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    Summary
    EudraCT Number:2018-001671-21
    Sponsor's Protocol Code Number:KRT-232-101
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-09-10
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2018-001671-21
    A.3Full title of the trial
    A Phase 2/3 Randomized, Controlled, Open-Label Study of KRT-232 in Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV-MF), Or Post-Essential Thrombocythemia MF (Post-ET-MF) who are Relapsed or Refractory to Janus Kinase (JAK) Inhibitor Treatment
    Randomizovaná, kontrolovaná studie fáze 2/3, Nezaslepená studie
    přípravku KRT-232 u pacientů s primární myelofibrózou (PMF),
    myelofibrózou po pravé polycytémii (post-PV-MF), nebo myelofibrózou po
    esenciální trombocytémii (post-ET-MF), kteří se dříve neúspěšně léčili
    inhibitorem JAK
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This global, multicenter, Phase 2 (Part A)/3 (Part B) randomized, controlled, open-label study will evaluate the safety and efficacy of KRT-232 versus BAT for the treatment PMF, post PV MF, or post ET MF in subjects who are relapsed or refractory to JAK inhibitor treatment
    A.3.2Name or abbreviated title of the trial where available
    BOREAS
    A.4.1Sponsor's protocol code numberKRT-232-101
    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 SponsorKartos Therapeutics, Inc.
    B.1.3.4CountryUnited States
    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 supportKartos Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKartos Therapeutics, Inc.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Drive
    B.5.3.2Town/ cityRedwood City, California
    B.5.3.3Post code94065
    B.5.3.4CountryUnited States
    B.5.6E-mailpryan@kartosthera.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.3.1Product nameKRT-232
    D.3.4Pharmaceutical form 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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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.3.1Product nameKRT-232
    D.3.4Pharmaceutical form 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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 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 nameKRT-232
    D.3.4Pharmaceutical form Film-coated 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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 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 nameKRT-232
    D.3.4Pharmaceutical form Film-coated 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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 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 nameKRT-232
    D.3.4Pharmaceutical form Film-coated 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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 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 nameKRT-232
    D.3.4Pharmaceutical form Film-coated 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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    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.IMP: 7
    D.1.2 and D.1.3IMP RoleComparator
    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 nameHydroxyurea
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHYDROXYCARBAMIDE
    D.3.9.1CAS number 127-07-1
    D.3.9.4EV Substance CodeSUB08076MIG
    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 RoleComparator
    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 nameChemotherapy
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    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 Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product Information not present in EudraCT
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Information not present in EudraCT
    D.3.11.7Plasma derived medicinal product Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms Information not present in EudraCT
    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 RoleComparator
    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 nameSupportive care (including but not limited to corticosteroids or androgens)
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Information not present in EudraCT
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product Information not present in EudraCT
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Information not present in EudraCT
    D.3.11.7Plasma derived medicinal product Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms Information not present in EudraCT
    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
    Primary Or Secondary (Post-PV MF or Post-ET-MF) Myelofibrosis (MF) With Intermediate Or High-Risk TP53 Wild-Type (TP53 WT) Who Are Relapsed Or Refractory to Janus Kinase (JAK) - Inhibitor Treatment.
    E.1.1.1Medical condition in easily understood language
    A disorder of the 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 20.0
    E.1.2Level PT
    E.1.2Classification code 10077161
    E.1.2Term Primary myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10074689
    E.1.2Term Post polycythemia vera myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10074690
    E.1.2Term Post essential thrombocythemia myelofibrosis
    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
    Part A: to determine spleen response.
    Part B: To compare the spleen volume reduction (SVR) at Week 24 between Arm 1 and Arm 2
    E.2.2Secondary objectives of the trial
    Part A:
    To determine the change in modified MPN-SAF Total Symptom Score (TSS) at Week 24 and Week 48;
    To determine the duration of spleen response (DoR-spleen);
    To determine spleen size reduction as measured by palpation;
    To determine RBC transfusion usage;
    To determine the clinical response rate at Week 24;
    To determine the overall survival (OS) rate;
    To determine the safety and tolerability of KRT-232;
    To determine the PK/PD profile of KRT-232
    Part B:
    To compare the improvement of TSS at Week 24 between Arm 1 and Arm 2;
    To compare the OS between Arm 1 and Arm 2;
    To compare the progression free survival (PFS) between Arm 1 and Arm 2;
    To compare the overall SVR at any time in each study arm;
    To evaluate the spleen response duration between Arm 1 and Arm2;
    To compare the rate of conversion from RBC transfusion dependent to independent at Week 24 between Arm 1 and Arm 2;
    To evaluate the safety between Arm 1 and Arm 2;
    To monitor the PK of KRT-232 (Arm 1 only)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A:
    1. Adults >18 years of age
    2. Palpable spleen measuring ≥ 5 cm below the left lower costal margin or spleen volume of ≥ 450 cm3 by MRI or CT scan assessment
    3. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF according to the World Health Organization (WHO) criteria
    4. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
    5. ECOG performance status of 0 to 2
    6. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of KRT-232)
    7. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study drug and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females includes (a) combined, estrogen and progestogen containing, hormonal contraception (oral, intravaginal, transdermal); (b) progestogen-only hormonal contraception (oral, injectable, implantable); (c) intrauterine device; (d) intrauterine hormone-releasing system; (e) bilateral tubal occlusion; and (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    Subjects in Part A must meet the following JAK inhibitor treatment failure criteria in order to be eligible for the study:
    JAK Inhibitor treatment failure in Part A must meet either criterion (a) or (b) below:
    a) Either a lack of spleen response defined as receiving at least 12 weeks of JAK inhibitor treatment and having both of the following:
    • Persistent splenomegaly, by physical exam, that is palpable ≥ 5 cm below the LLCM
    • and TSS of >10 on the MPN-SAF TSS v.2.0 or patients with a single symptom score of >5 or two symptoms of >3, including only the
    symptoms of left upper quadrant pain, bone pain, itching, or night sweats
    b) Or progressive disease any time while on JAK inhibitor treatment as defined by any one of the following:
    • Spleen volume increase by ≥ 25% from the nadir as assessed by MRI or CT
    • Appearance of new splenomegaly that is palpable at least 5 cm below the LCM
    • A ≥ 100% increase in palpable distance, below the LCM, for baseline splenomegaly of 5 to 10 cm
    • A ≥ 50% increase in palpable distance, below the LCM, for baseline splenomegaly of > 10 cm
    Part B:
    1. Adults >18 years of age
    2. Confirmed diagnosis of PMF, post PV MF, or post ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria (Appendix 3)
    3. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) (Appendix 4)
    4. Subjects with p53WT MF by central laboratory testing
    5. Relapsed or refractory to prior treatment with an approved JAK inhibitor defined as:
    Relapsed subjects are those with progressive disease after JAK inhibitor treatment, defined by one of the following:
    • Increase in spleen volume by ≥25% by radiographic imaging from nadir
    • ≥100% increase in palpable distance below LLCM for baseline splenomegaly of 5 to 10 cm
    • ≥50% increase in palpable distance below LLCM for baseline splenomegaly of >10 cm
    • Regrowth after achieving complete response
    Refractory subjects are those with a lack of spleen response after ≥12 weeks of JAK inhibitor treatment, defined as <10% spleen volume reduction by radiographic imaging or <30% decrease from baseline in spleen size by palpation
    6. A minimum of 2 symptoms with a score of at least 1 each on the MFSAF v4.0 TSS
    7. ECOG performance status of 0 to 2
    8. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of KRT-232):
    Hematologic function independent of growth factors support for 7 days or 14 days for pegylated G-CSF and darbepoetin
    9. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study treatment (ie, KRT-232 or BAT) and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study treatment.
    E.4Principal exclusion criteria
    Part A:
    1. Patients who are positive for p53 mutations
    2. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT-232 (participation in observational studies is permitted)
    3. Major surgery within the first 28 days of KRT-232
    4. Chemotherapy, immunomodulatory drug therapy within 14 days prior to first dose of KRT-232
    5. Prior splenectomy
    6. Splenic irradiation within 3 months prior to the first dose of KRT-232
    7. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation
    8. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors
    9. Prior MDM2 inhibitor therapy or p53-directed therapy
    10. Women who are pregnant or breastfeeding
    11. History of major organ transplant
    12. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; known history of human immunodeficiency virus (HIV)-positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
    13. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
    14. 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 nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
    15. Grade 2 or higher QTc prolongation (>480 milliseconds per NCICTCAE criteria, version 5.0)
    16. Growth factor treatment (e.g., erythropoeitin) within 14 days prior to first dose of KRT-232; no darbepoetin within 28 days prior to first dose of KRT-232
    17. Active or chronic bleeding within 4 weeks prior to the first dose of KRT-232
    Part B:
    1. Prior MDM2 inhibitor therapy or p53-directed therapy
    2. Participation in an interventional clinical trial within 28 days before randomization (participation in observational studies is permitted)
    3. Major surgery or radiotherapy within 21 days prior to randomization, or anticipation of needing such procedures while receiving study treatment
    4. JAK-, PI3k-, SYK-, BTK-, BET- or MTOR inhibitor treatment within 28 days prior to the Screening MRI/CT scan
    5. Treatment with any other anticancer agent including chemotherapy, immunotherapy or biologic therapy within 28 days prior to randomization. Hydroxyurea may be taken within 1 day prior to Cycle 1 Day 1
    6. Prior splenectomy
    7. Splenic irradiation within 12 weeks of randomization.
    8. Prior allogeneic stem-cell transplantation or plans for allogeneic stem cell transplantation
    9. Women who are pregnant, lactating, breastfeeding or intending to become pregnant during the study.
    10. History of major organ transplant
    11. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before randomization. Patients with acute infections requiring systemic antibiotic use should complete antibiotic therapy at least 2 weeks prior to randomization
    12. Uncontrolled intercurrent illness including, but not limited to clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
    13. 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 nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
    14. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0)
    15. History of major hemorrhage or intracranial hemorrhage within 6 months prior to randomization
    16. History of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease conditions that may hamper compliance and / or absorption of the study treatment
    17. History of severe hypersensitivity reaction to any component of KRT-232
    18. History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to randomization
    E.5 End points
    E.5.1Primary end point(s)
    Part A: The proportion of subjects achieving a ≥35% spleen volume reduction from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan
    Part B: The proportion of subjects in each arm achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A: The Primary Endpoint will be assessed 24 weeks after each subject is enrolled.
    Part B: Week 24
    E.5.2Secondary end point(s)
    Part A:
    Proportion of subjects who have at least a 50% reduction from baseline to Week 24 and Week 48 in the total symptom score as measured by the modified MPN-SAF v2.0.
    Duration of a ≥35% or more reduction from Baseline in spleen volume as measured by MRI (or by CT for applicable subjects)
    Reduction in spleen size from Baseline to each visit at which spleen is palpated, including the proportion of subjects who have a ≥50% decrease
    • RBC transfusions (average number of RBC units per patient-month)
    • RBC transfusion independence at Week 24 (proportion of patients who were transfusion-independent at Week 24, defined as absence of RBC transfusions and no hemoglobin <8 g/dL in the previous 12 weeks)
    Complete remission (CR) and partial remission (PR) defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and modified European LeukemiaNet (ELN) criteria
    Overall survival is defined as the interval from randomization to death from any cause
    Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs, (SAEs), ECGs, vital signs
    KRT-232 and acyl glucuronide metabolite (M1) PK parameters, including but not limited to, maximum observed concentration
    Cmax), minimum observed concentration (Cmin), area under the plasma concentrationtime curve (AUC), and terminal elimination half-life (t1/2z)
    Part B:
    The proportion of subjects in each arm with ≥ 50% reduction in TSS (MFSAF v4.0) at Week 24
    Time from randomization to death from any cause in each arm
    PFS is defined as the time from randomization to either the first occurrence of disease progression or death due to any cause. Disease progression is defined as any occurrence of the following:
    • Spleen progression (≥25% increase in spleen volume from baseline)
    • Leukemic transformation (bone marrow blast count of ≥20% or a peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1x109/L that lasts for at least 2 weeks)
    • Transformation to accelerated phase (peripheral blood blasts ≥ 15% or peripheral blood blast ≥ 10% confirmed with a repeat assessment at least 3 days later)
    • Leukocytosis (WBC ≥ 50x109/L (associated with at least 1% blasts and an increase in WBC of at least 1.5x from baseline)
    The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review)
    Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression
    The proportion of RBC dependent subjects achieving RBC transfusion independence at Week 24
    Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), ECGs, vital signs
    KRT-232 and acyl glucuronide metabolite (M1) plasma concentrations will be monitored in Cycles 1 and 2 with sparse sampling.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A: Week 24, Week 48 and duration of study. Please refer to the protocol for full details.
    Part B: Week 24, study duration, time from randomization to death from any cause, time from randomization to either the first occurrence of disease progression or death due to any cause, the first occurrence of disease progression. Please refer to the protocol for full details
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    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 Yes
    E.8.2.3.1Comparator description
    BAT: 1) hydroxyurea, 2) chemotherapy or 3) supportive care
    E.8.2.4Number of treatment arms in the trial2
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA128
    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
    Argentina
    Australia
    Brazil
    Bulgaria
    Canada
    Czechia
    France
    Germany
    Hungary
    Israel
    Italy
    Lithuania
    Poland
    Romania
    Spain
    Turkey
    United Kingdom
    United States
    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 which could be long term survival follow-up phone call
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months8
    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.1.1.1In 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: 250
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    due to anticipated age of patients it's possible a Legally authorised representative may consent for patients.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 261
    F.4.2.2In the whole clinical trial 385
    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)
    The study will be considered complete 2 years after the last subject is enrolled, at which time subjects will be evaluated for eligibility for a rollover study.
    Subjects will be treated until disease progression or lack of tolerability. Subjects who discontinue study treatment for any reason during the study will enter long-term follow-up and be followed for survival and subsequent anticancer therapy.
    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 Decision2018-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-03
    P. End of Trial
    P.End of Trial StatusOngoing
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