Clinical trial NCT04631731: Risk Factors of Immune-ChEckpoint Inhibitors MEdiated Liver, Gastrointestinal, Endocrine and Skin Toxicity
Official title: Risk Factors of Immune-ChEckpoint Inhibitors MEdiated Liver, Gastrointestinal, Endocrine and Skin Toxicity
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Lung Cancer, Nonsmall Cell
Renal Cell Carcinoma
Melanoma
Gastric Cancer
Hepatocellular Carcinoma
Endometrial Cancer
Mesothelioma
Keywords: Immune-checkpoint inhibitors
Immunotherapy
Nivolumab
Iplimumab
Pembrolizumab
Atezolizumab
Durvalumab
CTLA-4
PD-1
PD-L1
Tislelizumab
Lead sponsor: Western Sydney Local Health District
Sponsor class: OTHER
Collaborators: name: University of Western Sydney
name: Bristol-Myers Squibb
First posted: 2020-11-17
Enrollment: 200
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

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.

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

Primary outcomes:
measure: Differentially expressed genes in circulating immune cells between patients with and without irAEs.
timeFrame: Week 0-48
measure: Expression of TIM-3, LAG3, VISTA and other inhibitory checkpoint molecules on tumour-infiltrating T cells.
timeFrame: Week 0-48
Secondary outcomes:
measure: Association of pre-treatment BMI, neutrophil-to-lymphocyte ratio and other clinical parameters with irAEs.
timeFrame: Week 0-48
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Blacktown Mt Druitt Hospital
state: New South Wales
Study officials:
affiliation: Western Sydney Local Health District
name: Golo Ahlenstiel, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shek D, Read SA, Akhuba L, Qiao L, Gao B, Nagrial A, Carlino MS, Ahlenstiel G. Non-coding RNA and immune-checkpoint inhibitors: friends or foes? Immunotherapy. 2020 May;12(7):513-529. doi: 10.2217/imt-2019-0204. Epub 2020 May 7.
citation: Shek D, Read SA, Nagrial A, Carlino MS, Gao B, George J, Ahlenstiel G. Immune-Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Synopsis of Response Rates. Oncologist. 2021 Jul;26(7):e1216-e1225. doi: 10.1002/onco.13776. Epub 2021 Apr 21.
citation: Shek D, Akhuba L, Carlino MS, Nagrial A, Moujaber T, Read SA, Gao B, Ahlenstiel G. Immune-Checkpoint Inhibitors for Metastatic Colorectal Cancer: A Systematic Review of Clinical Outcomes. Cancers (Basel). 2021 Aug 27;13(17):4345. doi: 10.3390/cancers13174345.
citation: Shek D, Gloss B, Lai J, Ma L, Zhang HE, Carlino MS, Mahajan H, Nagrial A, Gao B, Read SA, Ahlenstiel G. Identification and Characterisation of Infiltrating Immune Cells in Malignant Pleural Mesothelioma Using Spatial Transcriptomics. Methods Protoc. 2023 Mar 28;6(2):35. doi: 10.3390/mps6020035.