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    Summary
    EudraCT Number:2012-000326-22
    Sponsor's Protocol Code Number:008260QM
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-05-11
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2012-000326-22
    A.3Full title of the trial
    A PHASE I/II DOSE ESCALATION TRIAL OF HDAC INHIBITOR TEFINOSTAT (CHR-2845) FOR CANCER ASSOCIATED INFLAMMATION IN HEPATOCELLULAR CARCINOMA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II dose escalation study of CHR-2845 in patients with liver cancer
    A.3.2Name or abbreviated title of the trial where available
    CHR258 in HCC
    A.4.1Sponsor's protocol code number008260QM
    A.5.4Other Identifiers
    Name:CRUKNumber:CRUKD/12/011
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorQueen Mary, University of London
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCancer Research UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportChroma Therapeutics Ltd.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Mary's, University of London
    B.5.2Functional name of contact pointDeanen Perumal
    B.5.3 Address:
    B.5.3.1Street AddressExperimental Cancer Medicine, Barts Cancer Institute
    B.5.3.2Town/ cityOld Anatomy Building, Charterhouse Square
    B.5.3.3Post codeEC1M 6BQ
    B.5.4Telephone number0207 882 8496
    B.5.5Fax number02078828409
    B.5.6E-mailCHR2845@qmcr.qmul.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTefinostat tartrate
    D.3.2Product code CHR-2845 tartrate
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtefinostat tartrate
    D.3.9.1CAS number 014382-60-8
    D.3.9.2Current sponsor codeCHR-2845 tartrate
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatocellular carcinoma
    E.1.1.1Medical condition in easily understood language
    Liver cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I:
    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

    Phase II:
    To perform a preliminary assessment of the anti-disease activity of tefinostat as measured by mRECIST.
    E.2.2Secondary objectives of the trial
    Phase I:
    To perform a preliminary assessment of the anti-disease activity of tefinostat as measured by mRECIST.

    Phase II:
    To determine the safety and tolerability of the recommended dose of tefinostat when administered orally to patients with advanced HCC

    To determine the anti-disease activity of tefinostat as measured by mRECIST

    Phase I and II:
    To determine pharmacokinetic parameters for tefinostat and CHR-2847 when administered orally at different dose levels and dose schedules

    To confirm monocyte specific delivery, protein acetylation will be measured in lymphocytes, granulocytes and monocytes
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed, informed consent

    2. Histologically or cytologically confirmed malignant HCC refractory to standard therapy or for which no standard therapy exists.
    a.Patients with alcoholic cirrhosis may be included dependent on clinical judgement as to their ability to conform to the protocol

    3. Patient is not a transplant candidate

    4. Recovered from all acute adverse effects of prior therapies

    5. Hepatitis is controlled by antiviral therapy (PEG-IFN, ribavirin, telaprevir, etc). Prophylactic Lamivudine for HBV carriers.

    6. Child-Pugh classification A or B7.

    7. Adequate bone marrow, hepatic and renal function including the following
    a.Hb ≥ 9.0 g/dL, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥75 x 109/L
    b.Total bilirubin ≤ 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
    c.AST (SGOT), ALT (SGPT) ≤ baseline + 4 x upper normal limit
    d.Creatinine ≤ 1.5 x upper normal limit
    e.Serum albumin > 28 g/L
    f.INR < 1.5 or a Pt/PTT within normal limits

    6. Age ≥ 18 years

    7. Performance status (PS) 0-2 (ECOG scale)

    8. Estimated life expectancy greater than 3 months

    9. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to start of trial. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment. Acceptable methods of contraception include IUD, oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge or contraceptive pessary)
    E.4Principal exclusion criteria
    1. Anti-cancer therapy including chemotherapy, radiotherapy, TACE, endocrine therapy, immunotherapy or use of other investigational agents within the 4 weeks prior to trial.

    2. Use of medicines known to prolong QTc within 14 days prior to the first dose of study drug
    3. Candidate for surgical resection, orthotopic liver transplantation, or loco-regional therapy such as radio-frequency ablation or chemoembolization

    4. History of organ allograft

    5. Co-existing active infection or serious concurrent illness

    6. Significant cardiovascular disease as defined by
    a.history of congestive heart failure requiring therapy
    b.history of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry
    c.presence of severe valvular heart disease
    d.presence of a ventricular arrhythmia requiring treatment
    e.LVEF < 50% (or less than institutional norm– some places have 45%)
    f.QTc interval ≥450 ms for men and ≥470 ms for women (using Bazett’s formula)

    7. Any co-existing medical condition that in the Investigator’s judgement will substantially increase the risk associated with the patient’s participation in the study

    8. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies

    9. Gastrointestinal disorders that may interfere with absorption of the study drug.

    10. Patients requiring palliative radiotherapy within the last 4 weeks of study entry

    11. Uncontrolled hypercalcaemia (>CTCAE v4.0 grade I)

    12. Pregnant or breast-feeding women

    13. Patients who have received an investigational drug within the last 4 weeks
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    a) Causality of each AE to tefinostat and grading severity according to CTCAE 4.03. MTD at either once or twice daily dosing.

    b) To determine the recommended Phase II dose (RP2D) of tefinostat in patients with advanced HCC

    Phase II:
    Radiological progression free survival (RPFS) rate at 3-months
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I:
    a) End of phase 1 part of study
    b) End of phase 1 part of study

    Phase II:
    3 months
    E.5.2Secondary end point(s)
    Phase I:
    To perform a preliminary assessment of the anti-disease activity of tefinostat as measured by mRECIST.

    Phase II:
    a) To determine the safety and tolerability of the recommended dose of tefinostat when administered orally to patients with advanced HCC

    b) To determine the anti-disease activity of tefinostat as measured by mRECIST

    Phase I and II:
    a) To determine pharmacokinetic parameters for tefinostat and CHR-2847 when administered orally at different dose levels and dose schedules

    b) To confirm monocyte specific delivery, protein acetylation will be measured in lymphocytes, granulocytes and monocytes
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I:
    End of phase 1 part of study

    Phase II:
    a) End of study
    b) End of study

    Phase I and II:
    a) Last patient Cycle 2 Day 1
    b) End of study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The ‘end of trial’ is defined as the date when all patients have been followed-up for survival up to 12 months following Cycle 1, Day 1, of the final patient recruited or when all patients have died.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 34
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state69
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 69
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will remain on trial treatment until disease progression or unacceptable toxicity or withdrawal of their consent.

    Following the end of study visit patients will have further treatment as per local policy at their treating centre.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-05-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-30
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-12-14
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