Liver Toxicity in Lung Cancer Patients Treated With Immune-checkpoint Inhibitors.

Sponsor

Western Sydney Local Health District (Other)

Overall Status

Recruiting

CT.gov ID

NCT04595734

Collaborator

University of Western Sydney (Other)

500

Enrollment

Locations

Anticipated Duration (Months)

166.7

Patients Per Site

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Immune-checkpoint inhibitors have recently become available as a new therapy for a variety of cancers. This drugs function by boosting the anti-cancer immune response, but unfortunately, may cause off-target, non-specific immune activation, resulting in liver and gut toxicity. In order to understand the development of liver immune-related adverse events we aim to collect full clinicopathological data from patients with advanced lung cancer treated with immune-checkpoint inhibitors at Blacktown, Westmead and Nepean Hospitals. Patients treated with standard chemotherapy will be used as a control group.

This study aims to establish clinical risk factors that can predict the occurrence of liver immune-related adverse events in patients with advanced lung cancer treated with immune-checkpoint inhibitors. Such predictors may assist in the stratification of patients based on their risk for development liver toxicity as a result of immunotherapy, allowing early cessation/modification of treatment prior to the development of severe adverse reactions. In addition, this retrospective study will aim to determine the significance of pre-existing liver damage on the development of liver adverse events as well as establish a timeline defining the development of adverse events in the liver.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer Stage IV Lung Cancer, Non-small Cell Hepatitis	Other: No intervention due to observational methods of study

Detailed Description

BACKGROUND AND RATIONALE.

Lung cancer is the most common cause of cancer-related mortality worldwide. This year alone 12,817 new lung cancer cases were registered in Australia, the mortality rate of which being 46% within 5 years. Chemotherapy is still considered the first-line treatment, however recent clinical trials have established that with treatment monoclonal antibodies known as immune-checkpoint inhibitors shows higher efficacy in terms of overall survival and progression-free survival. Despite higher efficacy, immune-checkpoint inhibitors can cause a number of immune-related adverse events which may force patients to cease treatment. Among these side effects, liver toxicity occurs rapidly and is asymptomatic in the early stages. These facts underscore the necessity of stratifying patients based on their risk of developing liver toxicity. We aim to predict liver toxicity early on in therapy using data collected from routine clinical testing.

STUDY AIMS / OBJECTIVES.

This retrospective study aims to answer following research questions:

Does pre-existing liver fibrosis/cirrhosis influence the development of liver immune-related adverse events?
What is the first time-point and subsequent timeline of liver immune-related adverse events occurrence and progression?
What clinical markers predict immunotherapy related toxicity?

STUDY DESIGN.

This is non-interventional retrospective study that plans to collect data from patients with stage IV lung cancer treated at Blacktown, Westmead and Nepean Hospitals. The main goal of this study is to establish statistically significant clinical predictors of liver toxicity in patients treated with immune-checkpoint inhibitors. Full clinicopathological data will be collected from hospital medical electronic databases. We will prioritise the examination of liver function blood tests in order to establish the first timepoint of liver function abnormalities and correlate them to pre-treatment blood results.

STUDY PROCEDURES.

This retrospective study will be conducted in 3 steps

Collection of full clinicopathological data of patients with advanced lung cancer treated at Blacktown, Westmead and Nepean Hospitals .
Blood tests results will be collected according to the following scheme: (1) The day prior to treatment commencement (baseline); (2) every 28th day for patients treated with tyrosine kinase inhibitors; (3) the last day of each therapeutic cycle for patients treated with immune-checkpoint inhibitors or platinum-doublet chemotherapy or combination.
Statistical analysis using SPSS v23 and STATA v16 software.

DATA COLLECTION:

Clinicopathological data

ID
Age
Sex
Clinical diagnosis
Histological diagnosis
TNM stage
Date of diagnosis
Date of treatment commencement
Therapeutic regimen
Cycling regime
Date of death
Cardiovascular comorbidities
Neurologic comorbidities
Respiratory comorbidities
Endocrine comorbidities
Gastrointestinal comorbidities
Renal comorbidities
Smoking status (pack/years)
Eastern Cooperation Oncology Group performance status (ECOG PS)
Programmed death ligand 1 (PD-L1) expression (%)
Genetic mutations
FibroScan data

Data from blood tests

Red blood cells (RBC)
Red blood cells distribution weight (RDW)
Haematocrit
Haemoglobin
Mean corpuscular volume (MCV)
Mean corpuscular haemoglobin (MCH)
Mean corpuscular haemoglobin concentration (MCHC)
Platelets
White blood cells (WBC)
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Sodium
Potassium
Bicarbonate
Estimated glomerular filtration rate
Urea
Creatinine
Glucose
Serum protein
Total globulin
Albumin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma glutamyltransferase (GGT)
Alkaline phosphatase (ALP)
Total bilirubin
C-reactive protein
Iron
Transferrin
Ferritin

Statistical considerations:

All variables will be analysed using descriptive statistics
Mann-Whitney test will be used for estimating differences in liver functional tests between two groups and to evaluate the significance of pre-existing liver damage (counted by APRI and Fib-4 scores) on the development of liver immune-related adverse events
Multivariate regression for establishment significant predictors of liver toxicity

Study Design

Study Type:

Observational

Anticipated Enrollment :

500 participants

Observational Model:

Cohort

Time Perspective:

Retrospective

Official Title:

A Retrospective Study of Clinical Outcomes and Liver-related Toxicity of Patients With Lung Cancer Treated With Immune-checkpoint Inhibitors

Actual Study Start Date :

Jan 7, 2020

Anticipated Primary Completion Date :

Jan 10, 2023

Anticipated Study Completion Date :

Jan 6, 2025

Outcome Measures

Primary Outcome Measures

Number of participants with immune-mediated hepatitis [Week 6-12 from treatment commencement]
Baseline risk factors significantly correlated with hepatic immune-related adverse events [Week 0]
Blood test results, BMI, FibroScan data will be correlated with the development of liver toxicity

Secondary Outcome Measures

Number of participants with non-hepatic immune-related adverse events [Week 3-32 from treatment commencement]
Baseline risk factors significantly correlated with non-hepatic immune-related adverse events [Week 0]
Blood test results and BMI will be correlated with the development of immune-related adverse events (non-hepatic)

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

- Advanced lung cancer (stage IV)
- Treatment - immune-checkpoint inhibitors or chemotherapy
- Data is fully available for the whole period of observation

Exclusion Criteria:

- Radiologically reported liver metastases
- Concurrent treatment with both therapeutic regimes

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Westmead Hospital	Sydney	New South Wales	Australia	2145
2	Blacktown Hospital	Sydney	New South Wales	Australia	2148
3	Nepean Hospital	Sydney	New South Wales	Australia	2747