Lowering steroid use for immune-related hepatitis

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

This randomized phase II non-inferiority trial compares active surveillance with corticosteroid rescue to early high‑dose corticosteroids in patients who develop grade 2–3 immune-related hepatitis while on PD‑1/PD‑L1 (± CTLA‑4) therapy. Participants are enrolled within 10 days of hepatitis diagnosis and randomized to either close liver monitoring with steroids only if liver tests worsen or to immediate high‑dose steroid treatment. The study collects clinical and laboratory data, using RUCAM causality assessment, to identify predictors of spontaneous resolution versus need for immunosuppression. Findings will inform when steroids can be safely withheld and when prompt treatment is required.

Why it matters

Who can join: the full rules

Inclusion Criteria:

1. Patients must be 18 years of age, or older on the day of signing informed consent.
2. Patients must be capable of providing consent to enrolment and treatment.
3. Patients with a performance status of ECOG 0-2 will be eligible for enrolment.
4. Patients with histologically confirmed cancer receiving anti-PD1 or anti-PDL1 monoclonal antibody ICI therapy, either alone or in combination with anti-CTLA-4 monoclonal antibody ICI therapy who develop CTCAEv5.0 grade 2 or grade 3 hepatitis that has developed on, or after, ICI therapy and is felt to be treatment related (irH). Patients must be enrolled on trial within 10 days of diagnosis of grade 2 or grade 3 hepatotoxicity.
5. Absence of any condition hampering compliance with the study protocol and follow- up schedule; those conditions should be discussed with the patient before registration in the trial.
6. Assessment by the Roussel Uclaf Causality Assessment Method (RUCAM) ≥6 showing probable relationship between ICI and liver injury (appendix)

Exclusion Criteria:

1. History underlying liver disease, including, but not limited to: hepatitis B, C, autoimmune hepatitis, primary biliary sclerosis, hemochromatosis, primary sclerosis cholangitis, portal vein thrombosis, Budd Chiari syndrome, alcohol induced hepatitis, suspected drug-induced liver injury from other cause (e.g. acetaminophen, antibiotics, statins, methyldopa, non-prescription herbs, see NIH LiverTox website https://livertox.nih.gov for comprehensive list).
2. If undertaken, liver biopsy supporting a cause of liver dysfunction other than irH
3. Patients with an indication for systemic immunosuppressive medications or corticosteroids. Patients with CTCAEv5.0 grade ≥2 irAE's other than irH (ie. colitis, pneumonitis, rash, etc.) are not eligible for trial, with the exception of endocrinopathies that are being treated with hormone replacement alone and not systemic immunosuppressive medications or corticosteroids.
4. Abnormal International Normalization Ratio (INR) at baseline (≥1.5) and bilirubin ≥60, ALT of ≥10X.
5. Previous use of targeted therapies for treatment of malignancy (e.g. BRAF, MEK, EGFR, and VEGF inhibitors) or current treatment with chemotherapy
6. Present use of warfarin.
7. Diagnosis of immunodeficiency.
8. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
9. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (CTCAEv5.0 Grade ≥ 3).
10. Other severe acute or chronic medical conditions including inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Where it's running

• Arthur J.E. Child Comprehensive Cancer Centre
  Calgary, Alberta, Canada Recruiting

Study contacts

• Principal investigator: Omar Khan, MD — AHS Cancer Control Alberta
• Study coordinator: Omar F Khan, MD
• Email: Omar.Khan@cancercarealberta.ca
• Phone: (587) 231-5082

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.