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    Summary
    EudraCT Number:2019-001201-24
    Sponsor's Protocol Code Number:KRT-232-104
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-30
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2019-001201-24
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined with Low-Dose Cytarabine (LDAC) or Decitabine in Patients with Acute Myeloid Leukemia (AML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined with Low-Dose Cytarabine (LDAC) or Decitabine in Patients with Acute Myeloid Leukemia (AML)
    A.4.1Sponsor's protocol code numberKRT-232-104
    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 pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Blvd.
    B.5.3.2Town/ cityRedwood City, CA
    B.5.3.3Post code94065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16505420136
    B.5.6E-mailjmei@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 Yes
    D.2.1.1.1Trade name Dacogen
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    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/3/06/370
    D.3 Description of the IMP
    D.3.1Product namedecitabine
    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 INNdecitabine
    D.3.9.1CAS number 2353-33-5
    D.3.9.4EV Substance CodeSUB06932MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.2.1.1.1Trade name ARA-cell ®
    D.2.1.1.2Name of the Marketing Authorisation holderSTADApharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 IMPSubcutaneous 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.3.11 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.2.1.1.1Trade name ARA-cell ®
    D.2.1.1.2Name of the Marketing Authorisation holderSTADApharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 IMPSubcutaneous 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 number40
    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 or refractory AML, AML secondary to myeloproliferative neoplasms (MPN), and JAK2 mutationpositive AML.
    E.1.1.1Medical condition in easily understood language
    Patients with Acute Myeloid Leukemia (AML).
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective for Part A: To determine KRT-232 recommended phase 2 dose (RP2D). Primary Objective for Part B: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh).
    E.2.2Secondary objectives of the trial
    (Secondary Obj. Part A/Part B): Part A Only-to determine rates complete remission (CR), complete remission w/partial hematological improvement (CRh). To determine Overall Response Rate.To determine rate of return chronic phase MPN w/peripheral blast count <10%. To determine prop. subjects transition to allogeneic stem cell transplant. To determine efficacy JAK2 mutational status. To determine Duration of Response. To determine Progression-Free Survival. To determine Overall Survival. To determine efficacy KRT-232 in CR and CRh subjects w/treatment-naïve blast-phase AML vs. subjects w/ blast-phase AML which has been previously treated. Safety and tolerability of KRT-232. To monitor PK of KRT-232 and metabolites.
    (Exploratory Obj.): To evaluate the combination relative to select PK,PD,disease markers,markers of resistance in subjects who respond and in those who relapse on therapy.To determine UGT1A1*28 genotype, compare KRT-232 and KRT-232 glucuronide plasma conc. across genotypes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adults ≥ 18 years of age
    2. ECOG performance status of 0 to 2
    3. Part A: Patients with relapsed or refractory AML, or treatment naïve AML secondary to MPN. Diagnosis of AML must be according to World Health Organization (WHO) criteria with at least 20% blasts in the marrow and/or extramedullary leukemia. Patients with known fms-like tyrosine kinase 3 (FLT3) mutations must have been treated with a FLT3 inhibitor (unless contraindicated) if FLT3 inhibitors are approved and available in the country in which the patient is to be treated. Patients who are known isocitrate dehydrogenase 1 (IDH1) or IDH2 mutation positive must have been previously treated with an IDH1 or IDH2 inhibitor, respectively, (unless contraindicated) if IDH1 or IDH2 inhibitors are approved and available in the country in which the patient is to be treated.
    4. Part B: Patients with AML secondary to MPN,as defined by ≥20% blasts in the bone marrow or peripheral blood,or JAK2 mutation positive AML.
    5. Part B: Patients may have been treated with 0 to 2 prior lines of therapy for their AML. Patients with known FLT3 mutations must have been treated with a FLT3 inhibitor (unless contraindicated) if FLT3 inhibitors are approved and available in the country in which the patient is to be treated. Patients with relapsed or refractory disease who are known IDH1 or IDH2 mutation positive, must have been previously treated with an IDH1 or IDH2 inhibitor (respectively) (unless contraindicated) if IDH1 or IDH2 inhibitors are approved and available in the country in which the patient is be treated.
    6. Adequate hepatic and renal function within 28 days prior to the first dose of KRT-232.
    Hepatic: Direct bilirubin ≤2.0 times the upper limit of normal (ULN), unless Gilbert’s
    Syndrome; aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT)
    and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 ULN. Renal: Estimated creatinine clearance ≥30 mL/min by Cockcroft Gault.
    7. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraception method during the study. In addition, males must continue to use contraception for 3 months and 1 week after the last dose of study drug and females must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control 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; (f) vasectomized partner; and (g) 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.
    E.4Principal exclusion criteria
    1. Patients who are TP53 mutation positive
    2. Participants who are either refractory to or relapsed within 90 days of receiving a regimen containing a cumulative dose of ≥ 18 g/m2 of cytarabine are not eligible to be treated with cytarabine on this study but may be treated with decitabine on this study
    3. Patients who have received prior treatment with decitabine are not eligible to receive decitabine in this study but may be treated with cytarabine on this study
    4. Patients who have received an allogeneic HSCT within 90 days of enrollment or who have active graft-versus-host disease requiring active therapy and have a donor
    5. Patients who are eligible for an allogeneic HSCT per the opinion of the investigator and have a donor. Patients who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
    6. Patients who have received immunosuppressive therapy for graft-versus-host disease within 1 month prior to enrollment into this study
    7. Patients with acute promyelocytic leukemia
    8. Patients with a history of bleeding diathesis
    9. Patients with known active CNS involvement with AML
    10. Concurrent anticancer treatment, such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy within 14 days of the first dose of KRT-232, provided they have recovered from treatment toxicity. Patients on hydroxyurea may continue therapy with hydroxyurea until the day before starting therapy on this study. Patients on FLT3 inhibitors may continue therapy with FLT3 inhibitors until the day before starting therapy on this study. Subjects on JAK inhibitors should be tapered off JAK inhibitor therapy prior to starting treatment on this study per the JAK inhibitor tapering guidelines outlined in Section 7.4.1 of this protocol.
    11. Patients previously treated with MDM2 antagonist therapies
    12. Patients who have had major surgery within 28 days prior to the first treatment with KRT-232
    13. Women who are pregnant or breastfeeding
    14. Uncontrolled intercurrent illness including, but not limited to, known active hepatitis A, B, or C; 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; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
    15. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these patients may be on antibiotics at enrollment.
    16. 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
    17. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0)
    E.5 End points
    E.5.1Primary end point(s)
    • Part A: Dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine and DLTs of KRT-232 in combination with decitabine at each dose level.
    • Part B: Responses will be assessed per the 2017 European LeukemiaNet (ELN) response criteria (Appendix 3). Blasts in the bone marrow will be defined morphologically by exam of the aspirate or biopsy (if aspirate not available). Blasts in the blood will be defined immunophenotypically. CRh is defined as <5% of blasts by morphology in the bone marrow, no evidence of disease (blasts in blood by flow cytometry) and at least partial recovery of peripheral blood counts (platelets >50,000/μL and ANC >500/ μL).
    E.5.1.1Timepoint(s) of evaluation of this end point
    • DLTs are defined as the following study treatment-related adverse events (TEAEs) occurring
    in the 1st cycle (i.e., in the first 28 days) of Part A.
    • 2017 ELN response criteria will be used to assess the Bone marrow aspirate and biopsy results. Bone marrow aspirate and biopsy will be obtained at: Screening; Within 4 days of the end of Cycles 1, 3, 6, 9, 12, 15, and 18; Thereafter, within 4 days of the end of every 6th cycle while on study treatment; At suspected disease progression.
    E.5.2Secondary end point(s)
    • Responses (in Part A and B) will be assessed per the 2017 European LeukemiaNet (ELN) response criteria (Appendix 3) to determine rates of complete remission (CR) and complete remission with partial hematological improvement (CRh) (in Part A); to determine the overall response rate (ORR); rate of return to chronic phase MPN with peripheral blast count <10%; duration of response (DoR); progression-free survival (PFS); overall survival (OS); efficacy of KRT-232 in CR and CRh subjects who have treatment-naïve blastphase AML vs. subjects who have blast-phase AML which has been previously treated. Blasts in the bone marrow will be defined morphologically by exam of the aspirate or biopsy (if aspirate not available). Blasts in the blood will be defined immunophenotypically. CRh is defined as <5% of blasts by morphology in the bone marrow, no evidence of disease (blasts in blood by flow cytometry) and at least partial recovery of peripheral blood counts (platelets >50,000/μL and ANC >500/ μL).
    • Number of subjects who transition to allogeneic transplant
    • Efficacy analyses will be evaluated in subjects who are JAK2 V617F positive and negative
    • Safety endpoints will include the following measurements or assessments: physical examinations; laboratory tests; KRT-232 dose reductions, interruptions and discontinuations; adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), vital signs
    • KRT-232 and acyl glucuronide metabolite (M1) PK will be monitored on Cycles 1 and 2 with sparse sampling.
    (Exploratory endpoints):
    • Biomarkers including but not limited to:
    -TP53 mutation status, JAK2 mutations, and other AML-, sAML-, and MPN-related genes
    -TP53-related gene expression: p21 (CDKN1A), MDM2, MDMX (MDM4), PUMA (BBC3)
    -Flow cytometry of peripheral blood blasts
    -MIC-1 protein in serum
    • UGT1A1*28 genotype (*1*1, *1*28, *28*28)
    E.5.2.1Timepoint(s) of evaluation of this end point
    • 2017 ELN response criteria will be used to assess the Bone marrow aspirate and biopsy results. Bone marrow aspirate and biopsy will be obtained at: Screening; Within 4 days of the end of Cycles 1, 3, 6, 9, 12, 15, and 18; Thereafter, within 4 days of the end of every 6th cycle while on study treatment; At suspected disease progression
    • Safety endpoints will be assessed at various timepoints as per the Schedule of Assessments (Appendix 1 of the Protocol).
    • PK: At Cycle 1, Cycle 2, Day 1: Pre-dose and a single point taken anytime from 0.5 to 6 hours post-dose. At Cycle 1 Day 8: 24 hours (window ±1 hour) after the Day 7 dose
    (Exploratory endpoints):
    • Biomarkers and UGT1A1*28 genotype: blood sample collected and stored at the time points indicated in Table 4.
    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 Yes
    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) 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
    This is a Phase 1b/2 study with a dose-escalation phase (Part A) and an expansion phase (Part B).
    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 Yes
    E.8.1.7.1Other trial design description
    KRT-232 combined with Low-Dose Cytarabine (LDAC) or Decitabine in AML Patients.
    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.8.2.4Number of treatment arms in the trial3
    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 EEA50
    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
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Poland
    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
    The study will be considered complete 2 years after the last subject is enrolled, at which time subjects who remain on study treatment will be evaluated for eligibility to enroll in a rollover study.
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In 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: 67
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 68
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 84
    F.4.2.2In the whole clinical trial 135
    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)
    Subjects will be evaluated for eligibility for a rollover study.
    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 Decision2020-12-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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