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

NCT04810156 | Unknown Phase 2 DMC

• 1 other identifier: AA2032
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 5

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.

Conditions

Hepatitis, Drug-Induced

Keywords

Hepatitis; Immunotherapy; Cancer; Adverse events; Immune checkpoint inhibitors; Steroid-refractory; Steroid-dependent

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• Relapse rate of immune related hepatitis ≥2 during tapering plan

  Through study completion, an average of 5 years

• Time to downgrading of hepatotoxicity assessed by CTCAE v5.0

  Through study completion, an average of 5 years

• Description of histopathological changes in liver tissue

  Until completion of the study, an average of 5 years

• Incidence of abnormal laboratory test results

  Until completion of the study, an average of 5 years

• Cumulated doses of corticosteroids and MMF respectively

  Until completion of the study, an average of 5 years

Other Outcomes (2)

• Blood biomarkers

  Until completion of the study, an average of 5 years

• Description of changes in the fecal microbiome

  Until completion of the study, an average of 5 years

Study Arms (2)

Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis

ACTIVE COMPARATOR

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; Drug: Solu-Medrol; Drug: Ursodeoxycholic acid; Drug: Prednisone tablet

Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)

ACTIVE COMPARATOR

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; Drug: Ursodeoxycholic acid; Drug: Prednisone tablet

Interventions

Mycophenolate Mofetil DRUG

Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day

Also known as: Cellcept, Myfenax

Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis; Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)

Solu-Medrol DRUG

2 mg/kg/day

Also known as: Methylprednisolone, Medrol, Corticosteroids, Steroid

Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis

Ursodeoxycholic acid DRUG

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

Also known as: ursochol

Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis; Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)

Prednisone tablet DRUG

Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.

Also known as: steroid, Corticosteroids

Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis; Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Inge Marie Svane: lead

Study Sites (5)

Herlev University Hospital

Herlev, Copenhagen, 2730, Denmark

RECRUITING

Aalborg University Hospital

Aalborg, 9000, Denmark

NOT YET RECRUITING

Aarhus University Hospital

Aarhus, 8000, Denmark

RECRUITING

Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

Odense University Hospital

Odense, 5000, Denmark

RECRUITING

MeSH Terms

Conditions

Chemical and Drug Induced Liver Injury; Hepatitis; Neoplasms

Interventions

Mycophenolic Acid; Methylprednisolone Hemisuccinate; Methylprednisolone; Adrenal Cortex Hormones; Steroids; Ursodeoxycholic Acid; Prednisone

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Fused-Ring Compounds; Polycyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Cholanes; Pregnadienediols

Study Officials

• Inge M Svane

  Study Director, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev

  STUDY DIRECTOR

• Rikke B Holmstrøm

  Ph.D student, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Inge Marie Svane, M.D. Professor

CONTACT

+38683868; inge.marie.svane@regionh.dk

Rikke B Holmstrøm, M.D

CONTACT

+4538682971; rikke.boedker.holmstroem@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: M.D. Professor

Model Details: 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

Study Record Dates

• First Submitted: March 17, 2021
• First Posted: March 22, 2021
• Study Start: April 7, 2021
• Primary Completion: April 7, 2025
• Study Completion: November 7, 2025
• Last Updated: December 14, 2022

Record last verified: 2022-12

Locations

DK (5)