Risk Factors of Immune-ChEckpoint Inhibitors MEdiated Liver, Gastrointestinal, Endocrine and Skin Toxicity

Study Overview
=================
Brief Summary
-----------------
Risk factors of Immune-ChEckpoint inhibitor MEdiated Liver, gastrointestinal, endocrine and skin Toxicity (ICEMELT) study is a prospective multicenter cohort study, enrolling patients who are scheduled to receive (1) single agent PD1/L1 inhibitor; (2) PD1/L1 inhibitor plus CTLA4 inhibitor; (3) platinum-based chemotherapy + PD1/L1 inhibitor; (4) PD1/L1 inhibitor and tyrosine kinase inhibitor and (5) PD1/L1 inhibitor and vascular endothelial growth factor (VEGF) inhibitor.

Detailed Description
-----------------
This project is based on strong multidisciplinary collaboration between oncologists, gastroenterologists/hepatologists, immunologists and basic scientists affiliated with (1) Western Sydney University, (2) University of Sydney, (3) Western Sydney Local Health District (4) New South Wales Health Pathology, (5) Westmead Institute for Medical Research. Recruitment sites: Blacktown Mt Druitt Hospital. Westmead Hospital. Research samples collection, processing and storage: Blacktown Clinical School, Western Sydney University. Westmead Institute for Medical Research, the University of Sydney. New South Wales Health Pathology. Potential patients will be identified by study investigators at Oncology clinics. After informed consent, clinicopathological data including patients' demographics, past medical history, cancer staging, relevant anticancer treatment, response/progression and survival will be collected longitudinally. The following specimens will be collected from all participating patients at baseline (pre-treatment stage): Peripheral blood (3 x 10mL EDTA tubes) FibroScan (CAP score for elucidating pre-existing liver fibrosis) Formalin-Fixed Paraffin-Embedded (FFPE) samples (one block) from core biopsies which is a part of routine care for cancer patients. The following specimens will be collected after IPI + NIVO therapeutic regimen will be commenced (week 6-9 after ICI-therapy commencement): • Peripheral blood (3 x 10mL EDTA tubes) Upon development of potential grade ≥2 irAEs, the following samples will be collected: Peripheral blood (3 x 10mL EDTA tubes) FibroScan (for patients with hepatic irAEs) Tissue samples (if biopsies are collected as per standard of care for patients with immune-mediated colitis who will be required to undergo colonoscopy) Peripheral blood samples from patients will be collected using 10ml EDTA vacutainer tubes (x3) and processed within 12 hours of collection by research staff at each site. Plasma will be used for miRNA assay. PBMCs will be split into 5 cryotubes and used for flow cytometry and single-cell sequencing. Consent to the study will allow researchers to access the baseline archive diagnostic FFPE tissue samples. With implementing cutting-edge spatial analysis we aim to elucidate the impact of tumour-infiltrating immune microenvironment on clinical outcomes of ICI therapy. Fresh tissue samples obtained from patients with severe immune-mediated colitis will be processed to obtain total RNA and immune cells for sequencing and mass spectrometry (CyTOF). In addition, tissue samples will be analysed with in situ spatial profiling technologies to map multi-omic data on subcellular level and to determine its association with the clinical outcomes of cancer immunotherapy.

Official Title
-----------------
Risk Factors of Immune-ChEckpoint Inhibitors MEdiated Liver, Gastrointestinal, Endocrine and Skin Toxicity

Conditions
-----------------
Lung Cancer, Nonsmall Cell, Renal Cell Carcinoma, Melanoma, Gastric Cancer, Hepatocellular Carcinoma, Endometrial Cancer, Mesothelioma

Intervention / Treatment
-----------------
* Diagnostic Test: Blood screening
* Diagnostic Test: Tissue screening


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able to comprehend the requirements and procedures for the study and to provide informed consent before entering the study Solid malignant tumour (stage III-IV) Treated with ICI-based therapeutic regimens Exclusion Criteria: Inability to give written informed consent Patients with a cognitive impairment, an intellectual disability or a mental condition that will interfere with the patient's ability to understand the requirements of the study
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single agent PD-1/L1 inhibitor<br> | Diagnostic Test: Blood screening<br>* Blood will be taken in order to elucidate transcriptomic and proteomic differences (1) pre- and post-ICI treatment commencement; (2) in patients with and without immune-related adverse events.<br>Diagnostic Test: Tissue screening<br>* Archival tumor tissue (FFPE) will be spatially analysed in order to define tissue heterogeneity in tumor samples regarding cancer immune cell transcriptional profiles and correlate it with the occurrence/development of immune-related adverse events.<br>|
| Experimental: PD-1/L1 inhibitor + CTLA-4 inhibitor<br> | Diagnostic Test: Blood screening<br>* Blood will be taken in order to elucidate transcriptomic and proteomic differences (1) pre- and post-ICI treatment commencement; (2) in patients with and without immune-related adverse events.<br>Diagnostic Test: Tissue screening<br>* Archival tumor tissue (FFPE) will be spatially analysed in order to define tissue heterogeneity in tumor samples regarding cancer immune cell transcriptional profiles and correlate it with the occurrence/development of immune-related adverse events.<br>|
| Experimental: Platinum-based chemotherapy + PD-1/L1 inhibitor<br> | Diagnostic Test: Blood screening<br>* Blood will be taken in order to elucidate transcriptomic and proteomic differences (1) pre- and post-ICI treatment commencement; (2) in patients with and without immune-related adverse events.<br>Diagnostic Test: Tissue screening<br>* Archival tumor tissue (FFPE) will be spatially analysed in order to define tissue heterogeneity in tumor samples regarding cancer immune cell transcriptional profiles and correlate it with the occurrence/development of immune-related adverse events.<br>|
| Experimental: PD-1/L1 inhibitor + tyrosine kinase inhibitor<br> | Diagnostic Test: Blood screening<br>* Blood will be taken in order to elucidate transcriptomic and proteomic differences (1) pre- and post-ICI treatment commencement; (2) in patients with and without immune-related adverse events.<br>Diagnostic Test: Tissue screening<br>* Archival tumor tissue (FFPE) will be spatially analysed in order to define tissue heterogeneity in tumor samples regarding cancer immune cell transcriptional profiles and correlate it with the occurrence/development of immune-related adverse events.<br>|
| Experimental: PD-1/L1 inhibitor + VEGF inhibitor<br> | Diagnostic Test: Blood screening<br>* Blood will be taken in order to elucidate transcriptomic and proteomic differences (1) pre- and post-ICI treatment commencement; (2) in patients with and without immune-related adverse events.<br>Diagnostic Test: Tissue screening<br>* Archival tumor tissue (FFPE) will be spatially analysed in order to define tissue heterogeneity in tumor samples regarding cancer immune cell transcriptional profiles and correlate it with the occurrence/development of immune-related adverse events.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differentially expressed genes in circulating immune cells between patients with and without irAEs. | This objective will be achieved through single-cell sequencing. | Week 0-48 | 
| Expression of TIM-3, LAG3, VISTA and other inhibitory checkpoint molecules on tumour-infiltrating T cells. | In order to ascertain this result, our objective is to utilize spatial transcriptomics and mass spectrometry. | Week 0-48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association of pre-treatment BMI, neutrophil-to-lymphocyte ratio and other clinical parameters with irAEs. |  | Week 0-48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immune-checkpoint inhibitors, Immunotherapy, Nivolumab, Iplimumab, Pembrolizumab, Atezolizumab, Durvalumab, CTLA-4, PD-1, PD-L1, Tislelizumab