I-HEP: Treatment Efficacy of Corticosteroids, Mycophenolate Mofetil and Tacrolimus in Patients With Immune Related Hepatitis

Sponsor

Inge Marie Svane (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04810156

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

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 refractory to steroids. The project aims to prospectively characterize the various histopathological, biochemical and phenotypical liver injury patterns induced by immune checkpoint inhibitors, and the response to treatment to corticosteroids. Furthermore, the effect of adding a second-line immunosuppressive drug, either MMF or tacrolimus in steroid refractory or steroid dependent cases will be explored and compared.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis, Drug-Induced	Drug: Mycophenolate Mofetil Drug: Tacrolimus Drug: Solu-Medrol Drug: Ursodeoxycholic acid	Phase 2

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 adverse event, here, estimated in up to 90% 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 case series and includes immunosuppressive treatment with mycophenolate mofetil (MMF). To date, no evidence exists for which second line treatment to choose.

Based on the similarity of immune related hepatitis with autoimmune hepatitis, tacrolimus may be more efficient than MMF in achieving complete and faster response in patients with steroid refractory or steroid dependent ir-hepatitis. Furthermore, patients with signs of biliary injury may benefit from adding ursodeoxycholic acid (UDCA).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The aim is to enrol around 80 patients to achieve 20 patients with a refractory to corticosteroids for block-randomization. During treatment initiation all patients will be treated with Solu-medrol 2 mg/kg/day for at least 72 hours. Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA. Patients with sufficient steroid response will undergo steroid tapering with transition to peroral steroids. Patients with insufficient treatment response are considered as having a steroid refractory condition and will undergo block-randomization to either MMF or tacrolimus (second line) meanwhile current steroid dose is continued. 10 patients will be allocated to mycophenolate mofetil 10 patients will be allocated to tacrolimus Meanwhile corticosteroids are continued until response of the above treatment, defined as least 20 percent reduction of liver parametersThe aim is to enrol around 80 patients to achieve 20 patients with a refractory to corticosteroids for block-randomization. During treatment initiation all patients will be treated with Solu-medrol 2 mg/kg/day for at least 72 hours. Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA. Patients with sufficient steroid response will undergo steroid tapering with transition to peroral steroids. Patients with insufficient treatment response are considered as having a steroid refractory condition and will undergo block-randomization to either MMF or tacrolimus (second line) meanwhile current steroid dose is continued. 10 patients will be allocated to mycophenolate mofetil 10 patients will be allocated to tacrolimus Meanwhile corticosteroids are continued until response of the above treatment, defined as least 20 percent reduction of liver parameters

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Patients With Hepatitis Induced by Checkpoint Inhibitors; Characterization of Liver Injury, Outcome of Therapy and Randomization to Either Mycophenolate Mofetil or Tacrolimus Treatment in Case of Steroid Resistance

Anticipated Study Start Date :

Apr 7, 2021

Anticipated Primary Completion Date :

Apr 7, 2023

Anticipated Study Completion Date :

Nov 7, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Mycophenolate mofetil If less than 20 percent reduction in ALT/AST or bilirubin during treatment with corticosteroids or corticosteroids plus UDCA at day 4 or at day 7 respectively, the patient will undergo block-randomized to an add on of MMF or tacrolimus Meanwhile tapering of corticosteroids in patients with sufficient response. MMF will be stopped 8 weeks after treatment stop of corticosteroids.	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: Methylprednisolone Prednisolone Medrol Corticosteroids Steroid Drug: Ursodeoxycholic acid Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA Other Names: ursochol
Active Comparator: Tacrolimus If less than 20 percent reduction in ALT/AST or bilirubin during treatment with corticosteroids or corticosteroids plus UDCA at day 4 or at day 7 respectively, the patient will undergo block-randomized to an add on of MMF or tacrolimus Meanwhile tapering of corticosteroids in patients with sufficient response. Tacrolimus will be stopped 8 weeks after treatment stop of corticosteroids.	Drug: Tacrolimus Day 1: Tacrolimus 1 mg twice a day Day 2-5: Tacrolimus 3 mg twice a day From day 6 and onwards: Dose adjustment according to trough level Other Names: Prograf Advagraf Adport Drug: Solu-Medrol 2 mg/kg/day Other Names: Methylprednisolone Prednisolone Medrol Corticosteroids Steroid Drug: Ursodeoxycholic acid Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA Other Names: ursochol

Arm

Intervention/Treatment

Active Comparator: Mycophenolate mofetil

If less than 20 percent reduction in ALT/AST or bilirubin during treatment with corticosteroids or corticosteroids plus UDCA at day 4 or at day 7 respectively, the patient will undergo block-randomized to an add on of MMF or tacrolimus Meanwhile tapering of corticosteroids in patients with sufficient response. MMF will be stopped 8 weeks after treatment stop of corticosteroids.

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:

Methylprednisolone

Prednisolone

Medrol

Corticosteroids

Steroid

Drug: Ursodeoxycholic acid

Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA

Other Names:

ursochol

Active Comparator: Tacrolimus

If less than 20 percent reduction in ALT/AST or bilirubin during treatment with corticosteroids or corticosteroids plus UDCA at day 4 or at day 7 respectively, the patient will undergo block-randomized to an add on of MMF or tacrolimus Meanwhile tapering of corticosteroids in patients with sufficient response. Tacrolimus will be stopped 8 weeks after treatment stop of corticosteroids.

Drug: Tacrolimus

Day 1: Tacrolimus 1 mg twice a day Day 2-5: Tacrolimus 3 mg twice a day From day 6 and onwards: Dose adjustment according to trough level

Other Names:

Prograf

Advagraf

Adport

Drug: Solu-Medrol

2 mg/kg/day

Other Names:

Methylprednisolone

Prednisolone

Medrol

Corticosteroids

Steroid

Drug: Ursodeoxycholic acid

Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA

Other Names:

ursochol

Outcome Measures

Primary Outcome Measures

Treatment-assessed hepatitis response rates [Through study completion, an average of 2 years]
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 [Until completion of the study, an average of 2.5 years]
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 [Through study completion, an average of 2 years]
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 [Through study completion, an average of 2 years]
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 [Until completion of the study, an average of 2.5 years]
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 [Until completion of the study, an average of 2.5 years]
Incidence of abnormal laboratory test results in blood
Cumulated doses of corticosteroids, MMF and tacrolimus respectively [Until completion of the study, an average of 2.5 years]
Cumulated doses of corticosteroids, MMF and tacrolimus respectively during the study period of 6 months
Cancer progression free survival at 6 months [Until completion of the study, an average of 2.5 years]
Cancer progression free survival at 6 months
Overall survival rates at 6 months [Until completion of the study, an average of 2.5 years]
Overall survival rates at 6 months

Other Outcome Measures

Blood biomarkers [Until completion of the study, an average of 2.5 years]
Correlation of the baseline immune markers, genomics and other biomarkers in blood

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Herlev University Hospital	Herlev	Copenhagen	Denmark	2730
2	Aalborg University Hospital	Aalborg		Denmark	9000
3	Aarhus University Hospital	Aarhus		Denmark	8000
4	Rigshospitalet	Copenhagen		Denmark	2100
5	Odense University Hospital	Odense		Denmark	5000

Sponsors and Collaborators

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