Steroid Sparing in Immune Related Hepatitis (irH)

February 28, 2024 updated by: AHS Cancer Control Alberta

A Study to Evaluate the Efficacy and Safety of Steroid Sparing Strategy in Immune Related Hepatitis

A multi-centre, randomized, non-inferiority trial in patients with irH, randomized to receive either close surveillance with corticosteroid rescue therapy or early high dose corticosteroids.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

Immune checkpoint inhibitors (ICIs) are a class of immunotherapy drugs that helps signal to the immune system to seek out and destroy cancer. However despite showing clinical benefit over traditional chemotherapy, ICIs can lead to certain toxicities called immune-related adverse events (irAEs).

One of these irAEs is immunotherapy related hepatitis (irH) and is an important and less common toxicity of ICI therapy that could develop into a rare but serious complication of sudden liver failure. The management of irH includes high-dose steroids and use of steroids is not without significant side effects, especially when used for longer term.

Given the potential consequences of high dose long-term corticosteroids along with the implications of permanently discontinuing therapy, it is necessary to better understand the pathophysiology associated with irH and clarify the role of steroids in managing this patient population. It is especially important to determine which patients require intervention with steroids and other immunosuppression versus those that could simply be monitored for spontaneous resolution.

The results of this trial will identify predictors of irH resolution and inform judicious use of corticosteroids and immunosuppressive therapy for this at-risk population.

This study has been designed as a randomized, phase II non-inferiority study to investigate the efficacy of an active surveillance with steroid rescue strategy compared to early initiation of corticosteroids in the setting of irH secondary to ICIs. The study treatment period is 12 weeks with twice weekly liver enzyme function assessments. Once irH has improved to by one CTCAE grade (i.e. grade 3 to 2, or grade 2 to 1), this can be decreased to weekly assessment. For patients who continue to have asymptomatic liver enzyme elevation of grade 2 or higher, maintaining a surveillance strategy beyond this point is not appropriate, as investigators may wish to adjust therapy, especially if this is resulting in delay in resuming ICI. In this setting, weekly liver enzyme assessment will continue. The frequency of liver enzyme monitoring can be increased at the discretion of the investigator or hepatologist.

Following the initial 12-week period, further surveillance with an observation period consisting of every 3 weekly assessments will be completed for a total of 40 weeks (total study duration of 52 weeks). Participants will continue follow up for a total of one year to allow the capture longer term data as well as other endpoints.

Study Type

Interventional

Enrollment (Estimated)

55

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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).
  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. 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1- Active Surveillance
Active surveillance with rescue corticosteroids
Close monitoring of liver enzymes with steroid rescue strategy (watch and wait approach)
Active Comparator: 2- Early initiation of steroid (Standard)
Early intervention with high-dose steroids
Immediate start of high-dose steroids

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Resolution of biochemical abnormalities in grade 2 and grade 3 irH at 12 weeks.
Time Frame: 12 weeks
The primary objective of this clinical trial is to determine if active surveillance with steroid salvage is a non-inferior strategy in grade 2 and grade 3 irH in patients without evidence of liver dysfunction. Resolution will be defined as improved in irH to grade ≤1. This was chosen as a clinically significant endpoint as it is often used by oncologists to determine if patients may resume ICI therapy. Assessment and grading will be completed by the investigator according to CTCAEv5.0
12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety of Steroid Sparing Strategy
Time Frame: 1 year
To evaluate the safety of surveillance strategy based on rates of hospitalization, ICU admission, development of clinically significant liver failure (e.g. decompensated hepatic failure) and death.
1 year
Total steroid usage
Time Frame: 1 year
Total steroid usage (defined as the total amount of prednisone or prednisone equivalent in mg required over the study period).
1 year
Development of immune related adverse events (irAE's) other than irH.
Time Frame: 1 year
Defined as the emergence of adverse events that were not present at study baseline that are deemed by the investigator to be related to prior use of immune checkpoint inhibitors. Causality will be investigator assessed and graded according to CTCAEv5.0.
1 year
Re-initiation of immune checkpoint inhibitor therapy.
Time Frame: 1 year
The proportion of patients in each study arm that are re-treated with an immune checkpoint inhibitor.
1 year
The time elapsed between randomization and tumor progression (radiographically or clinically) or death from any cause
Time Frame: 1 year
Progression free survival
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Omar Khan, MD, AHS Cancer Control Alberta

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 30, 2024

Primary Completion (Estimated)

February 1, 2027

Study Completion (Estimated)

February 1, 2028

Study Registration Dates

First Submitted

March 23, 2022

First Submitted That Met QC Criteria

April 21, 2022

First Posted (Actual)

April 26, 2022

Study Record Updates

Last Update Posted (Actual)

March 1, 2024

Last Update Submitted That Met QC Criteria

February 28, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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