Efficacy of high-dose steroids, mycophenolate mofetil and tacrolimus for treatment of patients with immune related hepatitis induced by cancer immunotherapy

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 - I-HEP

Status

Active, not recruiting

Phases

Phase 2

Study type

Interventional

Source

EU CTR

Registry ID

EUCTR2020-004483-26-DK

Enrollment

Registered

2020-09-17

Start date

2021-03-17

Completion date

Unknown

Last updated

2025-09-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cohort A: Immune related hepatitis induced by immune checkpoint inhibitor grade III-IV Cohort B: Immune related hepatitis induced by immune checkpoint inhibitor grade II-IV (relapse during prednsisolone tapering) MedDRA version: 20.1 Level: LLT Classification code 10019766 Term: Hepatitis drug-induced System Organ Class: 100000004871

Interventions

Trade Name: Mycophenolate mofetil (mycophenolatmofetil) Product Name: mycophenolatmofetil Pharmaceutical Form: Tablet INN or Proposed INN: mycophenolatmofetil Other descriptive name: MYCOPHENOLATE MOF

Eligibility

Sex/Gender

All

Inclusion criteria

Inclusion criteria: 4.3.1 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 CTLA-4, PD-1/PD-L1 or LAG3 inhibitor or a combination of CTLA-4 plus PD-1, PD-1 plus LAG3, and PD-1 plus IDO inhibitors within 6 months - = 18 years of age - 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40

Exclusion criteria

Exclusion criteria: 4.3.2 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 anti-cancer drugs - Pregnant or breastfeeding females - Phenylketonuria

Design outcomes

Primary

Measure	Time frame
Main Objective: This study is performed to evaluate the crucially important question of which patients with immune related hepatitis will respond to standard treatment with steroids and who needs treatment with a second line immunosuppressive agent in this case steroids plus mycophenolate mofetil or tacrolimus. Treatment efficacy is evaluated as percentage reduction of liver transaminases or bilirubin, and time to peroral prednisolone and discharge in days;Secondary Objective: Secondary objectives include which patients experience relapse during or after treatment with steroids and mycophenolate mofetil; time to downgrading of Common Terminology Criteria for Adverse Events (CTCAE) grade; changes in blood, liver tissue and phenotypical features during treatment; pre-events before debut of immune related hepatitis; and toxicity related to steroids and mycophenolate mofetil. In addition, the influence of ir-hepatitis and the treatment hereof on the cancer will be explored, including the eligibility for further antineoplastic treatment, and if the event of immune related hepatitis influence progression-free survival and survival rates. Furthermore, to achieve a deeper understanding of immune related adverse events and find potential biomarkers for the risk of developing immune related adverse events , immune responses in blood and in the affected organ are analyzed in a selected group of patients. ;Primary end point(s): 3.3.1Primary endpoints •Treatment-assessed hepatitis response rates with steroids, and increased dosis of steroids versus MMF •Time to response or downgrading of liver injury in patients with = grade 3 ir-hepatitis and patients with relapse of ir-hepatitis (=2 grade) measured as; - Days to =20% reduction in ALT/AST/ALP or bilirubin - Days to shift to peroral prednisolone and discharge - Days for stopping treatment ;Timepoint(s) of evaluation of this end point: Cohort A: Response rates for steroids is evaluate after minimum 72 hours of treatment, or	—

Measure

Time frame

Main Objective: This study is performed to evaluate the crucially important question of which patients with immune related hepatitis will respond to standard treatment with steroids and who needs treatment with a second line immunosuppressive agent in this case steroids plus mycophenolate mofetil or tacrolimus. Treatment efficacy is evaluated as percentage reduction of liver transaminases or bilirubin, and time to peroral prednisolone and discharge in days;Secondary Objective: Secondary objectives include which patients experience relapse during or after treatment with steroids and mycophenolate mofetil; time to downgrading of Common Terminology Criteria for Adverse Events (CTCAE) grade; changes in blood, liver tissue and phenotypical features during treatment; pre-events before debut of immune related hepatitis; and toxicity related to steroids and mycophenolate mofetil. In addition, the influence of ir-hepatitis and the treatment hereof on the cancer will be explored, including the eligibility for further antineoplastic treatment, and if the event of immune related hepatitis influence progression-free survival and survival rates. Furthermore, to achieve a deeper understanding of immune related adverse events and find potential biomarkers for the risk of developing immune related adverse events , immune responses in blood and in the affected organ are analyzed in a selected group of patients. ;Primary end point(s): 3.3.1Primary endpoints •Treatment-assessed hepatitis response rates with steroids, and increased dosis of steroids versus MMF •Time to response or downgrading of liver injury in patients with = grade 3 ir-hepatitis and patients with relapse of ir-hepatitis (=2 grade) measured as; - Days to =20% reduction in ALT/AST/ALP or bilirubin - Days to shift to peroral prednisolone and discharge - Days for stopping treatment ;Timepoint(s) of evaluation of this end point: Cohort A: Response rates for steroids is evaluate after minimum 72 hours of treatment, or

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Secondary

Measure	Time frame
Secondary end point(s): 3.3.2 Secondary endpoints • Relapse Rate: Percent of patients with relapse to grade =2 hepatitis during steroid tapering or MMF • Time to downgrading of hepatotoxicity from grade 4 to grade 3, to grade 2 and to grade 1, respectively • Changes in biochemical, histopathological and phenotypical features during treatment • Cumulated doses of corticosteroid and MMF respectively • Toxicity related to steroids and second line immunosuppressive treatment with MMF • Pre-events before developing ir-hepatitis will be analysed • Progression free survival and survival rates at 6 and 12 months. • Proportions of patients eligible for further antineoplastic treatment and re-start of ICI therapy will be studied;Timepoint(s) of evaluation of this end point: Cohort A: The evaluation will be performed before, during and after treatment for up to three months after treatment initiation in patients with proper steroid response and minimum for 6 months in patients with a steroid refractory condition Cohort B: The evaluation will be performed before, during and after treatment for up to six months after treatment initiation in all patients	—

Measure

Time frame

Secondary end point(s): 3.3.2 Secondary endpoints • Relapse Rate: Percent of patients with relapse to grade =2 hepatitis during steroid tapering or MMF • Time to downgrading of hepatotoxicity from grade 4 to grade 3, to grade 2 and to grade 1, respectively • Changes in biochemical, histopathological and phenotypical features during treatment • Cumulated doses of corticosteroid and MMF respectively • Toxicity related to steroids and second line immunosuppressive treatment with MMF • Pre-events before developing ir-hepatitis will be analysed • Progression free survival and survival rates at 6 and 12 months. • Proportions of patients eligible for further antineoplastic treatment and re-start of ICI therapy will be studied;Timepoint(s) of evaluation of this end point: Cohort A: The evaluation will be performed before, during and after treatment for up to three months after treatment initiation in patients with proper steroid response and minimum for 6 months in patients with a steroid refractory condition Cohort B: The evaluation will be performed before, during and after treatment for up to six months after treatment initiation in all patients

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Countries

Denmark

Contacts

Public ContactPrincipal investigator

National Center for Cancer Immune Therapy (CCIT-DK)

rikke.boedker.holmstroem@regionh.dk4538682971

Outcome results

None listed

Source: EU CTR (via WHO ICTRP) · Data processed: Feb 4, 2026