JAK1 inhibitor treatment of inflammatory liver adenomas

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

1 Oct 2024 → ongoing

Decision date (initial)

2024-03-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

French Ministry of Health

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To demonstrate that the combination of an experimental procedure (an oral JAK1/2 inhibitor baricitinib) to the standard of care (estrogen-based contraception discontinuation, if patients used estrogen-based contraception, and weight loss if overweight) lead to a significant decrease in size of large inflammatory HCA at imaging

Secondary objectives 10

1. Radiological response using RECIST 1.1 and at 3 months and 6 months
2. Decrease in size of the target lesions below 5 cm at 3 months and 6 months at imaging using RECIST 1.1 criteria
3. Need for liver surgery of HCA at 6 months and 24 months (end of the follow-up) due to absence of sufficient decrease in size of the tumor under baricitinib
4. Incidence of adverse events related to the experimental treatment (baracitinib)
5. In patients with multiple HCA, radiological response using RECIST 1.1 at 3 months and 6 months focusing of HCA at the exclusion of the IHCA confirmed at histology
6. Occurence of symptomatic bleeding of the HCA during follow-up
7. Incidence of malignant transformation of hepatocellular adenomas into hepatocellular carcinoma during the study
8. Occurence of increase in tumor size or number after discontinuation of baricitinib using RECIST 1.1 during follow-up
9. Increase in tumor size > 5 cm after discontinuation of baricitnib using RECIST 1.1 criteria during follow-up
10. Incidence of postoperative adverse events in cases requiring hepatic surgery for hepatocellular adenoma during follow-up

Conditions and MedDRA coding

-women with an inflammatory HCA proven at histology and with at least one inflammatory HCA of more than 5 cm. -male with at least one inflammatory HCA proven at histology whatever the size and considered as non resectable by the multidisciplinary tumor board

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Women (or male with inflammatory HCA considered as non resectable whatever the size of the HCA)
2. Written informed consent for participation in study
3. Histologically proven hepatocellular adenoma (confirmed by a centralized reviewing) with available FFPE
4. At least one HCA of inflammatory subtype confirmed at histology and immunohistochemistry (CRP or SAA immunohistochemistry) by a centralized reviewing
5. 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.
6. Diagnosed at histology over the last 5 years
7. Absence of desire of pregnancy while treated by baricitinib and for at least 4 weeks following the last dose of investigational product
8. 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.
9. 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
10. Past infection of Varicella zona Virus confirmed by serology or vaccine against Varicella zona Virus done more than 4 weeks before the inclusion
11. Coverage for medical insurance

Exclusion criteria 39

1. < 18 years old and > 65 years old
2. Anemia < 9 g/dl
3. Concomitant use of immunosuppressive treatment such as methotrexate, azathioprine, mycophenolate (at the exception of corticosteroid)
4. 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.
5. 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
6. 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
7. 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.
8. Renal impairment with estimated creatinine clearance < 50 ml/mn (Cockroft and Gault formula)
9. 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.
10. Past history of lymphoproliferative disease
11. Past history of acute myocardial infection or unstable angina
12. Pregnancy or breastfeeding woman
13. Past history of stroke (including transient ischemic attack)
14. 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
15. Past history NYHA (New York Heart Association) class III or IV congestive heart failure
16. Thromboembolic event within 6 months before inclusion
17. Second or third atrioventricular block
18. Active cancer
19. 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
20. Have had symptomatic herpes zoster infection within 6 months prior to screening
21. 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)
22. Have a history of disseminated/complicated herpes zoster (for example, multidermatomal involvement, ophthalmic zoster, CNS involvement, or post-herpetic neuralgia).
23. Ongoing estrogen-based contraception at inclusion
24. 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).
25. 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).
26. Patients under guardianship (tutelle/curatelle)
27. Patient deprived of liberty under judicial or administrative decision.
28. Participation in another interventional trial
29. Hypersensitivity to the active substance (baricitinib) or to any of the excipients
30. Past history of organ transplantation
31. 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
32. Patient on AME (state medical aid)
33. 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).
34. 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.
35. Thrombocytopenia < 100 000/mm3
36. Neutropenia < 1200/mm3
37. Lymphopénia < 750/mm3
38. hepatic impairment defined by Child Pugh B or C
39. Current or past long-time smokers defined by more than 15 pack years

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is that the experimental procedure (baricitinib 4 mg per day) led to a decrease of the target lesion size of at least 30% at 6 months MRI (without progression of the other lesions in cases of multiples HCA) in at least 50% of the patients according to RECIST 1.1 criteria (corresponding to the definition of partial or complete response) assessed by a blind centralized reading

Secondary endpoints 10

1. Proportion of overall radiological response (partial and complete response), stable disease, and progressive disease using RECIST 1.1 criteria at 3 months and 6 months MRI
2. Proportion of target lesions (inflammatory HCA > 5 cm) showing a decrease in size below 5 cm at 3 months and 6 months MRI using RECIST 1.1 thus modified RECIST criteria at MRI
3. Proportion patients treated by liver surgery for HCA at 6 months and the end of the 24 months follow-up
4. Adverse events within the 24 months of the study related to the experimental treatment (baricitinib) a) all adverse events b) occurrence of zona c) cancer d) major adverse cardiovascular events (MACE)
5. In patients with multiple HCA, the proportion patients with complete response, partial response, stable disease and progressive disease focusing on other HCA excluding the inflammatory HCA confirmed at histology according to RECIST 1.1 criteria at MRI at 3 months and 6 months.
6. Proportion of symptomatic bleeding of HCA during follow-up
7. Proportion of malignant transformation in HCC during follow-up at histology and confirmed by a multidisciplinary tumor board
8. Proportion of patients with a progressive disease between baricitinib discontinuation (6 months) and 24 months of follow-up using RECIST 1.1 criteria at imaging
9. Proportion of patients with an increase in tumor size below 5 cm between baricitinib discontinuation (6 months) and 24 months at MRI
10. Proportion of post-operative adverse events (using the Dindo-Clavien Classification) if liver surgery is required during follow-up

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Jean-Charles NAULT

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Jean-Charles NAULT

Locations

1 EU/EEA country · 34 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications