Clinical trial NCT06470997: Specific Biomarkers of Immune-mediated Hepatitis Secondary to Immune Checkpoint Inhibitors
Official title: Specific Biomarkers of Immune-mediated Hepatitis Secondary to Immune Checkpoint
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Immune-mediated Hepatitis
Keywords: proteomic analysis
blood biomarker
immune-mediated hepatitis secondary to immune checkpoint inhibitors
idiopathic autoimmune hepatitis
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
First posted: 2024-06-24
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: CHILI group: patients with hepatitis induced by immune checkpoint inhibitors Control group: patients with idiopathic autoimmune hepatitis

Brief summary: Identify specific blood biomarkers for hepatitis induced by immune checkpoint inhibitors in comparison to idiopathic autoimmune hepatitis.

Detailed description: Immune checkpoint inhibitors (ICI) have become a pillar of the oncological therapeutic arsenal. Their mechanism of action is based on the restoration of the innate anti-tumor function of T lymphocytes. This mode of action is also the cause of systemic immune-mediated adverse effects. The most common disorders are endocrine, cutaneous and gastrointestinal. The frequency of hepatic toxicities is estimated between 0.7 and 25% depending on the studies, the cancer treated and the ICI combinations used. Currently the description of these hepatitis is brief in the literature and the mechanism of toxicity is not known. Work has already compared histological damage between immune checkpoint inhibitors (CHILI) and autoimmune hepatitis; The investigators find in CHILI a higher ratio of CD8 + /CD4 + lymphocytes. Apart from these clinical, biological or histological descriptions, knowledge is limited. In particular, there are no known predictive factors or prognoses.

The investigators hypothesize that there are mechanistic differences between checkpoint inhibitors induced liver injury and idiopathic autoimmune liver disease. Proteomic analysis is a powerful tool for functional analysis.

Eligibility criteria: Inclusion criteria for patients in the CHILI group:

* Patient \> 18 years old
* Patient treated with immune checkpoint inhibitors (ICI) alone or in combination
* Patient suffering from Hepatitis secondary to immune checkpoint inhibitors (ICI) grade 3 or 4 Common Terminology Criteria For Adverse Events (CTCAE)\*
* Treatment with corticosteroids or Ursodeoxycholic acid (UDCA) not started, or started less than 7 days ago

  * Grade 3 or 4 hepatitis: increase in transaminases and/or alkaline phosphatases ≥ 5 x Upper Limit of Normal (ULN) or total bilirubin ≥ 3

Inclusion criteria for patients in the control group:

* Patient \> 18 years old
* Patient suffering from Primary Biliary Cholangitis (PBC)\* or Autoimmune Hepatitis (AIH)\*\* or Primary Sclerosing Cholangitis (PSC) \*\*\*

Primary Biliary Cholangitis (PBC)\* diagnosis :

Association of at least 2 of the following 3 criteria :

* Cholestasis (PAL \> 1.5N, Gamma GT \> 3N) chronic (\> 6 months) without ultrasound abnormality of the bile ducts.
* M2 type anti-mitochondria Ab \> 1/40th
* Characteristic histological lesions (non-suppurative destructive cholangitis) or compatible (portal inflammation, granulomas, ductular proliferation, ductopenia, cholestasis).

  \*\* AIH diagnosis : ALT \> 5 N / Ig G \> 1.5 - 2 N or anti-smooth muscle ≥ 1/80 / Interface hepatitis of marked intensity The Hepactic Activity Index (HAI) score makes it possible to confirm the diagnosis when all the diagnostic criteria are not met.

  \*\*\* PSC diagnosis: presence of chronic cholestasis (alkaline phosphatase \> 1.5 N or GGT \> 3 N) and typical abnormalities of the bile ducts on cholangio-MRI (Magnetic Resonance Imaging), and in the absence of cause of secondary sclerosing cholangitis
* Treatment with corticosteroids or Ursodeoxycholic acid (UDCA) not initiated, or started less than 30 days ago

Non-inclusion criteria:

* Impossibility of following the patient during the study period
* Liver biopsy not possible
* Other hepatitis diagnoses
* Failure to obtain consent
* Unemancipated minors, people unable to express their consent
* Non-affiliation to a social security or equivalent scheme,
* Persons placed under judicial protection,
* Person participating in another research including a period of exclusion still in progress.
* Pregnant or breastfeeding women
* De novo or old diagnosis (at the time of a flare-up)

Primary outcomes:
measure: Determination of the area under the ROC (Receiver Operation characteristic) curve for hepatitis.
timeFrame: Baseline
Secondary outcomes:
measure: Determination of the area under the ROC (Receiver Operation characteristic) curve for treatment response
timeFrame: Baseline, day 14, day 28, month 3, month 6
measure: Responses to treatments
timeFrame: Day 28
Other outcomes:
Locations:
city: Montpellier
country: France
facility: CHU de Montpellier
Study officials:
affiliation: University Hospital, Montpellier
name: Lucy MEUNIER, MD
role: STUDY_DIRECTOR
References:
citation: De Martin E, Michot JM, Rosmorduc O, Guettier C, Samuel D. Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors. JHEP Rep. 2020 Aug 11;2(6):100170. doi: 10.1016/j.jhepr.2020.100170. eCollection 2020 Dec.
citation: Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, Cauquil C, Chanson P, Collins M, Durrbach A, Ederhy S, Feuillet S, Francois H, Lazarovici J, Le Pavec J, De Martin E, Mateus C, Michot JM, Samuel D, Soria JC, Robert C, Eggermont A, Marabelle A. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016 Apr;27(4):559-74. doi: 10.1093/annonc/mdv623. Epub 2015 Dec 28.
citation: Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity From Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation. Hepatology. 2020 Jul;72(1):315-329. doi: 10.1002/hep.31227.
citation: Haanen J, Obeid M, Spain L, Carbonnel F, Wang Y, Robert C, Lyon AR, Wick W, Kostine M, Peters S, Jordan K, Larkin J; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Dec;33(12):1217-1238. doi: 10.1016/j.annonc.2022.10.001. Epub 2022 Oct 18. No abstract available.
citation: Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018 Jun;31(6):965-973. doi: 10.1038/s41379-018-0013-y. Epub 2018 Feb 5.
citation: Hountondji L, Ferreira De Matos C, Lebosse F, Quantin X, Lesage C, Palassin P, Rivet V, Faure S, Pageaux GP, Assenat E, Alric L, Zahhaf A, Larrey D, Witkowski Durand Viel P, Riviere B, Janick S, Dalle S, Maria ATJ, Comont T, Meunier L. Clinical pattern of checkpoint inhibitor-induced liver injury in a multicentre cohort. JHEP Rep. 2023 Mar 7;5(6):100719. doi: 10.1016/j.jhepr.2023.100719. eCollection 2023 Jun.
citation: Coukos A, Vionnet J, Obeid M, Bouchaab H, Peters S, Latifyan S, Wicky A, Michielin O, Chtioui H, Moradpour D, Fasquelle F, Sempoux C, Fraga M. Systematic comparison with autoimmune liver disease identifies specific histological features of immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2022 Oct;10(10):e005635. doi: 10.1136/jitc-2022-005635.
citation: Gudd CLC, Au L, Triantafyllou E, Shum B, Liu T, Nathwani R, Kumar N, Mukherjee S, Dhar A, Woollard KJ, Yone Y, Pinato DJ, Thursz MR, Goldin RD, Gore ME, Larkin J, Khamri W, Antoniades CG, Turajlic S, Possamai LA. Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis. J Hepatol. 2021 Jul;75(1):177-189. doi: 10.1016/j.jhep.2021.02.008. Epub 2021 Feb 22.
citation: Yoshimura K, Tamano Y, Nguyen Canh H, Zihan L, Le Thanh D, Sato Y, Terashima T, Shimoda S, Harada K. A novel pathologic marker, indoleamine 2,3-dioxygenase 1, for the cholangiopathy of immune checkpoint inhibitors-induced immune mediated hepatotoxicity as adverse events and the prediction of additional ursodeoxycholic acid treatment. Med Mol Morphol. 2023 Jun;56(2):106-115. doi: 10.1007/s00795-022-00344-7. Epub 2023 Jan 4.