explanations to the acute event (rather than ChILI).

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
ChILI	Obtaining biological samples	Patients who are already on CPI therapy and have developed liver injury
Control	Obtaining biological samples	Patients with cancer who are starting on checkpoint inhibitors

Primary Outcome Measures

Name	Time	Method
Incidence of checkpoint inhibitor-induced liver injury (ChILI) and other immune-mediated adverse reactions	3 years
Identify novel biomarkers associated with the diagnosis of ChILI	3 years	The investigators plan assessment of proposed circulating biomarkers including cytokines, microRNAs (miR-122, miR-4270 and miR-4463), total cytokeratin 18 (K18), macrophage colony-stimulating factor receptor (MCSFR), and any others identified in subsequent publications and measure their diagnostic and prognostic accuracy using the area under the receiver operating curve (AUROC).

Trial Locations

Locations (1)

University of Nottingham; 🇬🇧 Nottingham, United Kingdom