Itacitinib in Advanced Hepatocellular Carcinoma (JAKaL)

Inclusion Criteria:

1. Aged 18 or over

2. Diagnosis of hepatocellular carcinoma. If primary diagnosis of HCC: diagnosis based on the following criteria:

   • cyto-histological criteria, OR
   • radiological criteria: Focal lesion >1 cm with arterial hypervascularization in 2 coincident imaging techniques (CT, MRI, or US), OR
   • combined criteria: one imaging technique showing a focal lesion 1-2 cm with arterial hypervascularization AND AFP levels >400 ng/mL, OR
   • combined criteria: one imaging technique showing a focal lesion >2 cm with arterial hypervascularization AND AFP levels >200 ng/mL
3. Child-Pugh A and B up to 7 points (in patients receiving anticoagulant therapy; Child-Pugh score up to 5 points; INR category not regarded for calculation of the Child-Pugh score)
4. Progression or intolerance to first line therapy - N.B: Date of patients last dose of therapy must be more than 28 days before enrolment into this study.
5. ECOG Performance status 0, 1 or 2.

6. Adequate organ function as defined by:

   • Adequate hematologic function (ANC 1.0x109/l, platelet count 50x109/l, and hemoglobin 9g/dl).
   • Serum creatinine concentration < 1.5 times the upper limit of normal (ULN) and/or creatinine clearance >60 ml/min
   • Bilirubin level < 1.5 X ULN
   • PT-INR/PTT<1.5 x ULN
7. For women of child-bearing potential (defined as women who have not undergone surgical sterilization with a hysterectomy, and/or bilateral oophorectomy, and are not postmenopausal, defined as ≥12 months of amenorrhea) must have a negative serum pregnancy test within 14 days prior to the first study drug administration Effective contraception must be used throughout the duration of the study and up to 30 days following the last dose of the investigational medicinal product (IMP). Effective forms of contraception include complete abstinence from sexual intercourse, double barrier methods (condom with spermicide in conjunction with use of an intrauterine device or condom with spermicide in conjunction with use of a diaphragm), birth control patch or vaginal ring, oral, injectable, or implanted contraceptives and surgical sterilization (tubal ligation or vasectomy). Sperm and ova donation are prohibited during the duration of the study and 30days after the last dose. 8. Written informed consent prior to initiation of any study procedures and willing and able to comply with the study schedule

Exclusion Criteria:

1. Previous treatment with:

   • Study medication, any other JAK1 inhibitor and/or known hypersensitivity to the study medication
   • An investigational agent within 28 days prior to start of study treatment
2. Serious concurrent medical or psychiatric illness, including serious active infection
3. Uncontrolled ascites
4. Uncontrolled hypertension
5. History of organ transplant (including prior liver transplant)
6. Diagnosis of HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease or inflammatory bowel disease
7. Patients with active or latent tuberculosis
8. Patients with active hepatitis C or active hepatitis B that requires treatment
9. Patients who have received a live vaccine 30 days or fewer prior to enrolment as well as patients who intend to receive live vaccination during study participation or for three months after last dose administration

8. Patients who have a history of unprovoked venous thromboembolism (VTE) prior to the diagnosis of malignancy 9. Pregnant or breast feeding women Other clinically significant co-morbidities that could compromise the subject's participating in the study