Evaluation of Baricitinib in Combination with Standard Care for Treatment of Large Inflammatory Hepatocellular Adenomas in Histologically Confirmed Patients

Trial ID: 2023-505278-13-00
Protocol: APHP220916
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Hepatic adenoma

Objectives

The primary objective of this study is to evaluate the efficacy of an oral **JAK1/2 inhibitor**, baricitinib, in combination with standard care measures, such as discontinuation of estrogen-based contraception and weight loss, in achieving a significant reduction in the size of large inflammatory hepatocellular adenomas (HCA) as observed through imaging. This is clinically relevant as it aims to provide a non-surgical therapeutic option for patients with large inflammatory HCA, potentially reducing the need for invasive procedures.

Secondary objectives include:

Assessing the radiological response using RECIST 1.1 criteria at 3 and 6 months.
Evaluating the decrease in size of target lesions below 5 cm at 3 and 6 months.
Determining the need for liver surgery at 6 and 24 months due to insufficient tumor size reduction under baricitinib.
Monitoring the incidence of adverse events related to baricitinib.
Evaluating the radiological response in patients with multiple HCA, excluding inflammatory HCA confirmed at histology.
Observing the occurrence of symptomatic bleeding of HCA during follow-up.
Assessing the incidence of malignant transformation of hepatocellular adenomas into hepatocellular carcinoma.
Monitoring the occurrence of an increase in tumor size or number after discontinuation of baricitinib.
Evaluating the increase in tumor size greater than 5 cm after discontinuation of baricitinib.
Assessing the incidence of postoperative adverse events in cases requiring hepatic surgery for HCA.

Participants

The clinical trial involves a study population comprising both **female** and **male** participants. The age range of the participants is not specified, and the total number of participants is not provided by the sponsor. The trial focuses on individuals diagnosed with inflammatory **hepatocellular adenoma** (HCA), confirmed through histology. Female participants must have at least one inflammatory HCA larger than 5 cm, while male participants are included if they have a non-resectable inflammatory HCA, regardless of size. Participants are required to have a past infection of Varicella zoster Virus confirmed by serology or vaccination done more than four weeks prior to inclusion. The trial excludes vulnerable populations and requires participants to have medical insurance coverage. Lifestyle considerations include the discontinuation of estrogen-based contraception and weight loss if overweight, as part of the standard care. Participants must provide written informed consent and adhere to contraception guidelines during and after treatment with the investigational product, baricitinib. The trial does not include any vulnerable populations.

Plans and Procedures

The clinical trial is designed as a **phase 2 open-label single-arm study** to evaluate the efficacy of an oral JAK1/2 inhibitor, **baricitinib**, in combination with standard care for the treatment of large inflammatory hepatocellular adenomas (HCA). The trial aims to demonstrate a significant reduction in the size of large inflammatory HCA at imaging. The study will involve the administration of **baricitinib** in the form of film-coated tablets, with a maximum daily dose of 4 mg, over a treatment period of 26 weeks. The trial is expected to commence recruitment on September 2, 2024, and conclude by September 2, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven inflammatory HCA and past infection or vaccination against Varicella zoster virus. Follow-up visits will occur at 3 months and 6 months, during which MRI assessments will be conducted to evaluate the primary endpoint: a decrease in target lesion size by at least 30% in 50% of patients, as per RECIST 1.1 criteria. Secondary endpoints include the proportion of overall radiological responses, adverse events, and the need for liver surgery. The end-of-study visit will occur at 24 months post-treatment to assess long-term outcomes and adverse events.

Participant involvement is expected to last up to 24 months, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include the progression of disease, significant adverse events, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards, ensuring that all data is collected and analyzed in a controlled and unbiased manner.

Treatment

The clinical trial involves the administration of **Olumiant 2 mg film-coated tablets**, which contain the active substance **baricitinib**. Baricitinib is a chemical compound known for its role as a JAK1/2 inhibitor. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. The maximum daily dose for this formulation is 2 mg, with a total maximum dose of 364 mg over a treatment period of 26 weeks. The medication is manufactured by ELI LILLY NEDERLAND B.V. and is authorized for use in the European Union under the marketing authorization number EU/1/16/1170/001.

Additionally, the trial includes the use of **Olumiant 4 mg film-coated tablets**, also containing **baricitinib** as the active ingredient. This formulation is similarly presented as a film-coated tablet for oral administration. The maximum daily dose for the 4 mg tablets is 4 mg, with a total maximum dose of 728 mg over the same 26-week treatment period. This product is also produced by ELI LILLY NEDERLAND B.V. and holds the marketing authorization number EU/1/16/1170/009 within the European Union.

In conjunction with the experimental medication, the study protocol includes standard-of-care therapy, which involves the discontinuation of estrogen-based contraception for patients who were using it and weight loss interventions for those who are overweight. These non-experimental treatments are integral to the trial's objective of assessing the reduction in size of large inflammatory hepatocellular adenomas.

Efficacy

Efficacy in this clinical trial will be assessed primarily by evaluating the decrease in size of the target lesion in patients with large inflammatory hepatocellular adenomas (HCA) treated with the oral JAK1/2 inhibitor, **baricitinib**. The primary endpoint is defined as a reduction of at least 30% in the size of the target lesion at 6 months, as measured by MRI, without progression of other lesions in cases of multiple HCA. This assessment will be conducted according to RECIST 1.1 criteria and will be evaluated through a blind centralized reading.

Secondary endpoints include the proportion of overall radiological responses, categorized as partial and complete responses, stable disease, and progressive disease, using RECIST 1.1 criteria at 3 and 6 months MRI. Additionally, the trial will assess the proportion of target lesions showing a decrease in size below 5 cm at 3 and 6 months MRI, the proportion of patients undergoing liver surgery for HCA at 6 months and at the end of a 24-month follow-up, and the occurrence of adverse events related to the experimental treatment within the 24-month study period. Other secondary endpoints involve the evaluation of symptomatic bleeding, malignant transformation into hepatocellular carcinoma (HCC), and disease progression between baricitinib discontinuation and 24 months of follow-up.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Women (or male with inflammatory HCA considered as non resectable whatever the size of the HCA)
Written informed consent for participation in study
Histologically proven hepatocellular adenoma (confirmed by a centralized reviewing) with available FFPE
At least one HCA of inflammatory subtype confirmed at histology and immunohistochemistry (CRP or SAA immunohistochemistry) by a centralized reviewing
At least one HCA of more than 5 cm at imaging of inflammatory subtype (if the HCA of more than 5 cm is not the same HCA proved as inflammatory at histology this HCA should harbored the same imaging features than the HCA with available histology) for women.
Diagnosed at histology over the last 5 years
Absence of desire of pregnancy while treated by baricitinib and for at least 4 weeks following the last dose of investigational product
Females of childbearing potential should have a contraception (without estrogen) when engaging in sexual intercourse with a male partner while treated by baricitinib and for at least 4 weeks following the last dose of investigational product. In case of oral contraception, patients should have been using it for a minimum of one month before the beginning of the treatment. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Male when engaging in sexual intercourse with a female partner shoud have a contraception while treated by baricitinib and for at least 4 weeks following the last dose of investigational product. A man is considered fertile after puberty unless permanently sterile by bilateral orchiectomy
Past infection of Varicella zona Virus confirmed by serology or vaccine against Varicella zona Virus done more than 4 weeks before the inclusion
Coverage for medical insurance

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Exclusion Criteria

< 18 years old and > 65 years old
Anemia < 9 g/dl
Concomitant use of immunosuppressive treatment such as methotrexate, azathioprine, mycophenolate (at the exception of corticosteroid)
Have received etanercept, infliximab, certolizumab, adalimumab, golimumab, or anakinra within 12 weeks of screening; tocilizumab, abatacept, ustekinumab, rituximab, belimumab, or any other B cell targeted therapies (approved or investigational) within 24 weeks of screening; or any other biologic therapy within 4 weeks of inclusion, whichever is longer.
ASAT > 5 times upper fold of the normal or ALAT > 5 times upper fold of the normal or total bilirubin > upper 1.5 fold of the normal
Have evidence of active tuberculosis as documented by medical history, clinical symptoms, and abnormal chest x-ray at screening together with positive quantiferon or T spot test or positive culture
Have evidence of latent TB (as documented by a positive quantiferon or T spot test, no clinical symptoms consistent with active TB, and a normal chest x-ray at screening, or as outlined below) unless patient completes at least 4 weeks of appropriate treatment prior to inclusion and agrees to complete the remainder of treatment while in the trial.
Renal impairment with estimated creatinine clearance < 50 ml/mn (Cockroft and Gault formula)
Have had any major surgery within 8 weeks prior to screening or will require major surgery during the study that, in the opinion of the investigator in consultation with the principal investigator, would pose an unacceptable risk to the patient.
Past history of lymphoproliferative disease
Past history of acute myocardial infection or unstable angina
Pregnancy or breastfeeding woman
Past history of stroke (including transient ischemic attack)
Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic BP (SBP), or > 100 mm Hg diastolic BP (DBP) despite optimal antihypertensive treatment
Past history NYHA (New York Heart Association) class III or IV congestive heart failure
Thromboembolic event within 6 months before inclusion
Second or third atrioventricular block
Active cancer
Past history of cancer the 5 years before the inclusion with the following exception: • Patients with cervical carcinoma in situ that has been resected with no evidence of recurrence or metastatic disease for at least 3 years may participate in the study. • Patients with basal cell or squamous epithelial skin cancers that have been completely resected with no evidence of recurrence for at least 3 years may participate in the study
Have had symptomatic herpes zoster infection within 6 months prior to screening
Have a past history of recurrent symptomatic zona (one single symptomatic zona that had occurred more than 6 months before the inclusion is not a contra-indication)
Have a history of disseminated/complicated herpes zoster (for example, multidermatomal involvement, ophthalmic zoster, CNS involvement, or post-herpetic neuralgia).
Ongoing estrogen-based contraception at inclusion
Have been exposed to a live vaccine within 12 weeks prior to planned inclusion or are expected to need/receive a live vaccine during the course of the study (with the exception of herpes zoster vaccination that must occur > 4 weeks prior to inclusion).
Have active or chronic viral infection from hepatitis B virus (HBV, defined by positive aghbs), hepatitis C virus (HCV, defined by positive PCR), or human immunodeficiency virus (HIV, defined by positive serology).
Patients under guardianship (tutelle/curatelle)
Patient deprived of liberty under judicial or administrative decision.
Participation in another interventional trial
Hypersensitivity to the active substance (baricitinib) or to any of the excipients
Past history of organ transplantation
Surgery of the target IHCA required at diagnosis validated by a multidisciplinary tumor board during the screening process due to the following reason: • Male with HCA accessible to liver resection (male not accessible to surgery based on a multidisciplinary tumor board evaluation could be included) • Activation of the Wnt/B-catenin pathway at immunohistochemistry (diffuse positive glutamine synthase and/or nuclear translation of B-catenin) or mutations in exon 3 of CTNNB1 at molecular biology (except in this tumor is considered as unresectable) at the pathological reviewing • Signs of malignant transformation in HCC (suspected by multidisciplinary tumor board based on imaging features or results of histology) • Any other reasons validated by the multidisciplinary tumor board
Patient on AME (state medical aid)
Have a current or recent (<4 weeks prior to inclusion) clinically serious viral, bacterial, fungal, or parasitic infection (Note: For example, a recent viral upper respiratory tract infection or uncomplicated urinary tract infection should not be considered clinically serious).
Have screening electrocardiogram (ECG) abnormalities that, in the opinion of the investigator or the sponsor, are clinically significant and indicate an unacceptable risk for the patient’s participation in the study.
Thrombocytopenia < 100 000/mm3
Neutropenia < 1200/mm3
Lymphopénia < 750/mm3
hepatic impairment defined by Child Pugh B or C
Current or past long-time smokers defined by more than 15 pack years