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    Summary
    EudraCT Number:2019-001201-24
    Sponsor's Protocol Code Number:KRT-232-104
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-09-04
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    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).
    Estudio abierto, multicéntrico, de fase Ib/II de la seguridad y eficacia de KRT-232 en combinación con citarabina en dosis bajas (CDB) o decitabina en pacientes con leucemia mieloide aguda (LMA).
    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).
    Estudio abierto, multicéntrico, de fase Ib/II de la seguridad y eficacia de KRT-232 en combinación con citarabina en dosis bajas (CDB) o decitabina en pacientes con leucemia mieloide aguda (LMA).
    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.2.5The 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.2.5The 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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.
    LMA recidivante o resistente, LMA secundaria a neoplasia mieloproliferativa (NMP), o de LMA con mutación de JAK2 positiva.
    E.1.1.1Medical condition in easily understood language
    Patients with Acute Myeloid Leukemia (AML).
    Pacientes con leucemia mieloide aguda (LMA).
    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).
    Objetivo principal de la Parte A: Determinar la dosis recomendada para la fase 2 (DRF2) de KRT-232.

    Objetivo principal de la Parte B: Determinar las tasas de remisión completa (RC) y remisión completa con mejoría hematológica parcial (RCh).
    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.
    (Obj.secund. ParteA/Parte B):Solo parteA: Determinar:
    -tasas remisión completa(RC) y RC con mejoría hematológica parcial(RCh)
    -tasa de respuesta global.Para determinar la tasa de vuelta a la fase crónica de NMP con recuento blastos periféricos< 10 %
    -proporción de sujetos que pasan a trasplante alogénico de células madre
    -eficacia según estado de mutación de JAK2
    -duración de respuesta.Supervivencia sin progresión.
    -supervivencia general
    -eficacia de KRT-232 en sujetos con RC y RCh que tengan 1fase blástica de LMA sin tratamiento previo frente a LMA frente a sujetos que tengan fase blástica de LMA previamente tratada.
    Seguridad y tolerabilidad de KRT-232.Monitorizar FC de KRT-232 y metabolitos.(Obj. explor.):Evaluar combinación relativa para seleccionar FC,FD,marcadores de enfermedad,de resistencia en sujetos que responden y en los que experimentan 1recidiva en terapia.Determinar genotipo UGT1A1*28,comparar conc. plasmáticas de KRT-232 y glucurónido KRT-232 entre genotipos.
    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.
    1. Adultos ≥ 18 años de edad
    2. Estado funcional según la escala ECOG de 0 a 2
    3. Parte A: Pacientes con LMA recidivante o resistente al tratamiento, o no tratados anteriormente con LMA secundaria a una NMP. El diagnóstico
    de la LMA deben estar de acuerdo con los criterios de la Organización Mundial de la Salud (OMS) con al menos un 20 % de blastos en la médula ósea y/o leucemia extramedular. Los pacientes con fms-conocidos como mutaciones de la tirosina cinasa 3 (FLT3), deberán
    haber sido tratados con un inhibidor de FLT3 (a menos que esté contraindicado) en el caso de que los inhibidores de FLT3 estuvieran aprobados y disponibles en el país en el que el paciente a tratar se encuentre. Los pacientes que se sabe que son positivos para la mutación de la isocitrato deshidrogenasa 1 (IDH1) o de IDH2 deben haber sido
    tratados previamente con un inhibidor de IDH1 IDH2 (respectivamente),(a menos que esté contraindicado) si los inhibidores de IDH1 IDH2 están aprobados y disponibles en el país en el que el paciente a tratar se
    encuentre.
    4. Parte B: Los pacientes con LMA secundaria a una NMP, definida por ≥20 % de blastos en médula ósea o sangre periférica o con LMA con mutación positiva de JAK2.
    5. Parte B: Los pacientes pueden haber sido tratados con 0 a 2 líneas previas de tratamiento para su LMA. Los pacientes con mutaciones conocidas de FLT3 deben haber sido tratados con un inhibidor de FLT3 (a menos que esté contraindicado) en el caso de que los inhibidores FLT3
    estén aprobados y disponibles en el país en el que se encuentre el paciente a tratar. Los pacientes con enfermedad recidivante o resistente al tratamiento que se sabe que son positivos para la mutación de IDH1 o
    IDH2, deben haber sido tratados previamente con un inhibidor de IDH1 o IDH2, respectivamente, (a menos que esté contraindicado) si los inhibidores de IDH1 IDH2 están aprobados y disponibles en el país en el que se encuentre el paciente a tratar.
    6. Función hepática y renal adecuadas dentro de los 28 días previos a la primera dosis de KRT-232.
    Función hepática: Bilirrubina directa ≤ 2,0 veces el límite superior de la normalidad (LSN), a menos que padezca síndrome de Gilbert; aspartato transaminasa/transaminasa glutámica oxalacética sérica (AST/SGOT) y alanina transaminasa/transaminasa glutámico-pirúvica sérica (ALT/SGPT) ≤ 2,5 LSN
    Función renal: Estimación del aclaramiento de creatinina ≥ 30 ml/min según Cockcroft Gault:
    7. Las mujeres en edad fértil y los varones que tienen parejas en edad fértil deben aceptar utilizar un método anticonceptivo eficaz durante el estudio. Además, los hombres deben continuar usando métodos anticonceptivos durante 3 meses y 1 semana después de la última dosis del fármaco del estudio y las mujeres deben continuar usando métodos anticonceptivos durante 1 mes y 1 semana después de la última dosis del
    fármaco del estudio. El control eficaz de la natalidad incluye (a) anticonceptivos hormonales combinados que contengan estrógenos y progestágenos (orales, intravaginales, transdérmicos); (b) anticonceptivos hormonales de progestágeno solamente (orales,
    inyectables, implantables); (c) dispositivo intrauterino; (d) sistema intrauterino de liberación de hormonas; (e) oclusión tubárica bilateral; (f) pareja vasectomizada; y (g) abstinencia sexual cuando está en consonancia con el estilo de vida preferido y habitual del sujeto. La
    abstinencia periódica (por ejemplo, los métodos del calendario, sintotérmico y posovulación) y el coitus interruptus o marcha atrás no son métodos aceptables de anticoncepción.
    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)
    1. Pacientes positivos para la mutación TP53
    2. Los pacientes resistentes al tratamiento o recidivantes en los 90 días después de haber recibido un régimen con una dosis acumulada de ≥ 18 g/m2 de citarabina no son aptos para ser tratados con citarabina en este estudio, pero pueden ser tratados con decitabina en el mismo
    3. Los pacientes que hayan recibido tratamiento previo con decitabina no son aptos para recibir decitabina en este estudio, pero pueden ser tratados con citarabina en el mismo
    4. Pacientes que hayan recibido un TCMH alogénico en el plazo de 90 días antes de la inclusión o que tienen la enfermedad injerto contra huésped activa que requiera tratamiento activo
    5. Pacientes aptos para un TCMH alogénico según la opinión del investigador y que tienen un donante. Los pacientes aptos para un TCMH en opinión del investigador, pero que se niegan a hacerse un trasplante,
    son aptos para el estudio.
    6. Pacientes que han recibido un tratamiento inmunoterapia para la enfermedad de injerto contra huésped en el plazo de 1 mes antes de la inclusión en este estudio
    7. Pacientes con leucemia promielocítica aguda
    8. Pacientes con antecedentes de diátesis hemorrágica
    9. Pacientes con LMA con afectación del SNC activa conocida
    10. Tratamiento concomitante contra el cáncer, como quimioterapia, tratamiento citorreductor, inmunoterapia, o tratamiento con citocinas en un plazo de 14 días antes de la primera dosis de KRT-232, siempre que se hayan recuperado de la toxicidad de tratamiento. Los pacientes con hidroxiurea pueden continuar con el tratamiento con hidroxiurea hasta el día antes de comenzar el tratamiento en este estudio. Los pacientes con inhibidores de FLT3 pueden continuar con el tratamiento con inhibidores de FLT3 hasta el día antes de comenzar el tratamiento en este estudio. Los sujetos con inhibidores de la JAK deberán reducir progresivamente tratamiento con inhibidores de JAK antes de comenzar el tratamiento en este estudio de acuerdo con las directrices de reducción gradual de la dosis del inhibidor de JAK descrito en la Sección 7.4.1 de este protocolo.
    11. Pacientes tratados previamente con tratamientos antagonistas de MDM2
    12. Pacientes que se hayan sometido a cirugía mayor en los 28 días antes del primer tratamiento con KRT-232
    13. Mujeres embarazadas o en periodo de lactancia
    14. Enfermedades intercurrentes no controladas incluyendo, entre otras, hepatitis activa conocida A, B, o C; antecedentes conocidos de virus positivo de la inmunodeficiencia humana (VIH); cardiopatía clínicamente
    significativa (clase III o IV de la New York Heart Association);
    insuficiencia cardíaca congestiva sintomática; angina de pecho inestable;
    arritmia ventricular inestable; o enfermedad psiquiátrica/situaciones
    sociales que limiten el cumplimiento de los requisitos del estudio
    15. Sujetos con infección no controlada, bacteriana, micótica, parasitaria o vírica. Los sujetos con infecciones bacterianas agudas que requieren el
    uso de antibióticos no deben incluirse hasta que la infección sea estable según el criterio del médico responsable del tratamiento; estos pacientes
    pueden estar recibiendo tratamiento antibiótico en el momento de la inclusión.
    16. Otra neoplasia maligna en los últimos 3 años, distinta a carcinoma de piel basocelular o de células escamosas tratado con cura, carcinoma in situ del cuello uterino, cáncer de próstata limitado al órgano o no metastásico tratado con valores normales de antígeno prostático
    específico, carcinoma de mama in situ después de la resección quirúrgica completa, o carcinoma de vejiga de células de transición superficiales
    17. Prolongación del QTc de grado 2 o mayor (> 480 milisegundos según los criterios NCI-CTCAE , versión 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).
    • Parte A: Las toxicidades limitantes de la dosis (TLD) de KRT-232 en combinación con citarabina y TLD de KRT-232 en combinación con decitabina en cada nivel de dosis.
    • Parte B:Las respuestas serán evaluadas según los criterios de respuesta 2017 European LeukemiaNet (ELN) (Apéndice 3). Los blastos en médula ósea se definen morfológicamente mediante examen de aspirado o biopsia (si el aspirado no está disponible). Los blastos en
    sangre se definen inmunofenotípicamente.
    La RCh se define como < 5 % de blastos por su morfología en médula ósea, sin indicios de enfermedad (blastos en sangre mediante citometría de flujo) y al menos una recuperación parcial de los recuentos en sangre periférica (plaquetas > 50 000/μl y RAN > 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.
    • TLD (toxicidades limitantes de la dosis) están definidas como los siguientes acontecimientos adversos relacionados con el tratamiento del estudio (AATEs) que ocurren en el primer ciclo (p.ej. en los primeros 28 días) de la Parte A.
    • Se usarán los criterios de respuesta 2017 ELN para evaluar el aspirado de médula ósea y los resultados de la biopsia. El aspirado de médula ósea y la biopsia se obtendrán en: selección, en los 4 días tras final de los Ciclos 1, 3, 6, 9, 12, 15 y 18; Después, en los 4 días del final de cada sesto ciclo durante tratamiento del estudio; si se sospecha progresión de la enfermedad.
    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)
    • Las respuestas (en Parte A y B) serán evaluadas según los criterios de respuesta 2017 European LeukemiaNet (ELN) (Apéndice 3) para determiar las tasas de remisión completa (RC) y remisión completa con mejoría hematológica parcial (RCh) (en Parte A); para determinar la tasa de respuesta global (TRG); la tasa de vuelta a la fase crónica de NMP con recuento de blastos periféricos < 10 %; la duración de la respuesta (DR); la supervivencia general (SG); la eficacia de KRT-232 en los sujetos con RC y RCh que tengan una fase blástica de la LMA sin tratamiento previo frente a LMA vs. a sujetos que tengan fase blástica de la LMA que haya sido previamente tratada. Los blastos en médula ósea se definen morfológicamente mediante examen de aspirado o biopsia (si el aspirado no está disponible). Los blastos en sangre se definen inmunofenotípicamente. La RCh se define como < 5 % de blastos por su morfología en médula ósea, sin indicios de enfermedad (blastos en sangre mediante citometría de flujo) y al menos una recuperación
    parcial de los recuentos en sangre periférica (plaquetas > 50 000/μl y RAN > 500/μl).
    • Número de sujetos que pasan a trasplante alogénico.
    • Se evaluarán los análisis de la eficacia en los sujetos JAK2 V617F positivos y negativos.
    • Los análisis de los criterios de valoración de la seguridad incluirán las siguientes mediciones y evaluaciones: exploraciones físicas; análisis de laboratorio, reducciones de dosis de KRT-232, interrupciones y suspensiones del tratamiento, acontecimientos adversos (AA), AA graves
    (AAG), electrocardiogramas (ECG) y constantes vitales.
    • 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.
    • Se monitorizará la FC de KRT-232 y del metabolito acil glucurónido (M1) en los ciclos 1 y 2 con muestras dispersas.
    (Objetivos exploratorios):
    • Los biomarcadores incluyen, entre otros:
    - Estado de mutación de TP53, mutaciones JAK2 y otros LMA-, LMAs- y los genes relacionados con NMP
    - Relacionados con la expresión del gen TP53: p21 (CDKN1A), MDM2, MDMX (MDM4), PUMA (BBC3)
    - Citometría de flujo de blastos en sangre periférica
    - Proteína MIC-1 en suero
    • Genotipo de UGT1A1*28 (*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.
    •Se usarán criterios de respuesta 2017 ELN para evaluar aspirado de médula ósea y resultados de biopsia.Aspirado de médula ósea y biopsia se obtendrán en:selección,en los 4días tras final de los Ciclos 1,3,6,9,12,15 y 18; Después,en los 4días del final de cada sesto ciclo durante tto. del estudio;si se sospecha progresión de enfermedad.•Se evaluarán variables de seguridad en varios momentos según el esquema de evaluaciones(Apéndice 1 del protocolo).•FC:Ciclo1,día1 del ciclo2:Antes de dosis y de 1punto único tomado en cualquier momento desde 0,5 a 6 horas después de dosis.Día8 del ciclo1:24 horas(ventana
    ±1hora)después de la dosis del día7.
    (Variables exploratorias):•Biomarcadores y genotipo UGT1A1*28:la muestra de sangre recogida y almacenada en momentos específicos indicados en tabla 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).
    Es un estudio de fase 1b/2 con una fase de escalada de dosis(ParteA) y 1fase de expansión(Parte 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 combinado con una dosis baja de Cytarabine (LDAC) o Decitabine en pacientes con LMA
    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 concerned6
    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
    Austria
    Belgium
    Bulgaria
    Canada
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hong Kong
    Hungary
    Ireland
    Israel
    Italy
    Korea, Republic of
    Norway
    Poland
    Romania
    Russian Federation
    Singapore
    Spain
    Sweden
    Switzerland
    Taiwan
    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.
    El estudio se considerará completo al cabo de 2 años después de incluir al último sujeto, momento en el que los sujetos que permanezcan en el tratamiento del estudio se evaluarán para determinar su idoneidad para incluirse en un estudio de continuación.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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 state35
    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)
    Eligible participants will be allowed to take study medication until further progression of their disease, cessation of clinical benefit, unacceptable toxicity, or some other factor that necessitates discontinuation from study treatment. Once the participant has been discontinued from the study, the participant’s doctor will continue to manage them according to the routine standard of care.
    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 Decision2019-12-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-14
    P. End of Trial
    P.End of Trial StatusOngoing
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