Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis (I-HEP)

A National Prospective Study of Patients With Hepatitis Induced by Immune Checkpoint Inhibitors; Characterization of Liver Injury, Outcome of Therapy and Randomization to Either Prednisolone or Mycophenolate Mofetil Treatment in Case of Relapse

This clinical trial is to clarify and investigate the patterns of immune-related hepatitis and the optimal treatment choice for patients who are steroid-dependent. The project aims to prospectively characterize the various histopathological, biochemical, and phenotypical liver injury patterns induced by immune checkpoint inhibitors and the treatment responses to corticosteroids. Furthermore, the effect of adding a second-line immunosuppressive drug, either MMF in steroid-refractory or steroid-dependent cases will be explored and compared.

Study Overview

• Status: Recruiting
• Conditions: Hepatitis, Drug-Induced
• Intervention / Treatment: Drug: Mycophenolate Mofetil; Drug: Solu-Medrol; Drug: Ursodeoxycholic acid; Drug: Prednisone tablet

Detailed Description

The number of patients treated with immune checkpoint inhibitors (ICI) is expanding worldwide due to an increasing number of indications, including additional types of cancer, combination of ICI with other antineoplastic therapies and have recently moved into the adjuvant setting. According to clinical trial material, almost all patients in ICI treatment will eventually develop any grade of an adverse event, here, estimated in up to 90 percent of treated patients. Around 10-30 percent of ICI-treated patients will show signs of liver injury related to ICI treatment and will be diagnosed with immune-related hepatitis. The treatment hereof should include observation and medium-dose steroids in low-grade asymptomatic patients (grade ≤ 2 ir-hepatitis) and high-dose steroids in higher grades according to the current European and American guidelines. However, up to 25 percent of patients with ir-hepatitis may not respond properly to steroids due to primary resistance or relapse during tapering. These patients should be offered a second-line immunosuppressive treatment. The present recommendation for patients with steroid-dependent ir-hepatitis is based on the case series and includes immunosuppressive treatment with mycophenolate mofetil (MMF). To date, no evidence exists for which second-line treatment to choose.

However, in the clinic, the initiation of MMF may be delayed, meanwhile, patients are typically treated with an increased dose of steroids. In some cases, an increased dose of steroids with prolonged tapering can be sufficient. We want to explore if increased doses of steroids or adding MMF is the best strategy for relapse of hepatitis.

In addition, patients with signs of biliary or mixed liver injury may benefit from adding ursodeoxycholic acid (UDCA).

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Inge Marie Svane, M.D. Professor; Phone Number: +38683868; Email: inge.marie.svane@regionh.dk
• Study Contact Backup: Name: Rikke B Holmstrøm, M.D; Phone Number: +4538682971; Email: rikke.boedker.holmstroem@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Not yet recruiting
    • Aalborg University Hospital
    • Contact: Peter Holland-Fischer, Ph.d, MD
  • Aarhus, Denmark, 8000
    • Recruiting
    • Aarhus University Hospital
    • Contact: Niels Kristian Aagaard, Ph.d., DMsc, MD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Contact: Peter N Bjerring, Ph.D. MD
  • Odense, Denmark, 5000
    • Recruiting
    • Odense University Hospital
    • Contact: Annette D Fialla, Ph.d, MD
  • Copenhagen
    • Herlev, Copenhagen, Denmark, 2730
      • Recruiting
      • Herlev University Hospital
      • Contact: Rikke B Holmstrøm, MD; Phone Number: +4538682971; Email: rikke.boedker.holmstroem@regionh.dk
      • Sub-Investigator: Ane S Teisner, MD
      • Sub-Investigator: Eva Ellebaek, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Cohort A:

- Abnormal liver parameters equal to ≥ grade 3 ir-hepatitis defined as; AST/ALT/ALP >5 x ULN, INR ≥ 2.5 x ULN, or bilirubin > 3.0 x ULN

Cohort B:

- Patients who recur during or within one months of prednisolone tapering of ≥2 ir-hepatitis equal to AST/ALT ≥3 x ULN, ALP ≥2.5 x ULN, INR ≥ 1.5 x ULN, or bilirubin ≥ 3.0 x ULN

Cohort A and Cohort B

• Histologically confirmed solid cancer
• Treatment with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) or Programmed Cell Death-1 (PD-1)/Programmed Cell Death Ligand-1 (PD-L1) inhibitor or a combination of CTLA-4 plus PD-1 inhibitors within 6 months
• Age: ≥ 18 years
• Women of childbearing potential: Negative serum pregnancy test and must use effective contraception. This applies from screening and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered effective contraceptives
• Men with female partner of childbearing potential must use effective contraception from screening and until 6 months after treatment. Effective contraceptives are as described above for the female partner. In addition, documented vasectomy and sterility or double barrier contraception are considered effective contraceptives
• Signed statement of consent after receiving oral and written study information
• Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.

Exclusion Criteria:

• Concomitant chemotherapy treatment or tyrosine kinases or angiogenesis inhibitors
• Concomitant immunosuppressive medication except prednisolone
• Patients with hepatocellular carcinoma
• Known hypersensitivity to one of the active drugs or excipients
• Uncontrolled infection
• Acute viral hepatitis
• Any medical condition that will interfere with patient compliance or safety
• Simultaneous treatment with other experimental drugs or other anticancer drugs
• Pregnant or breastfeeding females
• Phenylketonuria

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis; Patients with ≥ 3 grade ir-hepatitis will be treated with high-dose steroids 2 mg/kg/day intravenously. A diagnostic liver biopsy will be taken. Patients with mixed or cholestatic liver injury patterns will be added UDCA. Treatment evaluation will be performed after 72 hours, patients in UDCA will be evaluated will be on day 7. Patients with sufficient steroid response defined as ≥ 20% reduction in ALT, AST, ALP or bilirubin at day 4 or day 7 will undergo steroid tapering with a transition to peroral steroids. Patients with initial insufficient treatment response, defined as less than < 20% reduction in ALT, AST, ALP, or bilirubin, are considered as having a steroid-refractory condition and will be added MMF. In case of no response or increase of ALT, AST, ALP, or bilirubin during treatment with steroids plus MMF a third-line treatment may be introduced according to the individual treating hepatologist.	Drug: Mycophenolate Mofetil; Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day; Other Names: Cellcept; Myfenax; Drug: Solu-Medrol; 2 mg/kg/day; Other Names: Corticosteroids; Medrol; Methylprednisolone; Steroid; Drug: Ursodeoxycholic acid; Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight; Other Names: ursochol; Drug: Prednisone tablet; Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.; Other Names: Corticosteroids; steroid
Active Comparator: Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized); Patients who experienced relapse of ir-hepatitis of grade ≥2 during prednisolone tapering or within one months after ended tapering will be randomized to either 100% dose of current steroid dose or restart of steroid 0.5-1 mg/kg versus adding MMF (if the patient received prednisolone the tapering plan hereof is continued, prednisolone up to 25 mg can be added if clinical indicated). Treatment efficacy is evaluated after seven days, if sufficient response the patients continued treatment, in case of insufficient response a cross-over will be performed.	Drug: Mycophenolate Mofetil; Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day; Other Names: Cellcept; Myfenax; Drug: Ursodeoxycholic acid; Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight; Other Names: ursochol; Drug: Prednisone tablet; Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.; Other Names: Corticosteroids; steroid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-assessed hepatitis response rates	Treatment-assessed hepatitis response rates with steroids and steroids plus either mycophenolate mofetil or tacrolimus	Through study completion, an average of 5 years
Time to response or downgrading of liver injury in days	Time to response or downgrading of liver injury in patients with ≥grade 3 ir-hepatitis measured as; Days to ≥20 percent reduction in liver specific transaminases (ALT/AST) or bilirubin Days to shift to peroral prednisolone and discharge	Until completion of the study, an average of 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse rate of immune related hepatitis ≥2 during tapering plan	Percent of patients with relapse to grade ≥2 hepatitis during steroid or during steroid plus either mycophenolate mofetil or tacrolimus tapering.	Through study completion, an average of 5 years
Time to downgrading of hepatotoxicity assessed by CTCAE v5.0	Time to downgrading of hepatotoxicity from grade 4 to grade 3, to grade 2 and to grade 1, respectively, assessed by CTCAE v5.0	Through study completion, an average of 5 years
Description of histopathological changes in liver tissue	Number of patients with hepatocellular, cholestatic and mixed liver injury respectively, assessed by histological findings of predominant injury to hepatocytes, bile ducts or combined.	Until completion of the study, an average of 5 years
Incidence of abnormal laboratory test results	Incidence of abnormal laboratory test results in blood	Until completion of the study, an average of 5 years
Cumulated doses of corticosteroids and MMF respectively	Cumulated doses of corticosteroids and MMF respectively, during the study period of 6 months	Until completion of the study, an average of 5 years
Cancer progression free survival at 6 months	Cancer progression free survival at 6 months	Until completion of the study, an average of 5 years
Overall survival rates at 6 months	Overall survival rates at 6 months	Until completion of the study, an average of 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood biomarkers	Correlation of the baseline immune markers, genomics and other biomarkers in blood	Until completion of the study, an average of 5 years
Description of changes in the fecal microbiome	Description of changes in the fecal microbiome and characterization of the prevalence of specific bacteria e.g. Faecalibacterium and Firmicutes	Until completion of the study, an average of 5 years

Collaborators and Investigators

• Sponsor: Inge Marie Svane
• Investigators: Study Director: Inge M Svane, Study Director, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev; Principal Investigator: Rikke B Holmstrøm, Ph.D student, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2021
• Primary Completion (Anticipated): April 7, 2025
• Study Completion (Anticipated): November 7, 2025

Study Registration Dates

• First Submitted: March 17, 2021
• First Submitted That Met QC Criteria: March 19, 2021
• First Posted (Actual): March 22, 2021

Study Record Updates

• Last Update Posted (Estimate): December 14, 2022
• Last Update Submitted That Met QC Criteria: December 11, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Cancer; Immunotherapy; Hepatitis; Adverse events; Immune checkpoint inhibitors; Steroid-refractory; Steroid-dependent
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Drug-Related Side Effects and Adverse Reactions; Poisoning; Hepatitis; Hepatitis A; Chemical and Drug Induced Liver Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Cholagogues and Choleretics; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Prednisone; Mycophenolic Acid; Ursodeoxycholic Acid
• Other Study ID Numbers: AA2032

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No