Back to resultsTreatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis (I-HEP)
Primary Purpose
Hepatitis, Drug-Induced
Status
Recruiting
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Mycophenolate Mofetil
Solu-Medrol
Ursodeoxycholic acid
Prednisone tablet
Sponsored by
About this trial
This is an interventional treatment trial for Hepatitis, Drug-Induced focused on measuring Hepatitis, Immunotherapy, Cancer, Adverse events, Immune checkpoint inhibitors, Steroid-refractory, Steroid-dependent
Eligibility Criteria
Inclusion Criteria:
- 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
- Abnormal liver parameters equal to ≥ grade 3 ir-hepatitis defined as; AST/ALT >5 x upper level of normal (ULN), International Normalised Ratio (INR) ≥ 2.5 x ULN, or bilirubin > 3.0 x ULN
- 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
Sites / Locations
- Herlev University HospitalRecruiting
- Aalborg University Hospital
- Aarhus University HospitalRecruiting
- RigshospitaletRecruiting
- Odense University HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis
Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Treatment-assessed hepatitis response rates
Treatment-assessed hepatitis response rates with steroids and steroids plus either mycophenolate mofetil or tacrolimus
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
Secondary Outcome Measures
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.
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
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.
Incidence of abnormal laboratory test results
Incidence of abnormal laboratory test results in blood
Cumulated doses of corticosteroids and MMF respectively
Cumulated doses of corticosteroids and MMF respectively, during the study period of 6 months
Cancer progression free survival at 6 months
Cancer progression free survival at 6 months
Overall survival rates at 6 months
Overall survival rates at 6 months
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04810156
Brief Title
Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis
Acronym
I-HEP
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
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 7, 2021 (Actual)
Primary Completion Date
April 7, 2025 (Anticipated)
Study Completion Date
November 7, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Inge Marie Svane
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis, Drug-Induced
Keywords
Hepatitis, Immunotherapy, Cancer, Adverse events, Immune checkpoint inhibitors, Steroid-refractory, Steroid-dependent
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
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)
Allocation
Randomized
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
Cellcept, Myfenax
Intervention Description
Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day
Intervention Type
Drug
Intervention Name(s)
Solu-Medrol
Other Intervention Name(s)
Methylprednisolone, Medrol, Corticosteroids, Steroid
Intervention Description
2 mg/kg/day
Intervention Type
Drug
Intervention Name(s)
Ursodeoxycholic acid
Other Intervention Name(s)
ursochol
Intervention Description
Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight
Intervention Type
Drug
Intervention Name(s)
Prednisone tablet
Other Intervention Name(s)
steroid, Corticosteroids
Intervention Description
Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.
Primary Outcome Measure Information:
Title
Treatment-assessed hepatitis response rates
Description
Treatment-assessed hepatitis response rates with steroids and steroids plus either mycophenolate mofetil or tacrolimus
Time Frame
Through study completion, an average of 5 years
Title
Time to response or downgrading of liver injury in days
Description
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
Time Frame
Until completion of the study, an average of 5 years
Secondary Outcome Measure Information:
Title
Relapse rate of immune related hepatitis ≥2 during tapering plan
Description
Percent of patients with relapse to grade ≥2 hepatitis during steroid or during steroid plus either mycophenolate mofetil or tacrolimus tapering.
Time Frame
Through study completion, an average of 5 years
Title
Time to downgrading of hepatotoxicity assessed by CTCAE v5.0
Description
Time to downgrading of hepatotoxicity from grade 4 to grade 3, to grade 2 and to grade 1, respectively, assessed by CTCAE v5.0
Time Frame
Through study completion, an average of 5 years
Title
Description of histopathological changes in liver tissue
Description
Number of patients with hepatocellular, cholestatic and mixed liver injury respectively, assessed by histological findings of predominant injury to hepatocytes, bile ducts or combined.
Time Frame
Until completion of the study, an average of 5 years
Title
Incidence of abnormal laboratory test results
Description
Incidence of abnormal laboratory test results in blood
Time Frame
Until completion of the study, an average of 5 years
Title
Cumulated doses of corticosteroids and MMF respectively
Description
Cumulated doses of corticosteroids and MMF respectively, during the study period of 6 months
Time Frame
Until completion of the study, an average of 5 years
Title
Cancer progression free survival at 6 months
Description
Cancer progression free survival at 6 months
Time Frame
Until completion of the study, an average of 5 years
Title
Overall survival rates at 6 months
Description
Overall survival rates at 6 months
Time Frame
Until completion of the study, an average of 5 years
Other Pre-specified Outcome Measures:
Title
Blood biomarkers
Description
Correlation of the baseline immune markers, genomics and other biomarkers in blood
Time Frame
Until completion of the study, an average of 5 years
Title
Description of changes in the fecal microbiome
Description
Description of changes in the fecal microbiome and characterization of the prevalence of specific bacteria e.g. Faecalibacterium and Firmicutes
Time Frame
Until completion of the study, an average of 5 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Inge Marie Svane, M.D. Professor
Phone
+38683868
Email
inge.marie.svane@regionh.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Rikke B Holmstrøm, M.D
Phone
+4538682971
Email
rikke.boedker.holmstroem@regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Inge M Svane
Organizational Affiliation
Study Director, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Rikke B Holmstrøm
Organizational Affiliation
Ph.D student, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev
Official's Role
Principal Investigator
Facility Information:
Facility Name
Herlev University Hospital
City
Herlev
State/Province
Copenhagen
ZIP/Postal Code
2730
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rikke B Holmstrøm, MD
Phone
+4538682971
Email
rikke.boedker.holmstroem@regionh.dk
First Name & Middle Initial & Last Name & Degree
Ane S Teisner, MD
First Name & Middle Initial & Last Name & Degree
Eva Ellebaek, MD
Facility Name
Aalborg University Hospital
City
Aalborg
ZIP/Postal Code
9000
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Holland-Fischer, Ph.d, MD
Facility Name
Aarhus University Hospital
City
Aarhus
ZIP/Postal Code
8000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Niels Kristian Aagaard, Ph.d., DMsc, MD
Facility Name
Rigshospitalet
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter N Bjerring, Ph.D. MD
Facility Name
Odense University Hospital
City
Odense
ZIP/Postal Code
5000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Annette D Fialla, Ph.d, MD
12. IPD Sharing Statement
Learn more about this trial
Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis
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