Clinical trial NCT04810156: Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Hepatitis, Drug-Induced
Keywords: Hepatitis
Immunotherapy
Cancer
Adverse events
Immune checkpoint inhibitors
Steroid-refractory
Steroid-dependent
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
First posted: 2021-03-22
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Treatment-assessed hepatitis response rates
timeFrame: Through study completion, an average of 5 years
measure: Time to response or downgrading of liver injury in days
timeFrame: Until completion of the study, an average of 5 years
Secondary outcomes:
measure: Relapse rate of immune related hepatitis ≥2 during tapering plan
timeFrame: Through study completion, an average of 5 years
measure: Time to downgrading of hepatotoxicity assessed by CTCAE v5.0
timeFrame: Through study completion, an average of 5 years
measure: Description of histopathological changes in liver tissue
timeFrame: Until completion of the study, an average of 5 years
measure: Incidence of abnormal laboratory test results
timeFrame: Until completion of the study, an average of 5 years
measure: Cumulated doses of corticosteroids and MMF respectively
timeFrame: Until completion of the study, an average of 5 years
measure: Cancer progression free survival at 6 months
timeFrame: Until completion of the study, an average of 5 years
measure: Overall survival rates at 6 months
timeFrame: Until completion of the study, an average of 5 years
Other outcomes:
measure: Blood biomarkers
timeFrame: Until completion of the study, an average of 5 years
measure: Description of changes in the fecal microbiome
timeFrame: Until completion of the study, an average of 5 years
Locations:
city: Herlev
country: Denmark
facility: Herlev University Hospital
state: Copenhagen
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
Study officials:
affiliation: Study Director, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev
name: Inge M Svane
role: STUDY_DIRECTOR
affiliation: Ph.D student, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev
name: Rikke B Holmstrøm
role: PRINCIPAL_INVESTIGATOR
References: