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    Summary
    EudraCT Number:2019-004839-23
    Sponsor's Protocol Code Number:CA-4948-102
    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:2022-10-11
    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 number2019-004839-23
    A.3Full title of the trial
    A Phase 1/2a, Open-Label Dose Escalation and Cohort Expansion Study of Orally Administered CA-4948(IRAK4i) as a Monotherapy in patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome and in Combination with Azacitidine or Venetoclax
    Estudio de fase I/IIa de ampliación de cohortes, con aumento escalonado de la dosis y sin enmascaramiento para evaluar CA-4948 (IRAK4i) administrado por vía oral en pacientes con leucemia mielógena aguda o síndrome mielodisplásico tanto en monoterapia como en combinación con azacitidina o venetoclax.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Orally Administered CA-4948(IRAK4i) as a Monotherapy in patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome and in Combination with Azacitidine or Venetoclax
    Estudio para evaluar CA-4948 (IRAK4i) administrado por vía oral en pacientes con leucemia mielógena aguda o síndrome mielodisplásico tanto en monoterapia como en combinación con azacitidina o venetoclax
    A.4.1Sponsor's protocol code numberCA-4948-102
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04278768
    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 SponsorCuris, 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 supportCuris, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCuris, Inc
    B.5.2Functional name of contact pointCatherine Wang
    B.5.3 Address:
    B.5.3.1Street Address128 Spring St., Building C, Suite 500
    B.5.3.2Town/ cityLexington, MA
    B.5.3.3Post code02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number16175036500
    B.5.5Fax number1617503-6501
    B.5.6E-mailCA-4948-102@curis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code CA-4948
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEmavusertib
    D.3.9.2Current sponsor codeCA-4948
    D.3.9.4EV Substance CodeSUB208117
    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.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
    Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).
    leucemia mielógena aguda(LMA) o alto riesgo de síndrome mielodisplásico(SDM).
    E.1.1.1Medical condition in easily understood language
    AML: cancer of the blood and bone marrow — the spongy tissue inside bones where blood cells are made
    MDS: group of disorders caused by poorly formed blood cells or ones that don't work properly
    LMA:Cancer sanguineo y medula osea
    SDM: grupo de trastornos causados por células sanguíneas mal formadas o que no funcionan correctamente
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10001941
    E.1.2Term AML
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10068361
    E.1.2Term MDS
    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
    Phase 1
    • To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for CA-4948 in monotherapy in patients with AcuteMyelogenous Leukemia (AML) or intermediate, high, or very high risk Myelodysplastic Syndrome (hrMDS) based on the safety and tolerability, dose-limiting toxicities (DLTs), and pharmacokinetic (PK) and pharmacodynamic findings.
    Phase 1b
    • To determine MTD and RP2D for CA 4948 in combination with azacitidine (AZA) in treatment naïve patients with AML or hrMDS or in combination with venetoclax (VEN) in relapsed/ refractory (R/R) patients with AML or hrMDS after first line treatment based on the safety and tolerability, DLTs and PK and pharmacodynamic findings
    Phase 2a: To assess anti-cancer activity of CA-4948 at RP2D in patients with R/R FLT-3 AML, and patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1
    FaseI:Determinar la dosis máxima tolerada(DMT) de CA 4948 y su dosis recomendada para la fase II(DRFII) en monoterapia en pacientes con leucemia mielógena aguda(LMA) o síndrome mielodisplásico de riesgo intermedio, alto (SMDra) o muy alto, en función de su perfil de seguridad y tolerabilidad, las toxicidades limitantes de la dosis(TLD), así como los hallazgos farmacocinéticos(FC) y farmacodinámicos(FD)
    FaseIb:Determinar la DMT y la DRFII de CA 4948 en combinación con azacitidina(AZA) en el tratamiento de pacientes con LMA o SMDra sin tratamiento previo,o en combinación con venetoclax(VEN) en pacientes con LMA o SMDra recidivante/refractario(R/R) tras haber recibido una primera línea de tratamiento, ambas en función de su perfil de seguridad y tolerabilidad,las TLD, así como los hallazgos FC y FD
    FaseIIa:Evaluar la actividad antineoplásica de CA-4948 con la DRFII en pacientes conLMA R/R FLT-3 y con SMDra R/R o LMA R/R con mutaciones en el complejo de corte y empalme SF3B1oU2AF1
    E.2.2Secondary objectives of the trial
    Phase 1 and Phase 1b
    - To characterize the PK parameters of CA 4948 using non-compartmental analysis and appropriate PK model
    - To assess anti-cancer activity
    Phase 2a:
    - To assess tolerability and long-term safety
    - To further assess anti-cancer activity of CA-4948 at RP2D
    Fases I y Ib
    • Caracterizar los parámetros FC de CA 4948 utilizando un análisis no compartimental y modelos FC adecuados
    • Evaluar la actividad antineoplásica
    Fase IIa
    • Evaluar la tolerabilidad y la seguridad a largo plazo
    • Evaluar más detalladamente la actividad antineoplásica de CA-4948 con la DRFII
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males and females >= 18 years of age
    2. Life expectancy of at least 3 months
    3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 (Appendix A)
    4. Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization [WHO] 2016 classification) with the following characteristics.

    Phase 1 Dose Escalation (Monotherapy)
    . AML (primary or secondary, including treatment-related; European Leukemia Net category) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation), based on the assessment of the Investigator.
    OR
    . High-risk R/R MDS (IPSS-R criteria) that are considered resistant/refractory following at least 2 to 3 cycles naïve of HMA or evidence of early progression

    Phase 1b (Combination Therapy)
    Doublet Arm: CA-4948 + AZAPatients with:
    • IPSS- R High, hrMDS
    • Ineligible for intensive chemotherapyDoublet Arm: CA-4948 + VEN
    Patients with:
    • R/R AML or hrMDS, after first line therapy

    Phase 2a Dose Expansion (Monotherapy)
    Patients with:
    · R/R AML with FLT3 mutations, R/R including a FLT3 inhibitor
    · R/R AML with spliceosome mutations of SF3B1 or U2AF1
    · R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1; bone marrow blast count ≥8%: ineligible for intensive chemotherapy
    · Number of pretreatments: 1 or 2
    5. Acceptable organ function at Screening as described below:
    a. Estimated creatinine clearance (CrCl) of ≥ 35 mL/min (Appendix H).
    b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2 × ULN
    c. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in patients with documented Gilbert’s syndrome
    d. WBC ≤ 25,000/µL (Hydroxyurea is allowed at pre-treatment and at least up to the first cycle for cytoreduction if needed for patients with AML)
    6. Creatinine phosphokinase (CPK) < Grade 2.
    7. Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start
    8. Ability to swallow and retain oral medications
    9. Negative serum pregnancy test in women of childbearing potential
    10. Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of CA-4948
    11. Willing and able to provide written informed consent and comply with the requirements of the trial
    12. Biopsy requirement for AML and MDS: patients must be amenable to serial bone marrow sampling and peripheral blood sampling during the study. The diagnosis and evaluation of AML and MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis is made from the core biopsy
    1. Varones y mujeres ≥18 años.
    2. Esperanza de vida de al menos 3 meses.
    3. Estado funcional según la escala del Eastern Cooperative Oncology Group (ECOG, por su sigla en inglés) de ≤1.
    4. Diagnóstico de SMD o LMA confirmado mediante un análisis citomorfológico (conforme a la clasificación de 2016 de la Organización Mundial de la Salud [OMS]) y con las siguientes características.

    Fase I de aumento escalonado de la dosis (monoterapia)
    LMA (primaria o secundaria, incluida la surgida durante un tratamiento, según la clasificación de la Red Europea de Leucemia [ELN, European LeukemiaNet]) sin respuesta a por lo menos un tratamiento de referencia (entre ellos, quimioterapia, terapia de reinducción o trasplante de precursores hematopoyéticos) conforme a la evaluación del investigador.
    O
    SDM de alto riesgo R/R (según los criterios del IPSS-R) que se considere resistente/refractario a AHM tras recibir al menos 2 a 3 ciclos de estos agentes, o bien con signos de progresión precoz.

    Fase Ib (tratamiento combinado) – Inscripción cerrada
    Grupo de tratamiento combinado de biquimioterapia: CA-4948 + AZA
    Pacientes con:
    -SMD de riesgo alto según los criterios del IPSS-R
    -Que no reúnen las condiciones para recibir quimioterapia intensiva
    Grupo de tratamiento combinado de biquimioterapia: CA-4948 + VEN
    Pacientes con:
    -LMA o SMDra R/R tras una primera línea de tratamiento.

    Fase IIa de ampliación de la dosis (monoterapia)
    Pacientes con:
    -LMA R/R asociada a mutaciones en el gen FLT-3, incluida R/R a un inhibidor de la proteína FLT3.
    - LMA R/R con mutaciones en el complejo de corte y empalme de SF3B1 o U2AF1.
    - SMDra R/R con mutaciones en el complejo de corte y empalme de SF3B1 o U2AF1; recuento de blastocitos en médula ósea ≥8 %: no reúnen las condiciones para recibir quimioterapia intensiva.
    -. Número de tratamientos previos: 1 o 2
    5.Función orgánica aceptable en el momento de la selección, conforme a lo descrito a continuación:
    a. Aclaramiento de creatinina estimado ≥35 ml/min.
    b. Niveles de aspartato aminotransferasa (AST) o de alanina aminotransferasa (ALT) ≤2 veces el límite superior de la normalidad (LSN).
    c. Niveles de bilirrubina total ≤1,5 × LSN o ≤3 × LSN en pacientes con síndrome de Gilbert documentado.
    d. Recuento de glóbulos blancos ≤25 000/μl (en caso necesario, se permite la administración de hidroxiurea con fines de citorreducción durante el período de pretratamiento y el ciclo 1 en pacientes con LMA).
    6.Creatina-cinasa (CPK) de grado <2.
    7.Los pacientes en tratamiento hipolipidemiante con estatinas deben estar recibiendo una dosis estable sin cambios en la dosis en las 3 semanas previas al inicio del estudio
    8.Capacidad para tragar y retener medicación administrada por vía oral.
    9.En caso de mujeres capaces de procrear, prueba de embarazo en suero negativa.
    10.Las mujeres capaces de procrear (MCP) y los varones que tengan relaciones con MCP deben aceptar utilizar métodos anticonceptivos de alta eficacia durante el transcurso del estudio y durante los 90 días posteriores a la administración de la última dosis de CA-4948.
    11.Disposición y capacidad de prestar el consentimiento informado por escrito y de cumplir los requisitos del ensayo.
    12. Requisito de biopsia en casos de LMA y SMD: los pacientes deben estar dispuestos a someterse a un muestreo en serie de la médula ósea y la sangre periférica durante el transcurso del estudio. El diagnóstico y la evaluación de la LMA y el SMD se realizarán mediante un aspirado medular, una biopsia de médula ósea, o ambos. Si no se puede obtener un aspirado medular (es decir, un «aspirado seco»), el diagnóstico se obtendrá a partir de una biopsia con aguja gruesa.
    E.4Principal exclusion criteria
    1. Diagnosed with acute promyelocytic leukemia (APL, M3)
    2. Known active central nervous system (CNS) leukemia; patients with previously treated CNS disease may participate if asymptomatic as determined by treating physician (without symptomatic active disease for at least 4 weeks prior to the first dose of treatment, and any neurologic symptoms have returned to baseline)
    3. Allogeneic hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of CA-4948
    Note: The use of a stable or tapering dose of immunosuppressive therapy post-HSCT and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval
    4. Chronic myelogenous leukemia
    5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to start of CA-4948. Localized radiation or surgical resection of skin cancers is allowed
    6. Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter, prior to start of CA-4948
    7. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of CA 4948 unless approved by the Medical Monitor
    8. Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study
    9. Major surgery, other than diagnostic surgery, <28 days from the start of CA-4948; minor surgery <14 days from the start of CA-4948
    Note: Insertion of a vascular access device is not considered minor surgery
    10. Known hypersensitivity to AZA or mannitol, as stated per label, Appendix J (Phase 1b only)
    11. Patients with active advanced malignant solid tumors.
    12. Viral Infections:
    a. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness. If HIV virus is undetectable and maintained on treatment, enrolment may be allowed after discussion with the Sponsor.
    b. Hepatitis B virus (HBV) DNA positive or hepatitis C virus (HCV) infection < 6 months prior to start of CA-4948 unless viral load is undetectable, or HCV with cirrhosis
    Note: testing only required in patients with history of HBV or history of HCV < 6 months prior to start of CA-4948
    13. Concomitant illnesses that would preclude safe participation in study, including:
    a. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, or QTc with Fridericia’s correction (QTcF) that is unmeasurable or > 450 msec on screening electrocardiogram (ECG)
    Note: for QTcF > 450 sec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the three screening ECGs must be ≤ 450 msec in order to meet eligibility for trial participation
    b. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948. This includes major abdominal surgery and/or significant bowel resection and/or gastrointestinal diseases that could alter the assessment of PK or safety
    c. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or CA-4948 administration, may interfere with the informed consent process and/or with compliance with the requirements of the trial, or may interfere with the interpretation of the trial results and, in the Investigator's opinion, would make the patient inappropriate for entry into this trial
    d. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
    14. Pregnant or lactating
    1. Diagnóstico de leucemia promielocítica aguda (LPA) de subtipo M3.
    2. Leucemia con afectación activa del sistema nervioso central (SNC), si bien los pacientes que tengan antecedentes de una enfermedad del SNC que ya fue tratada podrán participar en el estudio si se encuentran asintomáticos a criterio del médico responsable (es decir, sin una enfermedad sintomática activa durante un mínimo de 4 semanas antes de la administración de la primera dosis del tratamiento del estudio y cuyos síntomas neurológicos hayan retornado a la situación del inicio del estudio).
    3. Antecedentes de un alotrasplante de precursores hematopoyéticos (TPH) en los 60 días anteriores a la administración de la primera dosis de CA-4948 o presencia de enfermedad de injerto contra huésped (EICH) de trascendencia clínica que requiera continuar el ajuste ascendente de la dosis de medicación inmunosupresora antes de iniciar el tratamiento con CA-4948.
    Nota: Si así lo aprueba el monitor médico, se permite el uso de tratamiento inmunosupresor a una dosis estable o en fase de reducción gradual tras un TPH, así como el de esteroides de aplicación tópica por una EICH cutánea activa.
    4. Diagnóstico de leucemia mielógena crónica.
    5. Uso de cualquier tratamiento antineoplásico sistémico, como quimioterapia, tratamiento farmacológico inmunomodulador, etc., en los 14 días anteriores al inicio del tratamiento con CA-4948. La radiación localizada o la resección quirúrgica de tumores cutáneos están permitidas.
    6. Uso de cualquier producto en investigación en los 28 días o 5 semividas, lo que sea más corto, antes del inicio del tratamiento con CA-4948.
    7. Presencia de una toxicidad aguda o crónica generada por un tratamiento antineoplásico anterior, con la excepción de alopecia que no se haya resuelto a un grado ≤1 según lo establecido por la versión 4.03 de los criterios terminológicos comunes para acontecimientos adversos (CTCAE) del Instituto Nacional del Cáncer de los EE. UU. (NCI), en los 7 días anteriores al inicio del tratamiento con CA-4948, a menos que lo autorice el monitor médico.
    8. Alergia o hipersensibilidad conocida a algún componente de la formulación de CA-4948 utilizada en este estudio.
    9. Antecedentes de cirugía mayor, salvo con fines diagnósticos, en los 28 días anteriores al inicio del tratamiento con CA-4948 o antecedentes de cirugía menor en los 14 días anteriores al inicio de dicho tratamiento. Nota: La inserción de un dispositivo de acceso vascular no se considera cirugía menor.
    10. Hipersensibilidad conocida a la AZA o al manitol, según lo indicado en la ficha técnica (solo en la fase Ib).
    11. Pacientes con tumores sólidos malignos activos de estadio avanzado.
    12. Infecciones víricas:
    a. Estado portador conocido del virus de la inmunodeficiencia humana (VIH) o con una enfermedad relacionada con el síndrome de la inmunodeficiencia adquirida. Si la carga viral del VIH es indetectable y el paciente se encuentra en tratamiento, podría permitirse su inclusión tras debatir esta cuestión con el promotor.
    b. Positividad para ADN del virus de la hepatitis B (VHB) o infección por el virus de la hepatitis C (VHC) en los 6 meses anteriores al inicio del tratamiento con CA-4948, a menos que la carga viral de estos virus sea indetectable, o bien VHC asociada a cirrosis.
    Nota: Solo deberán realizarse pruebas de detección en el caso de pacientes que tengan antecedentes de VHB o de VHC en los 6 meses anteriores al inicio del tratamiento con CA-4948.
    13. Enfermedades concurrentes que impedirían la participación segura en el estudio, como:
    a. Enfermedad cardiovascular no controlada o grave, incluido infarto de miocardio o angina de pecho inestable, en los 6 meses anteriores al inicio del tratamiento con CA-4948, insuficiencia cardíaca congestiva de clase II o superior según la clasificación de la Asociación de Cardiología de Nueva York (NYHA, New York Heart Association), arritmias graves no controladas con tratamiento, enfermedad pericárdica de trascendencia clínica, amiloidosis cardíaca, o un intervalo QT corregido (QTc) con la fórmula de Fridericia (QTcF) no medible o >450 ms en el electrocardiograma (ECG) realizado en el momento de la selección. Nota:para un QTcF >450 s en el ECG realizado en el momento de la selección, esta prueba podrá repetirse dos veces con un intervalo de al menos 24 horas; el valor medio del intervalo QTcF obtenido de los tres ECG de la selección debe ser ≤450 ms para que se considere que el paciente reúne las condiciones para participar en el ensayo.
    Enfermedad o trastorno gastrointestinal que podría interferir en la capacidad para tragar el fármaco, o en la absorción oral o tolerancia al CA-4948. Esta limitación incluye antecedentes de cirugía abdominal mayor, resección extensa del intestino o enfermedades gastrointestinales que pudiesen provocar alteraciones en las evaluaciones FC o de la seguridad.
    (Ver Protocolo para lista completa de criterions de exclusión)
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1 Monotherapy /Phase 1b (Combination Therapy)
    • MTD (defined as the highest dose at which there is < 33% DLT rate in the first cycle of treatment in a minimum of 6 patients [time frame: 28 days])
    • RP2D (determined by the Sponsor in consultation with the Clinical Safety Committee [CSC], considering all aspects of safety, tolerability, biologic activity, PK and preliminary efficacy in the trial population [time frame: 24 months])
    • Safety measured by adverse events (AEs), electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations

    Phase 2a (Monotherapy Expansion)
    Clinical response in AML or hrMDS assessed as follows:
    • AML: Proportion of patients who achieve CR + CRh
    • hrMDS: ORR of CR + PR + mCR
    Fase I (monoterapia)/ Fase Ib (tratamiento combinado)
    •Determinar la DMT, definida como la dosis máxima a la que se observa una tasa de TLD <33 % durante el primer ciclo de tratamiento en un mínimo de 6 pacientes (plazo: 28 días)
    • Determinar la DRFII, definida por el promotor en consulta con el Comité de Seguridad Clínica (CSC), teniendo en cuenta todos los aspectos de seguridad, tolerabilidad, actividad biológica, FC y eficacia preliminar del tratamiento en la población del estudio (plazo: 24 meses)
    • Determinar la seguridad mediante los acontecimientos adversos (AA), electrocardiogramas (ECG), los valores de bioquímica clínica y análisis hematológicos, las constantes vitales y las exploraciones físicas.

    Fase IIa (ampliación de la monoterapia)
    Respuesta clínica en la LMA o el SMDra evaluada del siguiente modo:
    • LMA: proporción de pacientes que alcanzan RC + RCh
    • SMDra: TRO de RC + RP + RCm
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 months
    24 meses
    E.5.2Secondary end point(s)
    Phase 1 Monotherapy /Phase 1b (Combination Therapy)
    • PK parameters of CA 4948 measured by Cmax, Cmin, Tmax, AUC 0-24, AUC 0-inf, and T ½ (time frame 24 months)
    Clinical response in AML or hrMDS assessed as follows:
    • AML:
    o Proportion of patients who reach CR + CRh
    o Proportion of patients who reach CRi, or CR or CRh
    • hrMDS: ORR of CR + PR + mCR
    • Transfusion independence

    Phase 2a (Monotherapy Expansion)
    • Safety measured by AEs, ECGs, chemistry and hematology laboratory values, vital signs, and physical examinations
    Clinical response in AML or hrMDS assessed as follows:
    • Proportion of patients with AML who achieve CR or CRh or CRi
    • Proportion of patients with hrMDS who achieve CR or PR or mCR
    • DOR
    • Time to response
    • Transfusion independence
    • OS
    Fase I (monoterapia)/ Fase Ib (tratamiento combinado)
    • Determinar los parámetros FC de CA-4948, incluidos la concentración máxima (Cmáx), la concentración mínima (Cmín), el tiempo máximo (Tmáx), el área bajo la curva de concentración en función del tiempo en el plazo de 24 horas (ABC0-24), el área bajo la curva de concentración en función del tiempo de cero a infinito (ABC0-inf) y la semivida (T½) del fármaco (plazo: 24 meses)
    Evaluar la respuesta clínica en la LMA o el SMDra del siguiente modo:
    • LMA:
    o Proporción de pacientes que alcanzan RC + RCh
    o Proporción de pacientes que alcanzan RCi, o RC o RCh
    • SMDra: TRO de RC + RP + RCm
    • Independencia transfusional

    Fase IIa (ampliación de la monoterapia
    Seguridad medida mediante AA, ECG, valores de bioquímica clínica y análisis hematológicos, constantes vitales y exploraciones físicas
    Respuesta clínica en la LMA o el SMDra evaluada del siguiente modo:
    • Proporción de pacientes con LMA que alcanzan RC o RCh o RCi
    • Proporción de pacientes con SMDra que alcanzan RC o RCh o RCm
    • DR
    • Tiempo que tarda en alcanzarse la respuesta
    • Independencia transfusional
    • SG
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 months
    24 meses
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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
    Part 1b emavusertib + venetoclax doublet is not open to further enrollment.
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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
    Israel
    United States
    France
    Poland
    Spain
    Czechia
    Germany
    Italy
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Ultima Visit Ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months48
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months48
    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: 114
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 211
    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 state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 128
    F.4.2.2In the whole clinical trial 325
    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 Decision2023-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-11
    P. End of Trial
    P.End of Trial StatusOngoing
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