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Itacitinib in Advanced Hepatocellular Carcinoma (JAKaL)

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ClinicalTrials.gov Identifier: NCT04358185
Recruitment Status : Recruiting
First Posted : April 24, 2020
Last Update Posted : July 15, 2022
Sponsor:
Collaborator:
Incyte Biosciences UK Ltd
Information provided by (Responsible Party):
Imperial College London

Tracking Information
First Submitted Date  ICMJE April 17, 2020
First Posted Date  ICMJE April 24, 2020
Last Update Posted Date July 15, 2022
Actual Study Start Date  ICMJE December 3, 2018
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 21, 2020)
  • To assess the safety and tolerability of Itacitinib in patients with HCC: adverse events [ Time Frame: Throughout study completion, up to 1 year ]
    Assessment of adverse events relating to experimental drug intake according to the Common Terminology Criteria for Adverse Events (CTCAE) V4.03
  • To assess efficacy of Itacitinib by overall response rate: objective response rate (ORR) [ Time Frame: Throughout study completion, up to 1 year ]
    Measure objective response rate (ORR) as complete response, partial response, stable disease or progressive disease at 8 weeks post treatment according to RECIST criteria (mRECIST) V1.1
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 21, 2020)
  • Efficacy of Itacitinib by progression free survival [ Time Frame: Throughout study completion, up to 1 year ]
    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
  • Efficacy of Itacitinib by overall survival [ Time Frame: Throughout study completion, up to 1 year ]
    Overall survival (OS), defined as time from study entry to death due to any cause
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 21, 2020)
  • Presence of predefined JAK1 mutations in tumour tissue [ Time Frame: Throughout study completion, up to 1 year ]
    Assessment of presence of predefined JAK1 mutations in tumour tissue
  • Translational studies [ Time Frame: Throughout study completion, up to 1 year ]
    Assessment of presence of predefined JAK1 mutations in ctDNA
  • Translational studies 2 [ Time Frame: Throughout study completion, up to 1 year ]
    Correlation of changes in proinflammatory cytokines (multiplex bead array) with treatment response (mRECIST)
  • Correlation of JAK1 mutations with treatment [ Time Frame: Throughout study completion, up to 1 year ]
    Using mRECIST to find the correlation between the presence of predefined JAK1 mutations in tumour tissue with treatment outcome
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Itacitinib in Advanced Hepatocellular Carcinoma
Official Title  ICMJE A Phase Ib Study of Itacitinib, a JAK1 Inhibitor, in Advanced Hepatocellular Carcinoma
Brief Summary 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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Hepatocellular Carcinoma
Intervention  ICMJE Drug: Itacitinib (INCB039110)
Novel and small molecule selective inhibitor of JAK1
Study Arms  ICMJE Experimental: Itacitinib
Itacitinib (INCB039110) - novel and small molecule selective inhibitor of JAK1
Intervention: Drug: Itacitinib (INCB039110)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 21, 2020)
25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rohini Sharma, MD 02083833089 jakal@imperial.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04358185
Other Study ID Numbers  ICMJE 237279
2017-004437-81 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party Imperial College London
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Imperial College London
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Incyte Biosciences UK Ltd
Investigators  ICMJE
Principal Investigator: Rohini Sharma, MD Senior Lecturer Medical Oncology and Clinical Pharmacology
PRS Account Imperial College London
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP