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    Summary
    EudraCT Number:2018-003107-19
    Sponsor's Protocol Code Number:CHDM201A2101
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-23
    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 ConcernedGermany - BfArM
    A.2EudraCT number2018-003107-19
    A.3Full title of the trial
    A phase I/II multi-center study of HDM201 added to chemotherapy in adult subjects with relapsed/refractory (R/R) or newly diagnosed acute myeloid leukemia (AML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Global study to find the recommended dose of HDM201 added to chemotherapy and to assess safety and efficacy in patients with newly diagnosed or relapsed/refractory acute myeloid leukemia
    A.4.1Sponsor's protocol code numberCHDM201A2101
    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 SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma GmbH
    B.5.2Functional name of contact pointMedizinischer Infoservice
    B.5.3 Address:
    B.5.3.1Street AddressRoonstrasse, 25
    B.5.3.2Town/ cityNuernberg
    B.5.3.3Post code90429
    B.5.3.4CountryGermany
    B.5.4Telephone number+49 911 273 12 100
    B.5.5Fax number+49 911 273 12 160
    B.5.6E-mailinfoservice.novartis@novartis.com
    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.3.2Product code HDM201
    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 INNnot available yet
    D.3.9.2Current sponsor codeHDM201
    D.3.9.3Other descriptive nameHDM201
    D.3.9.4EV Substance CodeSUB129457
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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.IMP: 2
    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.3.2Product code HDM201
    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 INNnot available yet
    D.3.9.2Current sponsor codeHDM201
    D.3.9.3Other descriptive nameHDM201
    D.3.9.4EV Substance CodeSUB129457
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.IMP: 3
    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.2.5The 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 namecytarabine
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCytarabine
    D.3.9.3Other descriptive nameCYTARABINE
    D.3.9.4EV Substance CodeSUB06880MIG
    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.IMP: 4
    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.2.5The 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 namedaunorubicin
    D.3.4Pharmaceutical form Powder for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDAUNORUBICIN
    D.3.9.1CAS number 20830-81-3
    D.3.9.4EV Substance CodeSUB06917MIG
    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.IMP: 5
    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.2.5The 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 nameidarubicin
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIdarubicin
    D.3.9.3Other descriptive nameIDARUBICIN
    D.3.9.4EV Substance CodeSUB08111MIG
    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.IMP: 6
    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 Vyxeos
    D.2.1.1.2Name of the Marketing Authorisation holderJazz Pharmaceuticals
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/11/942
    D.3 Description of the IMP
    D.3.1Product nameLiposomal cytarabine/daunorubicin
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCytarabine
    D.3.9.3Other descriptive nameCYTARABINE
    D.3.9.4EV Substance CodeSUB06880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDAUNORUBICIN
    D.3.9.1CAS number 20830-81-3
    D.3.9.4EV Substance CodeSUB06917MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number44
    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.IMP: 7
    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 Rydapt
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/04/214
    D.3 Description of the IMP
    D.3.1Product namemidostaurin
    D.3.2Product code PKC412
    D.3.4Pharmaceutical form Capsule, soft
    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 INNmidostaurin
    D.3.9.1CAS number 120685-11-2
    D.3.9.3Other descriptive nameMIDOSTAURIN
    D.3.9.4EV Substance CodeSUB21040
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 8
    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.2.5The 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 nameposaconazole
    D.3.4Pharmaceutical form Gastro-resistant tablet
    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 INNPosaconazole
    D.3.9.3Other descriptive namePOSACONAZOLE
    D.3.9.4EV Substance CodeSUB20322
    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.IMP: 9
    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.2.5The 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 namemidazolam
    D.3.4Pharmaceutical form Oromucosal solution
    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 INNMIDAZOLAM
    D.3.9.1CAS number 59467-70-8
    D.3.9.4EV Substance CodeSUB08950MIG
    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
    Relapsed refractory (R/R) or newly diagnosed acute myeloid leukemia (AML)
    E.1.1.1Medical condition in easily understood language
    Cancer of the blood that has just been discovered and is untreated (1L AML) or that has previously been treated but did not respond to treatment or reoccurred since previous treatment (R/R AML)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of Part 1 of this study is to determine RDE of HDM201 combined with CT in subjects with 1L and in subjects with R/R AML.
    The primary objective of Part 2 of this study is to assess whether RDE of HDM201 combined with CT in 1L AML subjects enrolled to Expansion Cohort 1 (without documented FLT3 mutation) and in subjects with R/R AML enrolled to Expansion Cohort 4, respectively is the RP3D. For 1L AML subjects enrolled to Expansion Cohorts 2 and 3, the primary objective will be the safety and tolerability of HDM201 in combination with CT.
    The primary objective of Part 3 of this study is to evaluate in DDI Cohort 1, the adjusted dose of HDM201 that may be needed when a strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitor (posaconazole) is used in subjects treated with HDM201, and to evaluate in DDI Cohort 2 the effect of multiple doses of HDM201 on the PK of a single oral dose of a sensitive CYP3A4 substrate (midazolam).
    E.2.2Secondary objectives of the trial
    The secondary objectives of Part 1 of this study are to assess PK, as well as safety and tolerability of HDM201 in combination with CT in both study populations (1L AML without documented FLT3 mutation and R/R AML subjects irrespective of FLT 3 mutation status).
    The secondary objectives of Part 2 of this study are to assess PK of HDM201 at RDE, efficacy and blood count recovery of treatment with HDM201 in combination with CT in Expansion Cohorts 1, 3, and 4 and in combination with CT and midostaurin in Expansion Cohort 2. In Expansion Cohort 2 also the PK of midostaurin in combination with HDM201 at RDE and CT will be assessed. Minimal/measurable residual disease (MRD) negativity will be assessed in Expansion Cohorts 1 and 2.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All subjects
    1. Signed informed consent must be obtained prior to participation in the study.
    2. Age ≥ 18 years at the date of signing the informed consent form (ICF).
    3. Diagnosis of AML based on WHO 2016 classification (Arber et al 2016). Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible.
    4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) that is 0 to 2
    5. Adequate organ functions:
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
    • Total bilirubin (TBL) ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome)
    • Glomerular Filtration Rate (estimation based on Cockcroft-Gault formula) ≥ 30 mL/min
    6. Left ventricular ejection fraction (LVEF) > 45%
    R/R AML subjects eligible for inclusion in this study must additionally meet the following criteria:
    7. Diagnosis of relapsed or refractory AML
    8. Suitable for treatment with intermediate dose cytarabine (IDAC) as per investigator judgement
    9. For Part 3 only: willing and suitable to participate in DDI Cohort 1 or 2
    1L AML subjects eligible for inclusion in this study must additionally meet the following criteria, as applicable to the part/cohort they are to be enrolled in:
    For Part 1 or Part 2 Expansion Cohort 1 or Part 2 Expansion Cohort 2 only:
    10. Subjects with de novo AML
    11. Suitable for induction treatment with cytarabine and anthracyclines as per investigator judgement
    For Part 2 Expansion Cohort 2 only:
    12. Documented presence of FLT3 mutation (ITD or TKD)
    13. Suitable for midostaurin treatment as per investigator judgement
    For Part 3 Expansion Cohort 3 only:
    14. Subjects with secondary AML (e.g. AML with Myelodysplasia-Related Changes/AML-MRC, AML secondary to myelodysplasia/MDS or therapy-related AML). Prior use of hypomethylating agents or other therapies with curative intent for treating previous hematological malignancies or therapy-related AML is allowed.
    15. Suitable for induction treatment with liposomal cytarabine/daunorubicin as per investigator judgement
    E.4Principal exclusion criteria
    All subjects
    1. Prior exposure to MDM2 and MDM4 inhibitor (eg, idasanutlin)
    2. Known CNS leukemia with signs or symptoms that are not controlled by adequate therapy.
    3. Isolated extramedullary leukemia
    4. For Part 1 only: subjects with a known favorable-risk AML subtype at screening
    5. For Part 1 only: subjects with documented FLT3 mutation.
    6. Subjects with prior malignancy, except for: a) Adequately treated solid tumor for which the subject has been disease free for at least 2 years and if no anticancer therapy is ongoing or required during the course of the study; b) Subjects with history of hematological malignancies leading to secondary AML (eg, myelodysplasia/ myelodysplastic syndrome (MDS)) and subjects with therapy-related AML will not be excluded in dose Expansion Cohort 3.
    7. Any concurrent severe and/or uncontrolled medical condition eg, a) cardiovascular disease including congestive heart failure, or b) active uncontrolled infection requiring parenteral antibacterial, antiviral or antifungal therapy compromised by hemodynamic instability
    8. QTcF > 470 ms at screening
    9. Any other known disease that could compromise participation in the study including gastrointestinal (GI) disorders impacting absorption of HDM201, evidence of major active bleeding or history of bleeding diathesis or major coagulopathy not related to AML
    10. Known confirmed diagnosis of human immunodeficiency virus (HIV) infection
    11. Evidence of active hepatitis B (HBV) or hepatitis C (HCV) viral infection (hepatitis B surface antigen (HBsAg) in the absence of hepatitis B surface antibody (HBsAb) OR HCV Ab (antibody) positive with HCV RNA (ribonucleic acid) positive)
    12. Subjects who require treatment with moderate or strong CYP3A4 inducers within 14 days prior to starting study treatment, or are expected to receive moderate or strong CYP3A4 inducers during the entire study
    13. Subjects who require the use of herbal preparations/medications and dietary supplements (except for vitamins) within 7 days prior to first dose of study treatment or are expected to use such products during the entire study
    14. Subjects who require treatment with substrates of CYP3A4/5 with a narrow therapeutic index (within 24 hours prior to, during and 48 hours after HDM201 administration).
    15. Subjects taking medications with a known risk of prolonging the QT interval or inducing Torsade de pointes, if such medication cannot be discontinued or replaced safely with an alternative medication prior to starting first dose of HDM201
    16. Subjects who require treatment with moderate or strong CYP3A4 inhibitors within 48 hours prior to, during and 48 hours post HDM201 administration. Of note, this is not applicable for Part 3 Cycle 1
    17. Subject is pregnant or breastfeeding
    18. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 2 weeks after HDM201 discontinuation or for 4 months after midostaurin discontinuation (for 1L AML Expansion Cohort 2) or for 6 months after liposomal cytarabine/daunorubicin discontinuation (for 1L AML Expansion Cohort 3)
    Highly effective contraception methods are described in the protocol.
    Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to start of study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.
    19. Sexually active males unless they use a condom during intercourse while taking study drug and for 2 weeks after HDM201 discontinuation or for 4 months after midostaurin discontinuation (for 1L AML Expansion Cohort 2 only) or for 6 months after liposomal cytarabine/daunorubicin (for 1L AML Expansion Cohort 3 only) and thus do not attempt to father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
    If local regulations deviate from the contraception methods listed in the protocol (for women of child bearing potential or male) to prevent pregnancy, local regulations apply and will be described in the ICF.

    Additional exclusion criteria apply for R/R AML subjects and for 1L AML subjects as per protocol
    E.5 End points
    E.5.1Primary end point(s)
    Part 1:
    1L AML subjects
    • Incidence of DLT and time to DLT in subjects receiving induction therapy
    • Incidence and severity of AEs in 1L AML subjects
    R/R AML subjects
    • Incidence of DLT and time to DLT
    • Incidence and severity of AEs in R/R AML subjects
    Part 2:
    1L AML subjects
    • Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs (Expansion Cohort 1)
    • Proportion of CR/CRi with ABCR at the end of induction treatment (Expansion Cohort 1)
    • Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs (Expansion Cohort 2)
    • Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs (Expansion Cohort 3)
    R/R AML subjects
    • Incidence and severity of AEs, SAEs and abnormal laboratory values, ECG and vital signs
    • Proportion of CR/CRi with ABCR at the end of treatment
    Part 3:
    DDI Cohort 1
    • PK parameters for HDM201 such as AUClast, Cmax, cumulative AUC (Cycle 1) and average plasma concentration (Cycle 1)
    DDI Cohort 2
    • PK parameters of midazolam (e.g., AUClast, AUCinf, Cmax)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1:
    1L AML subjects
    - D1 of study treatment (ST) to 3 m after start of ST
    - D1 of ST to 3 m after start of ST
    R/R AML subjects
    - D1 of ST to 3 m after start of ST
    - D1 of ST to 3 m after start of ST
    Part 2:
    1L AML subjects
    - D1 of ST until 8.5 m after start of ST
    - D1 of ST until 4.5 m after start of ST
    - D1 of ST until 8.5 m after start of ST
    - D1 of ST until 8.5 m after start of ST
    R/R AML subjects:
    - D1 of ST until 8.5 m after start of ST
    - D1 of ST until 8.5 m after start of ST
    Part 3:
    DDI Cohort 1:
    - D1 of HDM201 dose to 10d after start of HMD201
    DDI Cohort 2:
    - first dose of midazolam (D2) to 8 days after start of ST (HMD201)
    E.5.2Secondary end point(s)
    Part 1:
    1L AML and R/R AML subjects
    • PK parameters of HDM201 (e.g., AUC, Cmax, Tmax)
    • Incidence of AEs, SAEs and abnormal laboratory values, ECG and vital signs
    Part 2:
    Expansion Cohort 1
    • OS, DFS, CIR , EFS
    • Proportion of subjects receiving HSCT
    • Proportion of subjects with MRD negativity
    Expansion Cohort 2
    • OS, DFS, CIR , EFS, proportion of subjects with CR/CRi with ABCR
    • Proportion of subjects receiving HSCT
    • Proportion of subjects with MRD negativity
    • PK parameters of midostaurin (e.g., AUC, Cmax, Tmax)
    Expansion Cohort 3
    • OS, DFS, CIR , EFS, proportion of CR/CRi with ABCR
    • Proportion of subjects receiving HSCT
    Expansion Cohort 4
    • OS, EFS
    • Proportion of subjects receiving HSCT
    All Expansion Cohorts
    • PK parameters of HDM201 (e.g., AUC, Cmax, Tmax)
    • Time to platelet recovery, time to neutrophil recovery
    Part 3:
    DDI Cohort 1
    • Overall safety information in subjects in DDI Cohort 1
    DDI Cohort 2
    • Overall safety information in subjects in DDI Cohort 2
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1:
    1L AML and R/R AML subjects
    - D1 of ST to 7.5 m after start of ST
    - D1 of ST to 8.5 m after start of ST
    Part 2:
    Expansion Cohort 1
    - D1 of ST to 3 y after last patients is enrolled in Part 2
    - D1 of ST to 3 y after last patients is enrolled in Part 2
    - D1 of ST to 7.5 m after start of ST
    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 Yes
    E.7.1.3.1Other trial type description
    dose escalation
    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 Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    Finland
    France
    Germany
    Hong Kong
    Israel
    Italy
    Japan
    Lebanon
    Singapore
    Spain
    United Kingdom
    United States
    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
    LVLS
    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 months5
    E.8.9.1In the Member State concerned days13
    E.8.9.2In all countries concerned by the trial years4
    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: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 105
    F.4.2.2In the whole clinical trial 180
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-13
    P. End of Trial
    P.End of Trial StatusOngoing
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