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    Summary
    EudraCT Number:2018-004050-16
    Sponsor's Protocol Code Number:HEAT-AML
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-06-04
    Trial 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 ConcernedSweden - MPA
    A.2EudraCT number2018-004050-16
    A.3Full title of the trial
    HEAT-AML (Hydroxyurea-Enhanced Ara-C Treatment of Adult Acute Myeloid Leukaemia):
    A phase I/II multicenter study to assess the tolerability and efficacy of the addition of hydroxyurea to standard ara-C and daunorubicin-based therapy for adults (age ≥ 18 years of age) with newly diagnosed acute myeloid leukaemia (AML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    HEAT-AML (Hydroxyurea-Enhanced Ara-C Treatment of Adult Acute Myeloid Leukaemia):
    A clinical study to assess whether addition of hydroxyurea to standard treatment against acute myeloid leukaemia (AML) is safe and efficacious
    A.3.2Name or abbreviated title of the trial where available
    HEAT-AML
    A.4.1Sponsor's protocol code numberHEAT-AML
    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 SponsorUniversity Hospital Karolinska
    B.1.3.4CountrySweden
    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 supportBarncancerfonden
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKarolinska University Hospital
    B.5.2Functional name of contact pointHEAT-AML Sweden
    B.5.3 Address:
    B.5.3.1Street AddressBarncancerforskningsenheten, Tomtebodavägen 18A
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code17177
    B.5.3.4CountrySweden
    B.5.4Telephone number00460852483204
    B.5.5Fax number00460852486111
    B.5.6E-mailelisabet.bergsten@ki.se
    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 Yes
    D.2.1.1.1Trade name Hydrea
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameHydroxycarbamide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Newly diagnosed acute myeloid leukaemia (AML) in patients ≥ 18 years of age
    E.1.1.1Medical condition in easily understood language
    Newly diagnosed acute myeloid leukaemia (AML) in patients ≥ 18 years of age
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10024291
    E.1.2Term Leukaemias acute myeloid
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To assess the safety and tolerability of HU at three different dose-levels added to standard AML therapy consisting of ara-C and daunorubicin (frequency and severity of toxicities; dose-finding)

    1. To assess the effect of HU added to standard AML therapy consisting of ara-C and daunorubicin on the rate of negative minimal residual disease (MRD-negativity) after the second standard chemotherapy cycle
    E.2.2Secondary objectives of the trial
    1. To assess the time to haematopoietic recovery after each chemotherapy treatment cycle
    2. To assess the effect of HU added to standard AML therapy consisting of ara-C and daunorubicin on ara-CTP accumulation in peripheral blasts
    3. To assess the effect of HU added to standard AML therapy on remission (CR/CRi/MLFS)
    4. To assess the effect of HU added to standard AML therapy on event-free survival (EFS)
    5. To assess the effect of HU added to standard AML therapy on relapse-free survival (RFS) two years after diagnosis
    6. To assess the effect of HU added to standard AML therapy on overall survival (OS) two years after diagnosis
    7. To assess the role of SAMHD1 protein expression for secondary objectives 2-6
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients with:
    - a diagnosis of AML and related myeloid precursor neoplasia according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
    - acute leukaemia of ambiguous lineage according to WHO 2008

    • Patients 18 years and older.

    • Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
    - Serum creatinine ≤ 220 μmol/L, unless considered AML-related
    - Serum bilirubin ≤ 2.5 x upper limit of normal (ULN, i.e. ≤65 µmol/L), unless considered AML-related or due to Gilbert’s syndrome
    - Alanine aminotransferase (ALAT) ≤ 2.5 x ULN, i.e. ≤ 1.9 µcat/L and ≤ 2.9 for females and males, respectively, unless considered AML-related


    • Male patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

    • Written informed consent.

    • Patient is capable of giving informed consent.
    E.4Principal exclusion criteria
    • Acute promyelocytic leukemia.

    • CNS leukaemia

    • Ongoing treatment with gemtuzumab-ozogamicin.

    • Major organ failure precluding administration of planned chemotherapy.

    • Glomerular filtration rate (GFR) < 30 ml/min

    • Cardiac dysfunction as defined by:
    - Myocardial infarction within the last 3 months of study entry, or
    - Reduced left ventricular function with an ejection fraction < 40% as measured by echocardiogram (will only be performed when clinically suspected) or
    - Unstable angina or
    - New York Heart Association (NYHA) grade IV congestive heart failure (see Appendix I) or
    - Unstable cardiac arrhythmias

    • Known intolerance to any of the chemotherapeutic drugs in the protocol.

    • Positive pregnancy test. Lactating female or female of childbearing potential not using adequate contraception.

    • Fanconi anaemia

    • Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.
    E.5 End points
    E.5.1Primary end point(s)
    • MRD-negativity after cycle 2

    Definition of MRD: malignant blasts as a percentage of total bone-marrow cells and as a percentage of the whole white blood cell compartment. These percentages are calculated based on the frequency of cells with an aberrant phenotype.

    It is nowadays well established that minimal residual disease (MRD) can be a clinical surrogate marker for survival, in particular relapse-free survival. A recent study of the Belgian-Dutch study consortium HOVON that is actively collaborating with the Swedish AML group has reported retrospective analyses on the power of MRD of patients in clinical remission to predict relapse. MRD-positivity was defined as ≥ 0.1% leukemic cells in bone marrow samples. The frequency of MRD-positivity declines with the number of chemotherapy courses and is approximately 50%, 30% and 25% after course 1, 2, and 3, respectively.
    MRD is assessed as described in the standard of care by the Swedish AML group. For the purpose of the study, MRD will be assessed around four weeks after chemotherapy cycle 2. MRD is patient-specific, and will be performed by flow cytometry that follows a specific leukaemia-associated immunophenotype (LAIP) that is established at diagnosis using a panel of 8-10 cell surface markers. A threshold of MRD-positivity is defined by the presence of more than 0.1% leukemic blasts in the sample.
    If a mutation in NPM1 or core binding factor (CBF) fusion genes have been identified, PCR-based MRD-assessment standardised local routine will be performed instead of flow cytometry
    In patients for whom a LAIP is not available and that do not have mutations in NPM1 or CBF fusions, other genetic aberrations detected in the routine genetic testing of diagnostic AML samples can be used for validated (digital droplet) polymerase-chain reaction ((dd)PCR) or next-generation sequencing (NGS) based MRD diagnostics. If no MRD values were determined at the local treating centre, ddPCR or NGS-based MRD analyses will be performed retrospectively on biobanked samples. If biobanked material is not available, material will be requested from routine diagnostic samples.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Following treatment cycle 2
    E.5.2Secondary end point(s)
    • Safety and tolerability (frequency and severity of non-hematological toxicities).
    • Time to hematopoietic recovery (ANC 0.5 and 1.0 x 109/L; platelets 50 x 109/L) after each chemotherapy treatment cycle, defined as the time from the start of the cycle until recovery.
    • Efficacy profile (response rate (CR, CRi, MLFS), event free survival (EFS), relapse-free survival (RFS), and overall survival (OS))
    E.5.2.1Timepoint(s) of evaluation of this end point
    MRD-negativity after cycle 2

    response rate (CR, CRi, MLFS, PR) after cycle 2

    event free survival (EFS) and overall survival (OS) after the end of the trial

    ara-CTP amounts after first and second ara-C infusion on day 1 of cycle 1
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 Yes
    E.7.1.3.1Other trial type description
    Evaluation of safety when combined with standard-AML therapy
    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 concerned7
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 33
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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.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)
    None
    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 Svenska AML-gruppen
    G.4.3.4Network Country Sweden
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-01
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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