Clinical Trials /

Itacitinib in Advanced Hepatocellular Carcinoma

NCT04358185

Description:

This research will assess the effects of Itacitinib as a second line treatment for patients with advanced inflammatory hepatocellular carcinoma (HCC), a type of liver cancer. Itacinib is a protein inhibitor of the tyrosine kinase, JAK1, which is believed to enable cancer cells to metastasise to other parts of the body.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Itacitinib in Advanced Hepatocellular Carcinoma
  • Official Title: A Phase Ib Study of Itacitinib, a JAK1 Inhibitor, in Advanced Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 237279
  • SECONDARY ID: 2017-004437-81
  • NCT ID: NCT04358185

Conditions

  • Advanced Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
Itacitinib (INCB039110)Itacitinib

Purpose

This research will assess the effects of Itacitinib as a second line treatment for patients with advanced inflammatory hepatocellular carcinoma (HCC), a type of liver cancer. Itacinib is a protein inhibitor of the tyrosine kinase, JAK1, which is believed to enable cancer cells to metastasise to other parts of the body.

Detailed Description

      JAKaL is a single arm phase Ib study evaluating the effect of Itacitinib in 25 patients with
      advanced HCC.

      Many patients diagnosed with HCC will have advanced disease where only palliative care is
      offered to them, this could account for the relatively low reported 5-year survival rate of
      approximately 10%. There are a number of epidemiological and pre-clinical studies that have
      investigated the role of chronic inflammatory conditions in the development of HCC and these
      provide evidence that inflammation promotes malignant transformation. The production of
      tumour-promoting cytokines by inflammatory cells can activate transcription factors, such as
      STAT3 via the JAK/STAT pathway in premalignant cells. STAT3, once activated, can cause the
      expression of further genes necessary for cell activation, localisation, survival and
      proliferation. Inhibition of JAK could therefore be a way of directly affecting malignant
      cell proliferation, as STAT3 in most malignancies are persistently phosphorylated and thereby
      stimulated to carry out its function; to sustain cell proliferation and block apoptosis.

      For reference, STAT3 is a member of the STAT protein family and is switched on, via
      phosphorylation, by receptor-associated Janus kinases (JAK), a type of tyrosine kinase, and
      together they form homo-/heterodimers that translocate to the cell nucleus and act as
      transcription activators. STAT3 mediates the expression of a variety of genes and therefore
      is integral to many cellular processes, as mentioned above, such as cell growth and
      apoptosis, and thus they can promote oncogenesis by being over-active in the different
      signalling pathways it is involved in.

      Itacitinib has not yet been approved by the U.S. Food and Drug Administration (FDA) for any
      clinical indication but has been developed as potential treatments for myelofibrosis (MF),
      rheumatoid arthritis (RA), psoriasis, graft-versus-host disease (GVHD), B cell malignancies
      and solid tumours like HCC. It is a small molecule selective inhibitor of JAK1 thereby
      preventing its phosphorylation of STAT proteins, particularly STAT3, resulting in a decrease
      in the expression of genes responsible for cell activation, localisation, survival and
      proliferation
    

Trial Arms

NameTypeDescriptionInterventions
ItacitinibExperimentalItacitinib (INCB039110) - novel and small molecule selective inhibitor of JAK1
  • Itacitinib (INCB039110)

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To assess the safety and tolerability of Itacitinib in patients with HCC: adverse events
Time Frame:Throughout study completion, up to 1 year
Safety Issue:
Description:Assessment of adverse events relating to experimental drug intake according to the Common Terminology Criteria for Adverse Events (CTCAE) V4.03

Secondary Outcome Measures

Measure:Efficacy of Itacitinib by progression free survival
Time Frame:Throughout study completion, up to 1 year
Safety Issue:
Description:Progression free survival (PFS), defined as time from study entry to first evidence of disease progression assessed by mRECIST v1.1 or death due to any cause
Measure:Efficacy of Itacitinib by overall survival
Time Frame:Throughout study completion, up to 1 year
Safety Issue:
Description:Overall survival (OS), defined as time from study entry to death due to any cause

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Imperial College London

Last Updated

April 21, 2020