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    Clinical Trial Results:
    A phase I/II dose escalation trial of HDAC inhibitor Tefinostat (CHR-2845) for cancer associated inflammation in Hepatocellular Carcinoma

    Summary
    EudraCT number
    2012-000326-22
    Trial protocol
    GB  
    Global end of trial date
    14 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Dec 2018
    First version publication date
    27 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    008260QM
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02759601
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    CRUK: CRUKD/12/011
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    CECM Trials Team, Queen Mary's, University of London, 0044 2078808196, bci-cecmmonitoring@qmul.ac.uk
    Scientific contact
    CECM Trials Team, Queen Mary's University of London, 0044 2078828196, bci-cecmmonitoring@qmul.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the safety, tolerability and dose-limiting toxicities (DLT) of tefinostat when administered orally to patients with advanced HCC. To determine the recommended Phase II dose (RP2D) of tefinostat in patients with advanced HCC.
    Protection of trial subjects
    Participant safety was continuously monitored through reporting of adverse events (including dose limiting toxicities), laboratory assessments and physical exams. Dose Escalation Meetings were convened when each cohort finished recruitment to assess the safety information and to assess if the trial could open to recruitment to the next cohort.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    9
    From 65 to 84 years
    7
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    From December 2012 to September 2016 17 patients with hepatocellular carcinoma (HCC) were enrolled into phase I of the CHR-2845 trial, from 4 centres within the UK. Phase II of the trial was not taken forward.

    Pre-assignment
    Screening details
    Malignant HCC who have not received prior systemic therapy, with a life expectancy of at least 12 weeks. ECOG performance status of 0-2, and a Child-Pugh classification A or B7. Adequate organ and bone marrow function with no history of cardiovascular disease. 37 patients were screened, and 17 of these patients were deemed to be eligible.

    Period 1
    Period 1 title
    Phase I cohort (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Tefinostat
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Tefinostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cohort Dose Level Tefinostat (once or twice daily for 28 day continuous dosing) 0 360mg OD 1 480mg OD 2 240mg BID 3 360mg BID

    Number of subjects in period 1
    Tefinostat
    Started
    17
    Completed
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I cohort
    Reporting group description
    -

    Reporting group values
    Phase I cohort Total
    Number of subjects
    17 17
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    9 9
        From 65-84 years
    7 7
        85 years and over
    1 1
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    14 14
    Race
    Units: Subjects
        White
    12 12
        Black (African)
    1 1
        Black (Caribbean)
    1 1
        Chinese
    1 1
        Asian
    1 1
        Other (Nepalese)
    1 1
    ECOG Performance Status
    Units: Subjects
        Status 0
    11 11
        Status 1
    6 6
    Child Pugh Score Points
    Units: Subjects
        Score 5
    8 8
        Score 6
    4 4
        Score missing
    5 5
    Child Pugh Score Class
    Units: Subjects
        Class A
    17 17

    End points

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    End points reporting groups
    Reporting group title
    Tefinostat
    Reporting group description
    -

    Primary: Dose Limiting Toxicity

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    End point title
    Dose Limiting Toxicity [1]
    End point description
    To determine the safety, tolerability and dose-limiting toxicities (DLT) of Tefinostat when administered orally to patients with advanced HCC. This will be done by determining causality of each adverse event (AE) to Tefinostat and grading severity according to National Cancer Institute (NCI) CTCAE V4.03. A DLT is defined as an event that is almost certainly/ probably dose-related, and drug related. Patients experiencing any of the following toxicities during the first 28 days of therapy will be considered to have experienced a dose-limiting toxicity (using CTCAE v4.03): • Absolute Neutrophil Count (ANC) ≤0.5x10 9/L lasting for > 5 days, or ANC ≤ 0.5x109 • Platelet count ≤25x109/L with fever. • Any other drug-related non-haematological toxicity (CTCAE v4.03 grade 3 or more. • Inability to tolerate a total of at least a 28 day course of Tefinostat due to toxicity; or any drugrelated adverse event resulting in a more than 14-day treatment delay.
    End point type
    Primary
    End point timeframe
    First 28 days of treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis required. Counts of DLTs provided instead. The maximum tolerated dose (MTD) was defined as 240mg BID (Dose Level 2). However, the recommended phase II dose was 360mg BID (Dose Level 3). Both dose level 2 and 3 were similarly tolerated, as per adverse events reported by each group, however, patients in Dosel level 3 showed better preliminary efficacy data. DLTs seen in Dose level 3 were fatigue (G3 CTCAE) and nausea (G3 CTCAE).
    End point values
    Tefinostat
    Number of subjects analysed
    17
    Units: DLT
        number (not applicable)
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Consent until 28 days after the end of treatment visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Tefinostat
    Reporting group description
    -

    Serious adverse events
    Tefinostat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 17 (29.41%)
         number of deaths (all causes)
    13
         number of deaths resulting from adverse events
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bloating
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tefinostat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    Vascular disorders
    Haemorrhages NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Portal hypertensions
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Vascular hypertensive disorders NEC
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Immune system disorders
    Atopic disorders
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenic conditions
         subjects affected / exposed
    15 / 17 (88.24%)
         occurrences all number
    43
    Body temperature altered
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pain and discomfort NEC
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    6
    Psychiatric disorders
    Disturbances in initiating and maintaining sleep
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Sleep disorders NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Speech articulation and rhythm disturbances
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Reproductive tract signs and symptoms NEC
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Vaginal and vulval infections and inflammations
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Non-site specific procedural complications
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Skin injuries NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Investigations
    Cholesterol analyses
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Liver function analyses
         subjects affected / exposed
    10 / 17 (58.82%)
         occurrences all number
    27
    Mineral and electrolyte analyses
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Physical examination procedures and organ system status
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    5
    Platelet analyses
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    4
    Protein analyses NEC
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    4
    Renal function analyses
         subjects affected / exposed
    6 / 17 (35.29%)
         occurrences all number
    14
    Tissue enzyme analyses NEC
         subjects affected / exposed
    7 / 17 (41.18%)
         occurrences all number
    9
    Triglyceride analyses
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Cardiac disorders
    Dyspnoeas
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Anaemias haemolytic immune
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Haemolyses NEC
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Coughing and associated symptoms
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    5
    Nervous system disorders
    Headaches
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nervous System disorder
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Neurologic visual problems NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Neurological signs and symptoms NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Paraesthesias and dysaesthesias
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Sensory abnormalities NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea (excl infective)
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    8
    Dyspeptic signs and symptoms
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal and abdominal pains
         subjects affected / exposed
    7 / 17 (41.18%)
         occurrences all number
    13
    Gastrointestinal atonic and hypomotility disorders NEC
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    13
    Gastrointestinal dyskinetic disorders
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal signs and symptoms NEC
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    7
    Nausea and vomiting symptoms
         subjects affected / exposed
    8 / 17 (47.06%)
         occurrences all number
    27
    Oral dryness and saliva altered
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Oral soft tissue signs and symptoms
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Stomatitis and ulceration
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Renal and urinary disorders
    Genitourinary tract infections and inflammations NEC
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Nephropathies and tubular disorders NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Renal failure and impairment
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Structural and obstructive urethral disorders (excl congenital)
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Urinary abnormalities
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    7
    Urinary tract signs and symptoms NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermal and epidermal conditions NEC
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Pruritus NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    6
    Rashes, eruptions and exanthems NEC
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Joint related signs and symptoms
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Muscle pains
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Muscle related signs and symptoms NEC
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    5
    Musculoskeletal and connective tissue pain and discomfort
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    9
    Endocrine disorders
    Female gonadal function disorders
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Appetite disorders
         subjects affected / exposed
    7 / 17 (41.18%)
         occurrences all number
    13
    Carbohydrate tolerance analyses (incl diabetes)
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Diabetes mellitus (incl subtypes)
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Elevated triglycerides
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General nutritional disorders NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hyperglycaemic conditions NEC
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Phosphorus metabolism disorders
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Total fluid volume decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Total fluid volume increased
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Infections and infestations
    Infections NEC
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Lower respiratory tract and lung infections
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2012
    - Updates to Protocol included changes to the inclusion criteria, kidney related laboratory tests and administrative changes - Updates to Patient Information Sheet and Informed Consent form were administrative clarifications
    30 Jan 2013
    - Updates to Protocol included changes to the inclusion criteria, re-wording of a secondary endpoint, information regarding research and safety bloods taken and clarification of responsibilities with regards to SUSAR reporting - Updates to the Patient Information Sheet included changes to ensure document in line with protocol, updates to CT scan timing and amount of blood collected and clarification with regards to future research of translational samples
    16 Oct 2013
    - New Investigator Brochure implemented for the IMP.
    31 Oct 2013
    - Updates to protocol included changes to inclusion criteria, and minor clarifications regarding registration process and timing of sample collection.
    26 Sep 2014
    - Change of Chief Investigator - Updates to Protocol included changes to the eligibility criteria, and changes to biopsies, lab tests and timing of study visits
    19 Feb 2015
    - Halt to recruitment - Change of Chief Investigator - Combining of the Patient Information Sheet and Consent Form - Updates to the Protocol included change in the eligibility criteria, biopsies required, study visit frequency, lab tests
    23 Dec 2015
    - Release of the temporary halt

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Feb 2015
    Temporary halt on recruitment.
    23 Dec 2015

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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