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    Summary
    EudraCT Number:2015-002281-23
    Sponsor's Protocol Code Number:Spon1345-14
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-04-19
    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 number2015-002281-23
    A.3Full title of the trial
    A phase 2 study of the monocyte-targeted histone deacetylase inhibitor tefinostat (CHR-2845) in chronic myelomonocytic leukaemia (CMML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to test the safety and effectiveness of a new drug, tefinostat, for patients with chronic myelomonocytic leukaemia
    A.3.2Name or abbreviated title of the trial where available
    Monocle
    A.4.1Sponsor's protocol code numberSpon1345-14
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN17394489
    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 SponsorCardiff University
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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
    D.3.2Product code CHR-2845
    D.3.4Pharmaceutical form Capsule
    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.3.9.2Current sponsor codeCHR-2845
    D.3.9.3Other descriptive nameTefinostat
    D.3.9.4EV Substance CodeAS1
    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
    Chronic myelomonocytic leukaemia (CMML)
    E.1.1.1Medical condition in easily understood language
    CMML is a form of leukaemia characterised by high numbers of white blood cells called monocytes in the blood and bone marrow.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10009018
    E.1.2Term Chronic myelomonocytic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Is tefinostat (CHR-2845) safe and tolerable for patients with CMML?

    2. Is tefinostat clinically effective in CMML? (primary efficacy endpoint will be overall clinical response rate according to the International Consortium MDS/MPN Response Criteria).

    E.2.2Secondary objectives of the trial
    1. Is tefinostat clinically effective in CMML? (Secondary efficacy endpoint will include the incidences of complete remission, partial remission and 'haematological improvement', overall survival, progression-free survival, and time to transformation to acute myeloid leukaemia. )

    2. Do clinical responses to tefinostat correlate with biological measures (including baseline hCE-1 expression level [Human carboxylesterase], differential effects on protein acetylation between monocytes and other haematological cell lineages and molecular mutational profile including targeted gene sequencing?)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients with newly-diagnosed or previously-treated CMML meeting WHO criteria with the following characteristics will be eligible for the study:

    1. All CMML-2 patients are eligible
    2. For patients classified as CMML-1, the following must be present:

    • Symptomatic bone marrow failure / myeloproliferation defined as one or more of: red cell transfusion dependence with pre-transfusion Hb <90g/l, symptomatic anaemia (Hb <115g/l), thrombocytopenia (platelets <50 x 109/l), mptomatic bleeding due to platelet function defect or DIC/fibrinolysis, hite blood cell count >50 x 109/l

    and/or

    • CMML-specific Prognostic Score (CPSS) of intermediate-2 or high risk (16)
    (details of derivation of CPSS score given below)

    and/or

    • Systemic symptoms including weight loss with no alternative explanation (10% of baseline weight within previous 6 months)
    • Symptomatic splenomegaly
    • Symptomatic extrameduallary involvement, eg. skin infiltration, serous effusions

    3. Subject is able and willing to sign the Informed Consent Form
    4. Age greater than or equal to 18 years at the time of signing the Informed Consent Form
    5. Willingness to undergo scheduled assessments as per the study protocol including bone marrow assessments
    6. ECOG performance status of 0-2 at study entry
    7. Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to starting study drug
    8. Women of childbearing potential must use at least two effective contraceptive methods throughout the study and for three months following the date of the last dose of study drug
    9. Men whose partner is a woman of childbearing potential must use at least two effective contraceptive methods
    E.4Principal exclusion criteria
    1. CMML with eosinophillia and 5q33 abnormality
    2. Previous chemotherapy for CMML except Hydroxycarbamide and 5-azacitidine
    3. Creatinine concentration > 2x the institutional upper limit of normal range
    4. Liver transaminases (AST / ALT) > 3x the institutional upper limit of normal range or serum bilirubin > 4x the institutional upper limit of normal range
    5. Pregnant or lactating females
    6. Use of experimental drug or therapy within 28 days of registration
    7. Other malignancy within the last 3 years other than curatively-treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with negative prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional
    cell bladder carcinoma
    8. Known seropositivity for HIV infection or infectious hepatitis (type B or C)
    9. Uncontrolled inter-current illness including, but not limited to, ongoing infection, psychiatric illness or social situation that the treating physician judges would limit compliance with study requirements
    E.5 End points
    E.5.1Primary end point(s)
    1. Safety and tolerability of tefinostat defined as the proportion of patients experiencing CTC grade 3-4 non-haematological toxicity or death thought to be at least possibly related to tefinostat.

    2. Overall clinical response rate (according to International Consortium MDS/MPN Response Criteria)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Overall clinical response rate will be defined as the cumulative proportion of patients achieving clinical benefit (or better) according to International Consortium MDS/MPN Response Criteria(28) at day 29 of the sixth or last cycle of tefinostat (whichever is the earliest).

    Patients will be followed up for 18 months to gather all data to effectively assess end points.
    E.5.2Secondary end point(s)
    - Incidence and duration of complete remission / partial remission / clinical benefit (according to International Consortium MDS/MPN Response Criteria)

    - Overall clinical response rate (according to Wattel and modified IWG criteria)

    - Achievement of red blood cell and platelet transfusion independence

    - Overall survival

    - Progression-free survival

    - Incidence of transformation of CMML to AML (and time to AML transformation)

    - Duration of tefinostat therapy

    - Quality of life

    - Biological correlates including hCE-1 expression and changes in protein acetylation
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be followed up for 18 months to gather all data to effectively assess end points.
    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) No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned15
    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 Yes
    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
    Patients will be followed up for a minimum of 18 months (to assess overall survival and progression free survival) following registration, or for 30 days after the last trial treatment if this exceeds 18 months.

    The end of trial will be 6 months after the last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input.
    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 days1
    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: 5
    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 state40
    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 receive tefinostat treatment for 6 continuous 4-week cycles (24 weeks) unless there is unacceptable toxicity, evidence of disease progression or the patient chooses to withdraw from the trial.

    Tefinostat therapy may be extended beyond 24 weeks if the patient is deriving clinical benefit in the absence of unacceptable toxicity.

    This is outlined in the Patient Information Sheet.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Haematology Clinical Trials Unit - Cardiff University
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-06-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-05-31
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