Management of Immune Checkpoint Inhibition-related Hepatitis Using Low-dose Corticosteroids

NCT ID: NCT07167251

Last Updated: 2025-09-11

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 63 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2025-08-25
• Study Completion Date: 2026-12-31

Brief Summary

This study evaluates the effectiveness of low-dose corticosteroids in managing grade 2-3 immune-related hepatitis in cancer patients treated with immune checkpoint inhibitors. It aims to determine whether of 0.5-1miligram per kilogram bodyweight prednisolone is sufficient to manage immune-related hepatitis without the need for dose escalation or additional immunosuppressive therapy.

Detailed Description

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are associated with immune-related adverse events (irAEs), including immune-related hepatitis, a potentially serious complication that affects up to 30% of patients undergoing ICI combination therapy. Current management guidelines recommend corticosteroids as the first-line treatment for moderate to severe irAEs. However, high doses of corticosteroids are associated with increased risks of infections, metabolic and psychiatric side effects, and potentially impaired anti-tumor efficacy. Retrospective data suggest that lower doses may be equally effective while reducing toxicity and preserving treatment efficacy.

This prospective, registry-based cohort study aims to evaluate the clinical performance and outcomes of low-dose corticosteroid treatment for managing grade 2 or 3 IR-hepatitis. The hypothesis is that a corticosteroid "test dose" approach (0.5-1 mg/kg prednisolone) followed by early evaluation of clinical response can identify patients who benefit from reduced immunosuppression, thus minimizing side effects without compromising the effectiveness of ICI therapy.

Patients will be recruited from participating oncology centers where standardized management of IR-hepatitis has been implemented. Eligible participants are adult cancer patients who develop grade 2 or 3 IR-hepatitis during ICI therapy, excluding those with prior high-dose corticosteroid use, concurrent neurological or cardiac irAEs requiring high-dose corticosteroids, or underlying chronic liver diseases.

The primary endpoint is resolution of IR-hepatitis (defined as return to baseline or grade 1 liver function tests) within 8 weeks without corticosteroid dose escalation, additional immunosuppressive therapy, and with tapering to ≤10 mg/day prednisolone. Secondary endpoints include the proportion of patients requiring dose escalation, time to hepatitis resolution, cumulative corticosteroid exposure, relapse rates, occurrence of additional irAEs, progression-free survival (PFS), overall survival (OS), and identification of predictors of steroid-refractory hepatitis.

Patients will be followed for six months after the onset of IR-hepatitis. Follow-up assessments will align with standard clinical care, with no additional study-specific visits. Liver function tests, immunotherapy status, corticosteroid and immunosuppressive use, and occurrence of new irAEs will be recorded. A liver biopsy is recommended in refractory or ambiguous cases. Data will be collected via the REDCap system, ensuring standardized electronic data capture.

The study is powered to detect a successful resolution rate of at least 80% in patients with grade 3 IR-hepatitis treated with low-dose corticosteroids, assuming a null hypothesis threshold of 65%. Descriptive and exploratory statistical methods will be used to analyze the data, including Kaplan-Meier estimates for time-to-event outcomes and logistic regression for exploratory subgroup analyses.

This study addresses a critical gap in prospective evidence on the management of IR-hepatitis. By evaluating the efficacy and safety of a pragmatic, low-cost, low-toxicity intervention, it may inform future guidelines and serve as a foundation for a randomized non-inferiority trial. The study's design allows for real-world applicability while ensuring scientific rigor through harmonized protocols and data collection.

Conditions

Immune Related Adverse Events; Immune-Mediated Hepatitis; Cancer

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Immune-related hepatitis grade 2

Grade 2 hepatitis is defined as an elevation of Aspartate transaminase (AST) and/or Alanine aminotransferase (ALT) levels to 3-5 times the upper limit of normal, in accordance with the guidelines of the European Society for Medical Oncology.

Low-dose corticosteroids for immune-related hepatitis grade 2

Intervention Type: DRUG

Hold immunotherapy and reassess liver function at the treating physician's discretion. If liver function tests persistently worsen or continue to rise, consider administering prednisolone at 0.5 mg/kg body weight

Immune-related hepatitis grade 3

Grade 3 hepatitis is defined as an elevation of Aspartate transaminase and/or Alanine aminotransferase levels to 5-20 times the upper limit of normal, in accordance with the guidelines of the European Society for Medical Oncology.

Low-dose corticosteroids for immune-related hepatitis grade 3

Intervention Type: DRUG

Prednisolone 0.5-1 mg/kg orally for grade 3 IR-hepatitis; adjusted based on liver function; treatment per local standard of care.

Interventions

Low-dose corticosteroids for immune-related hepatitis grade 3

Prednisolone 0.5-1 mg/kg orally for grade 3 IR-hepatitis; adjusted based on liver function; treatment per local standard of care.

Intervention Type: DRUG

Low-dose corticosteroids for immune-related hepatitis grade 2

Hold immunotherapy and reassess liver function at the treating physician's discretion. If liver function tests persistently worsen or continue to rise, consider administering prednisolone at 0.5 mg/kg body weight

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Cancer patients aged 18 years or older

2. Treatment with a programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) antibody, or a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or a combination of a PD-1 and CTLA-4 antibody, or a PD-1 and lymphocyte-activation gene 3 (LAG-3) antibody

3. Occurrence of immune-related hepatitis grade 2 to 3 (as per judgment of the investigator)

4. Ability of the patient to comply with the study procedures (management of immune-related hepatitis)

Exclusion Criteria

1. Previous Immune-related hepatitis that required systemic therapy

2. Treatment for Immune-related hepatitis has already been initiated with high-dose corticosteroids (>0.5 mg/kg body weight)

3. Immune-related hepatitis with bilirubin > 1.5 ULN or clinical suspicion of cholangitis or elevated INR (beyond baseline)

4. Immune-related hepatitis with grade 4 at first presentation

5. Prior irAE treated with systemic immunosuppression

6. Simultaneous immune-related neurological toxicity or immune-related myocarditis (since these usually have to be treated with high doses of corticosteroids)

a. Patients with other immune-related adverse events may be included according to the investigator's judgment

7. Known liver disease (e.g., autoimmune hepatitis, active hepatitis B, C or E, hemochromatosis, liver cirrhosis Child-Pugh Score B or C, primary biliary cholangitis, primary biliary cirrhosis, Morbus Wilson)

a. Patients with liver metastasis are eligible

8. Patients receiving cancer treatment other than immune checkpoint inhibitors in parallel (e.g., tyrosine kinase inhibitors or chemotherapy).

a. Patients who have received other cancer treatments in previous cycles are eligible, provided the treating physician does not assume any toxicity from the other medication.

9. Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to occurrence of IR hepatitis. Stable corticosteroid doses of < 10mg prednisone equivalent are allowed.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Royal Marsden NHS Foundation Trust

OTHER

Sponsor Role: collaborator

Odense University Hospital

OTHER

Sponsor Role: collaborator

UMC Utrecht

OTHER

Sponsor Role: collaborator

University Hospital, Basel, Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Andreas Schmitt

Deputy Physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andreas M Schmitt, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Basel, Switzerland

Locations

University Hospital Basel

Basel, Canton of Basel-City, Switzerland

Site Status: RECRUITING

Royal Marsden Hospital

London, , United Kingdom

Site Status: NOT_YET_RECRUITING

Countries

Switzerland; United Kingdom

Central Contacts

Andreas M Schmitt, MD

Role: CONTACT

andreasmichael.schmitt@usb.ch

+41 61 265 50 74

Facility Contacts

Andreas M Schmitt, MD

Role: primary

andreasmichael.schmitt@usb.ch

+41 61 265 50 74

Benjamin Kasenda, MD, PhD

Role: backup

benjamin.kasenda@usb.ch

+41 61 265 5074

Other Identifiers

2025-00696

Identifier Type: -

Identifier Source: org_study_id