Treatment Efficacy of Corticosteroids, Mycophenolate Mofetil and Tacrolimus in Patients With Immune Related Hepatitis
Treatment Efficacy of Corticosteroids, Mycophenolate Mofetil and Tacrolimus in Patients With Immune Related Hepatitis
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.
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).
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