Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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

Conditions
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Hepatitis, Drug-Induced

Intervention / Treatment
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* Drug: Mycophenolate Mofetil
* Drug: Solu-Medrol
* Drug: Ursodeoxycholic acid
* Drug: Prednisone tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The aim is to enroll around 40 patients in Cohort A for prospectively characterize the various patterns of liver injury histopathologically, biochemically, and phenotypically that are induced by ICI, and the response to treatment (steroids and MMF). Cohort B: 20 patients who experienced a relapse of ir-hepatitis (grade ≥2) during prednisolone tapering or within one month 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis<br>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<br>* Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day<br>* Other names: Myfenax;Drug: Solu-Medrol<br>* 2 mg/kg/day<br>* Other names: Steroid;Drug: Ursodeoxycholic acid<br>* Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight<br>* Other names: ursochol;Drug: Prednisone tablet<br>* Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.<br>* Other names: Corticosteroids;|
| Active Comparator: Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)<br>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<br>* Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day<br>* Other names: Myfenax;Drug: Ursodeoxycholic acid<br>* Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight<br>* Other names: ursochol;Drug: Prednisone tablet<br>* Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.<br>* Other names: Corticosteroids;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis, Immunotherapy, Cancer, Adverse events, Immune checkpoint inhibitors, Steroid-refractory, Steroid-dependent