A Phase 2 Open-label Single-arm Trial of JAK1 Inhibitor for the Treatment of Large Inflammatory Hepatocellular Adenomas

Hepatocellular adenomas (HCA) are tumors rare benign hepatic infections that develop on a liver normal and in young women taking a estrogen-based contraception. The main molecular subgroup of AHCs is the AHC subgroup inflammatory, characterized by activation of the pathway JAK/STAT due to mutations in IL6ST, STAT3, FRK, JAK1 or GNAS, with inflammatory infiltrates at histology. Hepatocellular adenomas are associated with a risk of bleeding from the tumor and malignant transformation. Therefore, most of women with large inflammatory AHC (>5 cm) require liver resection which can be associated with morbidity and aesthetic problems, and rarely to mortality. On the basis of the knowledge of the molecular classification of AHCs humans and preclinical data testing the JAK1/2 inhibitors, we hypothesize that a short duration of treatment with the inhibitor of JAK1/2 (baricitinib) may be effective in patients with large inflammatory AHC size.

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

Exclusion criteria

• < 18 years old and > 65 years old
• Pregnancy or breastfeeding woman
• Ongoing estrogen-based contraception at inclusion
• 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
• 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
• hepatic impairment defined by Child Pugh B or C
• 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
• 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
• current or past long-time smokers defined by more than 15 pack years
• 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).
• 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