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    Summary
    EudraCT Number:2018-000397-30
    Sponsor's Protocol Code Number:Ponatinib-3001
    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:2018-08-21
    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 number2018-000397-30
    A.3Full title of the trial
    A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Patients With Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
    Estudio de fase 3, multicéntrico, aleatorizado, abierto, para comparar ponatinib frente a imatinib, administrados en combinación con quimioterapia de intensidad reducida en pacientes con leucemia linfoblástica aguda positiva para el cromosoma Filadelfia de nuevo diagnóstico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Efficacy Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Participants With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
    Estudio de eficacia para comparar ponatinib frente a imatinib, administrados en combinación con quimioterapia de intensidad reducida en pacientes con leucemia linfoblástica aguda positiva para el cromosoma Filadelfia de nuevo diagnóstico
    A.4.1Sponsor's protocol code numberPonatinib-3001
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1206-2370
    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 SponsorMillenium Pharmaceuticals, Inc (a wholly owned subsidiary of Takeda pharmaceutical Company Limited)
    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 supportMillenium Pharmaceuticals, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMillennium Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDrug Information Call Center
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne St
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number900 811 335
    B.5.6E-mailmedical@mlnm.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 Yes
    D.2.1.1.1Trade name Iclusig
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences UK Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameponatinib
    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 INNponatinib
    D.3.9.1CAS number 943319-70-8
    D.3.9.2Current sponsor codePonatinib
    D.3.9.3Other descriptive namePONATINIB
    D.3.9.4EV Substance CodeSUB91901
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 30
    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 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.2.1.1.1Trade name Gleevec
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameImatinib
    D.3.4Pharmaceutical form Capsule
    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 INNImatinib
    D.3.9.1CAS number 152459-95-5
    D.3.9.2Current sponsor codeImatinib
    D.3.9.3Other descriptive nameIMATINIB
    D.3.9.4EV Substance CodeSUB25387
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
    Leucemia linfoblástica aguda positiva para el cromosoma Filadelfia de nuevo diagnóstico
    E.1.1.1Medical condition in easily understood language
    Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
    Leucemia linfoblástica aguda positiva para el cromosoma Filadelfia de nuevo diagnóstico
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10080018
    E.1.2Term Philadelphia positive acute lymphocytic 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
    To compare the efficacy of ponatinib versus imatinib, administered as first-line therapy in combination with
    reduced-intensity chemotherapy, in patients with newly diagnosed Ph+ ALL, as measured by the MRD-negative CR rate at the end of induction.
    Comparar la eficacia de ponatinib frente a imatinib, administrados como tratamiento de primera línea en combinación con quimioterapia de intensidad reducida en pacientes con LLA Ph+ de nuevo diagnóstico, según la determinación de la tasa de RC negativa para EMR al final de la inducción.
    E.2.2Secondary objectives of the trial
    To compare the rates of EFS between the 2 cohorts
    Comparar las tasas de SSA entre las 2 cohortes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients aged 18 years or older.
    2. Newly diagnosed Ph+ or BCR-ABL1 positive ALL, as defined by the 2017 National Comprehensive Cancer Network guidelines.
    3. Molecular assessment of BCR-ABL1 must demonstrate the presence of a p190 (ie, e1a2) or p210 (ie, e13a2 or
    e14a2 [also known as b2a2 or b3a2]) transcript type.
    4. Eastern Cooperative Oncology Group performance status of ≤2.
    5. Clinical laboratory values as follows, within 30 days before randomization:
    a) Total serum bilirubin ≤1.5× the upper limit of normal (ULN).
    b) Alanine aminotransferase or aspartate aminotransferase ≤2.5× the ULN.
    c) Serum creatinine ≤1.5× the ULN and estimated creatinine clearance ≥40 mL/minute (Cockcroft-Gault formula).
    d) Serum lipase and amylase <1.5× the ULN.
    6. Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram, defined as QTcF of
    ≤450 ms in males or ≤470 ms in females.
    7. Female patients who:
    a) Are postmenopausal for at least 1 year before the screening visit, OR
    b) Are surgically sterile, OR
    c) If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 1 month after the last dose of study drug, OR
    d) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
    (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal,
    spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male
    condoms should not be used together.)
    8. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    a) Agree to practice effective barrier contraception during the entire study treatment period and through
    120 days after the last dose of study drug, OR
    b) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
    (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal,
    spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
    10. Willingness and ability to comply with scheduled visits and study procedures.
    1. Ser un hombre o una mujer de 18 años en adelante.
    2. LLA Ph+ o positiva para BCR-ABL1 de nuevo diagnóstico, según la definición de las directrices de 2017 de la Red Nacional Integral del Cáncer de los EE. UU. (National Comprehensive Cancer Network).
    3. El análisis molecular de BCR-ABL1 debe demostrar la presencia de un tipo de transcrito p190 (es decir, e1a2) o p210 (es decir, e13a2 o e14a2 [también denominado b2a2 o b3a2]).
    4. Estado funcional ≤2 según el Grupo Oncológico Cooperativo del Este (ECOG).
    5. Presentar los siguiente valores analíticos en los 30 días anteriores a la aleatorización:
    a) Bilirrubina total en suero ≤1,5× el límite superior de la normalidad (LSN).
    b) Alanina aminotransferasa o aspartato aminotransferasa ≤2,5× el LSN.
    c) Creatinina sérica ≤1,5× el LSN y aclaramiento de creatinina estimado ≥40 ml/minuto (fórmula de Cockcroft-Gault).
    d) Lipasa y amilasa en suero <1,5× el LSN.
    6. Intervalo QT normal corregido según el método de Fridericia (QTcF) en el electrocardiograma de selección, definido como QTcF ≤450 ms en hombres o ≤470 ms en mujeres.
    7. Ser una mujer que:
    a) haya tenido la menopausia al menos 1 año antes de la visita de selección, o
    b) se haya sometido a esterilización quirúrgica, o
    c) si tiene capacidad de concebir, acceda a utilizar simultáneamente 1 método anticonceptivo altamente eficaz y 1 método eficaz adicional (de barrera) desde la firma del consentimiento informado hasta 1 mes después de la última dosis del fármaco del estudio, o
    d) acepte mantener una abstinencia total, cuando ello esté en consonancia con el estilo de vida preferido y habitual del sujeto. (La abstinencia periódica [p. ej., métodos del calendario, sintotérmico, de posovulación], la marcha atrás, el uso de espermicidas solamente, y la amenorrea de lactancia no son métodos anticonceptivos aceptables. No deben usarse conjuntamente preservativos masculinos y femeninos.)
    8. Ser varón, incluso si se ha sometido a esterilización quirúrgica (es decir, estado posterior a la vasectomía), que:
    a) acepte practicar anticoncepción de barrera eficaz durante el período completo del tratamiento del estudio y durante los 120 días siguientes a la administración de la última dosis del fármaco del estudio, o
    b) acepte mantener una abstinencia total, cuando ello esté en consonancia con el estilo de vida preferido y habitual del sujeto. (La abstinencia periódica [p. ej., métodos del calendario, sintotérmico, de posovulación], la marcha atrás, el uso de espermicidas solamente, y la amenorrea de lactancia no son métodos anticonceptivos aceptables. No deben usarse conjuntamente preservativos masculinos y femeninos.)
    9. El consentimiento voluntario por escrito debe obtenerse antes de llevar a cabo cualquier procedimiento relacionado con el estudio que no forme parte de la práctica clínica habitual, entendiendo que el paciente puede retirar su consentimiento en cualquier momento sin que ello afecte a la asistencia médica que reciba en el futuro.
    10. Voluntad y capacidad para cumplir con las visitas programadas y los procedimientos del estudio.
    E.4Principal exclusion criteria
    1. Patients with a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid
    leukemia.
    2. Prior/current treatment with any systemic anticancer therapy (including but not limited to any TKI) and/or
    radiotherapy for cancer, with the exception of an optional prephase therapy, which should be discussed with the
    sponsor’s medical monitor/designee.
    3. Treatment with any investigational products within 30 days before randomization or 6 half-lives of the agent,
    whichever is longer.
    4. Currently taking drugs that are known to have a risk of causing prolonged QTc or torsades de pointes (unless these can be changed to acceptable alternatives or discontinued) (Appendix E).
    5. Taking any medications or herbal supplements that are known to be strong inhibitors or strong inducers of
    cytochrome P450 3A4 within at least 14 days before the first dose of study drug.
    6. Active serious infection requiring antibiotics within 14 days before the first dose of study drug.
    7. Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or BM biopsy are not exclusionary criteria).
    8. Ongoing or active systemic infection, known seropositive HIV, or known active hepatitis B or C infection.
    9. History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis.
    10. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
    11. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are excluded if they have not undergone complete resection.
    12. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis,
    aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome,
    or psychosis.
    13. Active ALL in the CNS (confirmed by cerebrospinal fluid analysis).
    14. Autoimmune disease with potential CNS involvement.
    15. Known significant neuropathy of Grade ≥2 severity.
    16. Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or peripheral vascular disease, or history of or active VTE disease, including, but not restricted to:
    a) Complete left bundle branch block.
    b) Right bundle branch block plus left anterior hemiblock, or bifascicular block.
    c) History of or presence of clinically significant ventricular or atrial tachyarrhythmias.
    d) Clinically significant resting bradycardia (<50 beats per minute).
    e) Uncontrolled hypertension (HTN; systolic blood pressure [BP] ≥150 mmHg and/or diastolic BP
    ≥90 mmHg). Patients with Stage 2 HTN (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) should be
    under treatment at study entry per the current American Heart Association guidelines to ensure BP control.
    Patients requiring 3 or more antihypertensive medications should have controlled HTN for the past 6 months.
    f) Any history of myocardial infarction, unstable angina, coronary artery disease, cerebrovascular accident,
    ischemic stroke, or transient ischemic attack.
    g) History of congestive heart failure (New York Heart Association class III or IV) or left ventricular ejection fraction <40%, within 6 months before randomization.
    h) Symptomatic peripheral vascular disease or history of infarction, including visceral infarction.
    i) History of any revascularization procedure, including the placement of a stent.
    j) History of pleural or pericardial effusions.
    k) Any history of venous thromboembolism, including but not limited to deep venous thrombosis or pulmonary
    embolism within 6 months before randomization.
    17. Poorly controlled diabetes, defined as glycosylated hemoglobin values of >7.5%. Patients with preexisting,
    well-controlled diabetes are not excluded.
    18. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
    19. Ongoing uncontrolled nausea or vomiting of any severity.
    20. Diarrhea of Grade >1, based on the National Cancer Institute Common Terminology Criteria for Adverse Events categorization.
    21. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime
    sleepiness, such as severe chronic obstructive pulmonary disease.
    22. Have a significant bleeding disorder unrelated to ALL.
    23. Life-threatening illness unrelated to cancer, such as severe CNS, pulmonary, renal, or hepatic disease unrelated to cancer.
    24. Female patients who are lactating or breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug is administered.
    25. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
    26. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
    1. Antecedentes o diagnóstico actual de leucemia mielógena crónica en fase crónica, acelerada o blástica
    2. Tratamiento previo/actual con algún tratamiento antineoplásico sistémico y/o radioterapia contra el cáncer, excepto tratamiento de prefase opcional, que deberá comentarse con el monitor médico/representante del promotor
    3. Tratamiento con cualquier producto en investigación 30 días antes de la aleatorización o 6 semividas del fármaco, lo más prolongado
    4. Estar tomando fármacos con riesgo conocido de causar un QTc prolongado o torsades de pointes (a menos que puedan interrumpirse o cambiarse)
    5. Estar tomando inhibidores o inductores potentes del citocromo P450 3A4 al menos 14 días antes de la primera dosis
    6. Infección grave activa que precise antibióticos 14 días antes de la primera dosis
    7. Cirugía mayor 28 días antes de la aleatorización (las menores no constituyen criterios de exclusión)
    8. Infección sistémica activa o en curso, seropositividad del VIH conocida, o infección activa conocida por el virus de la hepatitis B o C
    9. Antecedentes de pancreatitis aguda 1 año antes de la selección del estudio o antecedentes de pancreatitis crónica
    10. Hipertrigliceridemia no controlada (triglicéridos >450 mg/dl)
    11. Cáncer de piel no melanómico o carcinoma localizado de cualquier tipo si no se han sometido a una extirpación completa
    12. Antecedentes o presencia de patología del SNC relevante (epilepsia, convulsiones en la infancia o la edad adulta, paresia, afasia, accidente cerebrovascular, lesiones cerebrales graves, demencia, enfermedad de Parkinson, enfermedad cerebelar, síndrome cerebral orgánico o psicosis)
    13. LLA activa en el SNC (confirmada por análisis del líquido cefalorraquídeo)
    14. Enfermedad autoinmunitaria con afectación potencial del SNC
    15. Neuropatía significativa conocida con una intensidad de Grado ≥2
    16. Enfermedad cardiovascular, cerebrovascular o vascular periférica no controlada o activa de importancia clínica, o antecedentes de TEV o TEV activa, incluyendo, entre otros:
    a) Bloqueo de rama izquierda completo
    b) Bloqueo de rama derecha más hemibloqueo anterior izquierdo, o bloqueo bifascicular
    c) Antecedentes o presencia de taquiarritmias ventriculares o auriculares clínicamente significativas
    d) Bradicardia en reposo clínicamente significativa (<50 latidos por minuto)
    e) Hipertensión no controlada (HTN; tensión arterial [TA] sistólica ≥150 mm Hg y/o TA diastólica ≥90 mm Hg). Los pacientes con HTN en estadio 2 (TA sistólica ≥140 mm Hg y/o TA diastólica ≥90 mm Hg) deberán estar recibiendo tratamiento en el momento de entrada en el estudio según las directrices de la American Heart Association para garantizar el control de la TA. Los pacientes que requieran 3 o más medicamentos antihipertensivos deberán tener la HTN controlada durante los últimos 6 meses
    f) Antecedente de infarto de miocardio, angina inestable, arteriopatía coronaria, accidente cerebrovascular, accidente cerebrovascular isquémico o accidente isquémico transitorio
    g) Antecedentes de insuficiencia cardíaca congestiva (clase III o IV de la New York Heart Association) o fracción de eyección ventricular izquierda <40 %, 6 meses antes de la aleatorización
    h) Enfermedad vascular periférica sintomática o antecedentes de infarto, incluido el infarto visceral
    i) Antecedentes de cualquier procedimiento de revascularización, incluida la colocación de un stent
    j) Antecedentes de derrame pleural o pericárdico
    k) Antecedentes de tromboembolia venosa, incluyendo, entre otras, trombosis venosa profunda o embolia pulmonar 6 meses antes de la aleatorización
    17. Diabetes mal controlada, definida como un valor de hemoglobina glicosilada de >7,5 %. Los pacientes con diabetes preexistente bien controlada no quedan excluidos
    18. Enfermedad gastrointestinal (GI) conocida o procedimiento GI que pudiese interferir en la absorción oral o en la tolerancia del fármaco del estudio, incluida la dificultad para tragar
    19. Náuseas o vómitos no controlados en curso
    20. Diarrea de Grado >1, con base en la categorización de los Criterios Terminológicos Comunes para Acontecimientos Adversos del Instituto Nacional del Cáncer
    21. Antecedentes de síndrome de la apnea del sueño no controlado y otras afecciones que podrían provocar una somnolencia diurna excesiva, como enfermedad pulmonar obstructiva crónica grave
    22. Presentar un trastorno hemorrágico significativo no relacionado con la LLA
    23. Enfermedad potencialmente mortal no relacionada con el cáncer
    24. Mujeres en lactancia o con resultado positivo de embarazo en suero durante el período de selección o resultado positivo de embarazo en orina el día 1 antes de la primera dosis
    25. Cualquier enfermedad médica o psiquiátrica grave que, en opinión del investigador, podría interferir con la administración completa del tratamiento de conformidad con este protocolo
    26. Hospitalización a causa de o signos de abuso de drogas ilegales, fármacos o alcohol
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint: MRD-negative CR (BCR-ABL/ABL1 ≤0.01% and meeting criteria for CR)
    Criterio de valoración principal de la eficacia: RC negativa para EMR (BCR-ABL/ABL1 ≤0,01 % y cumple los criterios de RC)
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of 3 cycle induction
    Al final del ciclo 3 de la inducción
    E.5.2Secondary end point(s)
    EFS is defined as the dates of randomization until death due to any cause or failure to achieve MRD-negative CR by end of induction or relapse from CR.

    CR is defined as meeting all of the following for at least 4 weeks (ie, no recurrence): 1. No circulating blasts and <5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC >1000/μl (or >1.0*10^9/L). 5. Platelets >100,000/μl (or >100*10^9/L).

    CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.

    ORR is defined as CR + CRi.

    Duration of MRD-negative CR is defined as interval between the first assessment at which the criteria for MRD-negative CR are met until the earliest date at which loss of MRD negativity or relapse from CR occurs.

    Duration of CR is defined as interval between the first assessment at which the criteria for CR are met until the earliest date at which relapse from CR occurs.

    Time to treatment failure is defined as time to being off study randomized treatment (except for hematopoietic stem cell transplantation [HSCT] without loss of MRD-negative CR) due to both safety and/or loss of efficacy benefit reasons.

    Molecule response is assessed by 3-Log Reduction (MR3), Molecular Response 4-Log Reduction (MR4) and Molecular Response 4.5-Log Reduction (MR4.5).

    PIF is defined as participants who received treatment for chromosomepositive acute lymphoblastic leukemia (ALL) but never achieved CR or CRi by the end of induction. PIF is not limited by the number of
    unsuccessful treatments; this disease status only applies to recipients who have never been in CR or CRi.

    MR4.5 is molecular response 4.5-log reduction (≤0.0032% BCRABL1/ ABL1), or undetectable BCR-ABL1 transcripts in cDNA with ≥ 32,000 ABL1 transcripts.

    On-study participants with or without HSCT will be evaluated. OS is defined as the interval between the first dose date of study drug and death due to any cause, censored at the last contact date when the participant was alive.

    On-study participants with or without HSCT will be evaluated. Relapse from CR is defined as reappearance of blasts in the blood or BM (>5%) or in any extramedullary site after a CR.

    OS is defined as interval between the first dose date of study drug and death due to any cause, censored at the last contact date when the participant was alive.
    SSA, definida como el tiempo transcurrido desde la fecha de aleatorización hasta la muerte por cualquier causa o ausencia de RC negativa para EMR al final de la inducción o recidiva desde RC.
    RD se define como el cumplimiento de todos lo siguiente durante al menos 4 semanas (es decir, no recurrencia): 1. Sin blastos circulantes y <5% de blastos en la MO. 2. Maduración normal de todos los componentes celulares en la MO. 3. No enfermedad extramedular (afectación del SNC, linfadenopatía, esplenomegalia, infiltración de piel / encías, masa testicular). 4. RAN> 1000 / μl (o> 1.0 * 10 ^ 9 / L). 5. Plaquetas> 100,000 / μl (o> 100 * 10 ^ 9 / L).
    RCi se define como remisión completa hematológica con recuperación hematológica incompleta y cumpliendo todos los criterios para RC excepto plaquetas contar y / o RAN.
    TRG se define como RC + RCi.
    La duración de la RC sin EMR se define como el intervalo entre la primera evaluación en la que se cumplen los criterios para RC sin EMR hasta el fecha más temprana en la cual ocurre la pérdida de negatividad de EMR o recaída de RC.
    La duración de la RC se define como el intervalo entre la primera evaluación a la que los criterios para RC se cumplen hasta la fecha más temprana en la que la recaída desde RC ocurre.
    El tiempo hasta el fracaso del tratamiento se define como el tiempo para estar fuera del estudio tratamiento aleatorizado (excepto para el trasplante de células madre hematopoyéticas [TCMH] sin pérdida de RC sin EMR) debido a razones de seguridad y / o pérdida de beneficio de eficacia.
    La respuesta molecular se evalúa mediante una reducción 3-Log (Rm3), respuesta molecular por reducción 4-Log (RM4) y respuesta molecular por reducción 4.5-Log (RM4.5).
    FIP se define como participantes que recibieron tratamiento para leucemia linfoblástica aguda (LLA) cromosómica positiva pero nunca alcanzó RC o RCi al final de la inducción. FIP no está limitado por el número de tratamientos fallidos; este estado de enfermedad solo se aplica a los destinatarios que nunca han estado en RC o RCi.
    MR4.5 es la respuesta molecular con reducción 4.5 log (≤0.0032% BCRABL1 / ABL1), o transcripciones indetectables de BCR-ABL1 en ADNc con ≥ 32,000 transcripciones ABL1.
    Los participantes en el estudio con o sin TCMH serán evaluados. SG se define como el intervalo entre la primera fecha de dosis del medicamento del estudio y muerte por cualquier causa, considerada en la fecha del último contacto cuando el participante estaba vivo.
    Los participantes en el estudio con o sin TCMH serán evaluados. Recaída de CR se define como la reaparición de blastos en la sangre o MO (> 5%) o en cualquier sitio extramedular después de un RC.
    OS se define como el intervalo entre la primera fecha de dosis del fármaco del estudio y muerte por cualquier causa, considerada en la fecha del último contacto cuando el participante estaba vivo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    •EFS: Baseline up to 3 years
    •% of Pts with CR and CRi: End of C1 (approximately 1 month), C2
    (approximately 2 months) and C3 (approximately 3 months)
    •% of Pts with Molecular Response: End of cycle 1 (approximately 1
    month), cycle 2 (approximately 2 months) and cycle 3: approximately 3
    months
    •Percentage of PIF: Up to 3 months
    •% of Participants with ORR: Up to 3 months
    •Duration of MRD-Negative CR: Up to 5 years
    •Duration of CR: Up to 5 years
    •Time to Treatment Failure: Every year after 3 years up to 5 years
    •% of Pts with MR4.5 Including Best Response: Up to 5 years
    •Duration of MR4.5: Up to 5 years
    •% of On-Study Pts with OS: Every year after 3 years up to 5 years
    •% of On-Study Pts with Relapse From CR: Every year after 3 years up to
    5 years
    •OS:Up to 5 years
    + SSA: desde referencia hasta 3 años
    +% de Pts con RC y RCi: fin de C1 (aprox. 1 mes), C2 (aprox. 2 meses) y C3 (aprox. 3 meses)
    +% de Pts con respuesta molecular: final del ciclo 1 (aproximadamente 1 mes), ciclo 2 aproximadamente 2 meses) y ciclo 3: aproximadamente 3 meses
    + Porcentaje de FIP: hasta 3 meses
    + % de participantes con TRG: hasta 3 meses
    + Duración de RC MR-Negativo: hasta 5 años
    + Duración de RC: hasta 5 años
    + Tiempo hasta fallo del tratamiento: cada año después de 3 años hasta 5 años
    + % de Pts con MR4.5 que incluye la mejor respuesta: hasta 5 años
    + Duración de MR4.5: hasta 5 años
    + % de Pts en estudio con SO: cada año después de 3 años hasta 5 años
    + % de Pts en estudio con recaída de CR: cada año después de 3 años hasta 5 años
    + SG: hasta 5 años
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) No
    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 No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Imatinib
    Imatinib
    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 EEA37
    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
    Belarus
    Brazil
    Bulgaria
    Canada
    Finland
    Greece
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    Turkey
    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
    The study will be considered completed when the death of all patients has been recorded or when the study has been terminated by the sponsor.
    El estudio se considerará completado cuando la muerte de todos los pacientes haya sido registrada o cuando el promotor lo finalice.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    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: 272
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 48
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 107
    F.4.2.2In the whole clinical trial 320
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-10-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-05
    P. End of Trial
    P.End of Trial StatusOngoing
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