Clinical trial NCT04476563: Checkpoint Inhibitor-induced Liver Injury
Official title: Checkpoint Inhibitor-induced Liver Injury Study (ChILI)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Immune-Mediated Hepatitis
Keywords: Immune checkpoints inhibitors
Immune-related adverse events
Hepatotoxicity
Liver injury
Lead sponsor: University of Nottingham
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2020-07-20
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: ChILI group:

Adults with cancer receiving checkpoint inhibitors (CTLA-4, PD-1 or PD L1 inhibitor) as monotherapy or combination (without chemotherapy) and developed acute liver injury secondary to checkpoint inhibitor.

Control Group:

Patients with malignant melanoma, renal cell carcinoma, non-small cell lung cancer or any other cancer, receiving single or combination therapy using checkpoint inhibitors (CPIs).

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Incidence of checkpoint inhibitor-induced liver injury (ChILI) and other immune-mediated adverse reactions
timeFrame: 3 years
measure: Identify novel biomarkers associated with the diagnosis of ChILI
timeFrame: 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: University of Nottingham
Study officials:
References: