Infections

Digestive System Diseases

All Conditions

Substance Related Disorders

Symptoms and General Pathology

Hepatitis A

Hepatitis

Chemical and Drug Induced Liver Injury

Liver Diseases

Gastrointestinal Diseases

Hepatitis, Viral, Human

Virus Diseases

Communicable Diseases

Enterovirus Infections

Picornaviridae Infections

RNA Virus Infections

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Poisoning

Antineoplastic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Anti-Infective Agents

Gastrointestinal Agents

Hematinics

Antiemetics

Neuroprotective Agents

Immune Checkpoint Inhibitors

Prednisone

Prednisolone

Immunomodulating Agents

Mycophenolic Acid

Ursodeoxycholic Acid

Liver Extracts

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Bilirubin

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Enzyme Inhibitors

Protective Agents

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.

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

Mycophenolate Mofetil

Solu-Medrol

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

Ursodeoxycholic acid

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

Prednisone tablet

Inge Marie Svane, M.D. Professor

Rikke B Holmstrøm, M.D

Rikke B Holmstrøm, MD

Ane S Teisner, MD

Eva Ellebaek, MD

Peter Holland-Fischer, Ph.d, MD

Niels Kristian Aagaard, Ph.d., DMsc, MD

Peter N Bjerring, Ph.D. MD

Annette D Fialla, Ph.d, MD

Inge M Svane

Rikke B Holmstrøm

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.

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).

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

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

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

Correlation of the baseline immune markers, genomics and other biomarkers in blood

Description of changes in the fecal microbiome and characterization of the prevalence of specific bacteria e.g. Faecalibacterium and Firmicutes

Treatment-assessed hepatitis response rates with steroids and steroids plus either mycophenolate mofetil or tacrolimus

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

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 from grade 4 to grade 3, to grade 2 and to grade 1, respectively, assessed by CTCAE v5.0

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 in blood

Cumulated doses of corticosteroids and MMF respectively, during the study period of 6 months

Cancer progression free survival at 6 months

Inge Marie Svane

M.D. Professor

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Abiraterone Acetate

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Subjects will receive a regimen of Olaparib tablets 300 mg twice daily in combination with Abiraterone acetate 1000 mg plus Prednisone 5mg once daily until radiographic disease progression (assessed by the investigator according to RECIST1.1 and PCWG3) or intolerable adverse events (assessed by the investigator according to the actual clinical situation).

Lynparza (Olaparib tablets) 300 mg should be taken orally twice daily.

Olaparib tablet

Qingkeshu (Abiraterone acetate tablets) 1000 mg should be taken orally once daily.

Abiraterone acetate

Prednisone Tablets should be taken 5 mg once daily.

Junlong Zhuang, MD

This is a single-center, single-arm, prospective study to assess the efficacy and safety of Olaparib combined with Abiraterone plus Prednisone in subjects with metastatic hormone sensitive prostate cancer (mHSPC) who carry deleterious germline or homologous recombination repair (HRR) mutations.

Olaparib is an oral, highly selective poly (ADP-ribose) polymerase (PARP) inhibitor that potently inhibits the activity of deoxyribonucleic acid repair polymerases. Abiraterone acetate (AA) is a prodrug of abiraterone that potently inhibits cytochrome P450c17, a key enzyme in androgen biosynthesis.

A total of 30 mHSPC subjects with HRR gene mutations that meet the criteria will be included in the study. Eligible subjects will receive oral Olaparib tablets 300 mg BID, combined with Abiraterone acetate 1000 mg QD plus Prednisone 5 mg, and the study will end when the primary endpoint radiographic progression-free survival (rPFS) data maturity reaches 60%. During the treatment and follow-up periods, all subjects will have regular visits to assess the efficacy and safety of Olaparib in combination with abiraterone acetate plus prednisone. Radiographic progression-free survival (rPFS), prostate-specific antigen response (PSA response rate), prostate-specific antigen progression-free survival (PSA-PFS), radiological objective response rate (ORR) and other indicators will be assessed and calculated.

The Study of Olaparib Combined With Abiraterone and Prednisone in mHSPC Patients With HRR Gene Mutation

A Single-center, Single-arm, Prospective Study to Investigate the Efficacy and Safety of Olaparib Combined With Abiraterone and Prednisone in mHSPC Patients With HRR Gene Mutation

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment

Time from the start of study drug to radiographic progression, or death due to any cause, whichever occurs first.

PSA response is defined as a ≥ 50% decline in PSA from baseline PSA value. This PSA decline must be confirmed as sustained by a second PSA value obtained ≥ 3 weeks later.

PSA-PFS is defined as the time from the start of study drug to the first PSA progression or death due to any cause without progression. PSA progression is defined as a first PSA increase greater than or equal to 25% of baseline and ≥ 2 ng/ml and confirmed a second time after 3 or more weeks.

ORR is the percentage of patients with at least one visit response of Complete response (CR) or Partial response (PR), in their soft tissue disease assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), in the absence of progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3)). Per RECIST v1.1, CR=Disappearance of all target lesions; PR = \>=30% decrease in the sum of diameters of target lesions; For each treatment group, ORR is the number of patients with a CR and PR.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis	NCT04810156	Hepatitis, Drug...	Mycophenolate M... Solu-Medrol Ursodeoxycholic... Prednisone tabl...	18 Years -	Herlev Hospital
The Study of Olaparib Combined With Abiraterone and Prednisone in mHSPC Patients With HRR Gene Mutation	NCT05167175	Prostate Cancer Prostate Carcin... Metastatic Pros...	Olaparib tablet Abiraterone ace... Prednisone tabl...	18 Years -	The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
The Study of Olaparib Combined With Abiraterone and Prednisone in mHSPC Patients With HRR Gene Mutation	NCT05167175	Prostate Cancer Prostate Carcin... Metastatic Pros...	Olaparib tablet Abiraterone ace... Prednisone tabl...	18 Years -	The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

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