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    Summary
    EudraCT Number:2021-003768-29
    Sponsor's Protocol Code Number:DAY101-102
    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:2021-12-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2021-003768-29
    A.3Full title of the trial
    A Phase 1b/2, Open Label Study of DAY101 Monotherapy or Combination with Other Therapies for Patients with Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations
    Estudio en fase Ib/II, abierto, de DAY101 en monoterapia o en combinación con otros tratamientos para pacientes con tumores sólidos recurrentes, progresivos o resistentes que albergan anomalías en la vía MAPK
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1b/2 study to Test Effects of Using DAY101 Monotherapy or Combination in patients with Solid Tumors Harboring MAPK Pathway Aberrations
    Estudio en fase Ib/II para evaluar los efectos de DAY101 en monoterapia o en combinación, en pacientes con tumores sólidos que albergan anomalías en la vía MAPK
    A.4.1Sponsor's protocol code numberDAY101-102
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/050/2020
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDOT Therapeutics-1 Inc. (Day One)
    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 supportDOT Therapeutics-1 Inc. (Day One)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationParexel International (IRL) Limited
    B.5.2Functional name of contact pointMelissa Kenny
    B.5.3 Address:
    B.5.3.1Street Address70 Sir John Rogerson's Quay
    B.5.3.2Town/ cityDublin
    B.5.3.3Post code2
    B.5.3.4CountryIreland
    B.5.6E-mailclinicaltrial.enquiries@parexel.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 nameDAY101
    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 INNtovorafenib
    D.3.9.1CAS number 1096708-71-2
    D.3.9.2Current sponsor codeDAY101
    D.3.9.3Other descriptive nameMLN2480, TAK-580, BSK1369, BIIB024
    D.3.9.4EV Substance CodeSUB89679
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.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 nameDAY101
    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 INNtovorafenib
    D.3.9.1CAS number 1096708-71-2
    D.3.9.2Current sponsor codeDAY101
    D.3.9.3Other descriptive nameMLN2480, TAK-580, BSK1369, BIIB024
    D.3.9.4EV Substance CodeSUB89679
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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
    Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations
    Tumores sólidos recurrentes, progresivos o resistentes que albergan anomalías en la vía MAPK
    E.1.1.1Medical condition in easily understood language
    Brain tumor in children
    Tumor cerebral en niños
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1b
    The Phase 1b objectives will apply to the investigation of DAY101 in combination with other therapies. Additional objectives may be specified according to the related sub-study protocol.
    Primary Objective:
    • To determine the safety of DAY101 in combination with other therapies.
    • To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of DAY101 in combination with other therapies.

    Phase 2
    The Phase 2 objectives will apply to the investigation of DAY101 as monotherapy and in combination with other therapies. Additional objectives may be specified according to the relevant sub-study protocol.
    Primary Objective:
    To evaluate the efficacy of DAY101 by RECIST version 1.1 or appropriate tumor response criteria as a monotherapy or in combination with other therapies
    Fase Ib
    Los objetivos de la fase Ib se aplicarán a la investigación de DAY101 en combinación con otros tratamientos. Los objetivos adicionales pueden especificarse de acuerdo con el protocolo del subestudio relacionado.
    Objetivo principal:
    • Determinar la seguridad de DAY101 en combinación con otros tratamientos.
    • Determinar la dosis máxima tolerable (DMT) y la dosis recomendada para la fase II (DRFII) de DAY101 en combinación con otros tratamientos.

    Fase II
    Los objetivos de la fase II se aplicarán a la investigación de DAY101 en monoterapia y en combinación con otros tratamientos. Se podrán especificar objetivos adicionales de acuerdo con el protocolo del subestudio correspondiente.
    Objetivo principal:
    Evaluar la eficacia de DAY101 en monoterapia o en combinación con otros tratamientos según los criterios RECIST versión 1.1 o los criterios de respuesta tumoral adecuados.
    E.2.2Secondary objectives of the trial
    Phase 1b:
    • To assess the efficacy of DAY101 in combination with other therapies.
    • To characterize the pharmacokinetic (PK) profile of DAY101 in combination with other therapies.
    • To characterize pharmacodynamic (PD) effects of DAY101 in combination with other therapies.

    Phase 2:
    •To assess the safety and tolerability of DAY101 as monotherapy or in combination with othertherapies.
    •To assess additional efficacy parameters of DAY101 as monotherapy or in combination with othertherapies.
    •To characterize the tumor responses observed with DAY101 as monotherapy or in combination withother targeted therapies.
    •To characterize the PK profile of DAY101 in combination with other therapies, according to therelevant sub-study protocol.
    •To characterize the PD effects of DAY101 as monotherapy or in combination with other therapies.
    •To determine the relationship between PK and PD of DAY101 in combination with other therapies.
    Fase Ib:
    • Evaluar la eficacia de DAY101 en combinación con otros tratamientos.
    • Caracterizar el perfil farmacocinético (FC) de DAY101 en combinación con otros tratamientos.
    • Caracterizar los efectos farmacodinámicos (FD) de DAY101 en combinación con otros tratamientos.

    Fase II:
    • Evaluar la seguridad y tolerabilidad de DAY101 en monoterapia o en combinación con otros tratamientos.
    • Evaluar parámetros de eficacia adicionales de DAY101 en monoterapia o en combinación con otros tratamientos.
    • Caracterizar las respuestas tumorales observadas con DAY101 en monoterapia o en combinación con otros tratamientos dirigidos.
    • Caracterizar el perfil FC de DAY101 en combinación con otros tratamientos, de acuerdo con el protocolo del subestudio correspondiente.
    • Caracterizar los efectos FD de DAY101 en monoterapia o en combinación con otros tratamientos.
    • Determinar la relación entre la FC y la FD de DAY101 en combinación con otros tratamientos.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Clinical Protocol DAY101-102a (Monotherapy Substudy): A Phase 2, Subprotocol of DAY101 Monotherapy for Patients with Recurrent, Progressive, or Refractory Solid Tumors with Activating BRAF Gene Fusion
    Subprotocolo en fase II de DAY101 en monoterapia para pacientes con tumores sólidos recurrentes, progresivos o resistentes que albergan anomalías en la vía MAPK
    E.3Principal inclusion criteria
    1. Signed informed consent by patients >=18 years of age and, assent for patients >= 12 up to < 18 years of age and, unless legally emancipated, his/her parent or legal guardian must be able to understand and willing to provide informed consent concurrently.
    2. Patients must have a histologically confirmed diagnosis of tumor with concurrent MAPK pathway alteration as assessed by sequencing, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or another clinically accepted molecular diagnostic method recognized by local laboratory or regulatory agency (archival tissue < 3 years will be acceptable; otherwise, a fresh sample will be collected at screening)
    3. Patients must have radiographically-recurrent or radiographically-progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1). Imaging must be performed within 28 days prior to the first dose of study drug. Please see sub-studies for additional inclusion criteria.
    4. Patients must have progressed after, are intolerant of, or refused standard-of-care treatment prior to documented radiographic progression.
    5. Archival tumor tissue preferably less than 3 years old or, if unavailable, freshly acquired tumor tissue for correlative studies is required for all patients, where safe to obtain as determined by the Investigator.
    6. Previous chemotherapy and hormone therapy (excluding physiologic replacement) must be completed at least 4 weeks or 5 half-lives, whichever occurs first, prior to initiation of therapy.
    7. Previous immunotherapy/monoclonal antibody use must be completed at least 4 weeks or 5 half-lives (whichever is shorter) prior to initiation of therapy. In addition, radiation therapy to the target lesion must be completed at least 6 months prior to initiation of therapy.
    8. All associated toxicity from previous therapies must be resolved to <= Grade 1 or considered baseline prior to initiation of therapy.
    9. If brain metastases are present, they must have been previously treated and be stable by radiographic imaging (must have at least 2 images taken >= 4 weeks apart) AND, if receiving corticosteroids, the patient must be neurologically stable by clinical examination and on a stable or a decreasing dose of corticosteroids within 7 days prior to study start.
    10. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1. For patients <16 years of age, a Lansky Performance Score > 70.
    11. Acceptable end-organ function as demonstrated by the following laboratory values:
    • Absolute neutrophil count (ANC) > 1000/μL
    • Platelet count > 75,000/μL
    • Hemoglobin > 9 g/dL (hemoglobin may not be supported by transfusion, erythropoietin, or other approved hematopoietic growth factors within 2 weeks of the laboratory test)
    • Serum bilirubin < 1.5 × upper limit of normal (ULN) or < 2 × ULN if patient is known to have Gilbert’s Disease as the only underlying hepatic disorder
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 × ULN
    • Serum creatinine clearance > 60 mL/min/1.73m2 calculated according to CKD-EPI (Appendix I)
    12. Thyroid function tests must be consistent with stable thyroid function. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting study drug are eligible.
    13. Left ventricular ejection fraction (LVEF) >=50% or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) within 28 days before the first dose of study drug.
    14. Ability to comply with outpatient treatment, laboratory monitoring, required clinic visits, and required imaging studies for the duration of study participation
    15. Willingness of male and female patients with reproductive potential to use double highly effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Highly effective birth control methods are described in Appendix F.
    16. Male patients must agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug.

    In addition to those outlined in Study Protocol DAY101-102 (Master Protocol), the following additional inclusion criteria must be met to be eligible for enrollment in this study:
    2a. Patients must have a histologically confirmed diagnosis of melanoma or other solid tumor with an activating BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplifications as assessed by sequencing, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or another sponsor-accepted method
    1.Consentimiento informado firmado por los pacientes >=18 años de edad y asentimiento en el caso de los pacientes de >=12 a <18 años de edad, a menos que estén legalmente emancipados; capacidad del progenitor o tutor legal de comprender y voluntad de proporcionar el consentimiento informado de forma simultánea.
    2.Los pacientes deben tener un diagnóstico confirmado histológicamente de tumor con alteración simultánea de la vía MAPK evaluada mediante secuenciación, reacción en cadena de la polimerasa (PCR), hibridación in situ con fluorescencia (FISH) u otro método de diagnóstico molecular clínicamente aceptado reconocido por el laboratorio local o las autoridades sanitarias (se aceptará tejido de archivo <3 años; de lo contrario, se recogerá una muestra reciente en la selección).
    3.Los pacientes deben presentar enfermedad radiográficamente recurrente o progresiva que sea medible mediante los criterios de respuesta tumoral adecuados (p. ej., criterios RECIST versión 1.1). Las pruebas de diagnóstico por imagen deben realizarse en los 28 días anteriores a la primera dosis del fármaco del estudio. Consulte los subestudios para conocer los criterios de inclusión adicionales.
    4.Los pacientes deben haber presentado progresión después, ser intolerantes o haber rechazado el tratamiento estándar antes de la progresión radiográfica documentada.
    5.Se requiere de todos los pacientes tejido tumoral de archivo, preferiblemente de menos de 3 años o, si no está disponible, tejido tumoral recién adquirido para estudios correlativos, cuando sea seguro obtenerlo según determine el investigador.
    6.La quimioterapia y hormonoterapia previas (excluida la sustitución fisiológica) deben completarse al menos 4 semanas o 5 semividas antes del inicio del tratamiento, lo que ocurra primero.
    7.El uso previo de inmunoterapia/anticuerpos monoclonales debe completarse al menos 4 semanas o 5 semividas (lo que sea más corto) antes del inicio del tratamiento. Además, la radioterapia de la lesión diana debe completarse al menos 6 meses antes del inicio del tratamiento.
    8.Toda la toxicidad asociada a tratamientos anteriores debe resolverse a grado <=1 o considerarse como valor inicial antes del inicio del tratamiento.
    9.Si hay metástasis cerebrales, deben haber sido tratadas previamente y estar estables mediante pruebas de diagnóstico por imagen radiográficas (debe haber al menos 2 imágenes tomadas con >=4 semanas de diferencia) Y, si se reciben corticoesteroides, el paciente debe estar neurológicamente estable mediante exploración clínica y con una dosis estable o decreciente de corticosteroides en los 7 días previos al inicio del estudio.
    10.Puntuación funcional de 0 o 1 según el Grupo Oncológico Cooperativo del Este (ECOG). Para pacientes <16 años de edad, puntuación de 70 en la escala funcional de Lansky>.
    11.Función orgánica final aceptable demostrada por los siguientes valores analíticos:
    •Recuento absoluto de neutrófilos (RAN) >1000/μl.
    •Recuento de plaquetas >75 000/μl.
    •Hemoglobina >9 g/dl (la hemoglobina puede no estar respaldada por transfusión, eritropoyetina u otros factores de crecimiento hematopoyéticos aprobados en las 2 semanas siguientes a la prueba analítica).
    •Bilirrubina sérica <1,5 × límite superior de la normalidad (LSN) o <2 × LSN si se sabe que el paciente tiene enfermedad de Gilbert como único trastorno hepático subyacente.
    •Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) <2,5 × LSN.
    •Aclaramiento de creatinina sérica >60 ml/min/1,73m2 calculado según CKD-EPI (Apéndice I).
    12.Las pruebas de la función tiroidea deben ser coherentes con una función tiroidea estable. Son aptos los pacientes que reciban una dosis estable de tratamiento sustitutivo tiroideo durante un mínimo de 3 semanas antes de iniciar el fármaco del estudio.
    13.Fracción de expulsión del ventrículo izquierdo (FEVI) del >=50 % o superior, medida mediante ecocardiograma (ECO) o ventriculografía con radionúclidos (MUGA) en los 28 días anteriores a la primera dosis del fármaco del estudio.
    14.Capacidad para cumplir con el tratamiento ambulatorio, la monitorización analítica, las visitas clínicas requeridas y los estudios de imagen requeridos durante la participación en el estudio.
    15.Disposición de los pacientes tanto de sexo masculino como femenino con capacidad reproductora a utilizar métodos anticonceptivos dobles altamente eficaces, definidos como un método utilizado por el paciente y otro, por su pareja, durante el tratamiento y durante 180 días después de la última dosis del fármaco del estudio. Los métodos anticonceptivos altamente eficaces se describen en el Apéndice F.
    16.Los pacientes de sexo masculino deben aceptar no donar esperma en el transcurso de este estudio ni en los 180 días posteriores a la última dosis del fármaco del estudio.
    E.4Principal exclusion criteria
    1. Prior receipt of any BRAF-, MEK-, or MAPK-directed inhibitor therapy, except for tumor types and indications where such therapy has been approved by the FDA or applicable regulatory authorities.
    2. Known presence of concurrent activating alterations. Examples include, but are not limited, to the following: EGFR, ALK, MET, ROS, FGFR, RET, NTRK, EGFR, PIK3A, IDH1/2, EGFR, and cKIT. Genetic profile of tumor under study, if available, will be reviewed by the Sponsor to confirm eligibility.
    3. Current enrollment in any other investigational treatment study
    4. Patients with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at screening or baseline who would be considered a risk factor for CSR or RVO
    5. Patients who have an unstable neurological condition, despite adequate treatment (e.g., uncontrolled seizures)
    6. Evidence of current uncontrolled cardiovascular conditions, including but not limited to clinically significant cardiac arrythmias, congestive heart failure, angina, myocardial infarction, or cerebrovascular accident (CVA), within the past 6 months
    7. Mean resting QT calculated using Fridericia’s formula (QTcF) interval > 470 ms based on triplicate electrocardiogram (ECG) average; or family or personal history of long or short QT syndrome; Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12 months of screening
    8. Concomitant treatment with strong CYP2C8 inhibitor and/or inducers within 14 days before initiation of therapy. See sub-study protocol for details on prohibited medications with DAY101.
    9. Concomitant treatment with medications that are sensitive substrates of CYP2C8 and CYP2C9 or predominantly transported by a breast cancer resistance protein (BCRP) (See sub-study protocol for details on prohibited medications with DAY101. Additional restricted medications may apply depending on the combination partner. Refer to the eligibility criteria for each sub-study for additional restrictions specific to the combination that may apply.)
    10. Unable to swallow investigational product or has refractory nausea and vomiting, malabsorption, external biliary diversion, or any significant small bowel resection that may interfere with adequate absorption of investigational product
    11. Major surgery within 28 days of Day 1 (does not include central venous access or ventriculoperitoneal shunts).
    12. Active, uncontrolled systemic bacterial, viral, or fungal infection.
    13. History of any major disease that might interfere with safe protocol participation, as determined by the Investigator (e.g., allogeneic bone marrow transplantation, organ transplantation, or interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis).
    14. Patients with subclinical pneumonitis who have received immunotherapy previously can be included if his/her condition is stable without any medical intervention.
    15. History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens Johnsons syndrome (SJS), or hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of the investigational medicinal product(s)
    16. History of second malignancy within 3 years prior to study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer, or superficial bladder cancer
    17. Female patients who are pregnant or currently breastfeeding
    18. Other unspecified reasons that, in the opinion of the Investigator, make the patient unsuitable for enrollment
    1. Recepción previa de cualquier tratamiento con inhibidores de BRAF, MEK o MAPK, excepto para los tipos de tumor y las indicaciones en los que dicho tratamiento haya sido aprobado por la Administración de Alimentos y Medicamentos (FDA) de los Estados Unidos o las autoridades reguladoras correspondientes.
    2. Presencia conocida de alteraciones activadoras simultáneas. Son ejemplos, entre otras: EGFR, ALK, MET, ROS, FGFR, RET, NTRK, EGFR, PIK3A, IDH1/2, EGFR y cKIT. El promotor revisará el perfil genético del tumor en estudio, si está disponible, para confirmar la elegibilidad.
    3. Inscripción actual en cualquier otro estudio de tratamiento en investigación.
    4. Pacientes con indicios actuales o antecedentes de retinopatía serosa central (RSC), oclusión de la vena retiniana (OVR) u oftalmopatía presente en la selección o al inicio que se consideraría un factor de riesgo de RSC o de OVR.
    5. Pacientes que tienen una afección neurológica inestable, a pesar de recibir un tratamiento adecuado (p. ej., convulsiones no controladas).
    6. Indicios de afecciones cardiovasculares no controladas actuales, incluidas, entre otras, arritmias cardíacas clínicamente significativas, insuficiencia cardíaca congestiva, angina de pecho, infarto de miocardio o accidente cerebrovascular (ACV) en los últimos 6 meses.
    7. Media del intervalo QT en reposo calculado utilizando el intervalo de la fórmula de Fridericia (QTcF) >470 ms a partir del promedio de electrocardiogramas (ECG) por triplicado; o antecedentes familiares o personales de síndrome de QT largo o corto; síndrome de Brugada o antecedentes conocidos de prolongación de QTc o taquicardia ventricular en entorchado en los 12 meses previos a la selección.
    8. Tratamiento concomitante con inhibidores o inductores potentes del CYP2C8 en los 14 días anteriores al inicio del tratamiento. Consulte el protocolo del subestudio para obtener detalles sobre los medicamentos prohibidos con DAY101.
    9. Tratamiento concomitante con medicamentos que son sustratos sensibles de CYP2C8 y CYP2C9 o predominantemente transportados por una proteína de resistencia al cáncer de mama (BCRP) (véanse en el protocolo del subestudio más detalles sobre los medicamentos prohibidos con DAY101. Podría haber otros medicamentos restringidos dependiendo de la pareja de la combinación. Consulte en los criterios de aptitud de cada subestudio posibles restricciones adicionales específicas de la combinación).
    10. Incapacidad para tragar el producto en investigación o presentar náuseas y vómitos resistentes al tratamiento, malabsorción, desviación biliar externa o cualquier resección significativa del intestino delgado que pueda interferir con una absorción adecuada del producto en investigación.
    11. Cirugía mayor en los 28 días previos al día 1 (no incluye un acceso venoso central ni derivaciones ventriculoperitoneales).
    12. Infección bacteriana, vírica o fúngica sistémica activa no controlada.
    13. Antecedentes de cualquier enfermedad importante que pudiera interferir con el seguimiento seguro del protocolo, según determine el investigador (p. ej., alotrasplante de médula ósea, trasplante de órgano, enfermedad pulmonar intersticial o neumonitis intersticial, incluida la neumonitis por radiación clínicamente significativa).
    14. Los pacientes con neumonitis subclínica que hayan recibido inmunoterapia anteriormente se pueden ser incluir si su afección está estable sin intervención médica.
    15. Antecedentes de reacción farmacológica con eosinofilia y síndrome de síntomas sistémicos (DRESS), síndrome de Stevens-Johnson (SSJ) o hipersensibilidad al medicamento en investigación, a cualquier fármaco con una estructura química similar o a cualquier excipiente presente en la forma galénica de los medicamentos en investigación.
    16. Antecedentes de segunda neoplasia maligna en los 3 años anteriores al tratamiento del estudio, excepto cáncer de cuello uterino in situ tratado de forma curativa, cáncer de piel no melanoma o cáncer de vejiga superficial.
    17. Pacientes de sexo femenino embarazadas o en periodo de lactancia.
    18. Otros motivos sin especificar que, en opinión del investigador, hagan que el paciente no sea apto para la inscripción.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b:
    • Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5
    • Change from baseline in targeted vital signs
    • Change from baseline in targeted clinical laboratory test results
    • Incidence of dose-limiting toxicities (DLTs)

    Phase 2:
    Overall response rate (ORR) as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or PR according to the appropriate response assessment criteria for the disease setting as assessed by the Investigator.
    Fase 1b:
    • Incidencia y severidad de los acontecimientos adversos, con determinación de su severidad según los NCI CTCAE v5
    • Cambio frente al basal en las constantes vitales de interés
    • Cambio frente al basal en los resultados de las determinaciones de laboratorio de interés
    • Incidencia de toxicidad limitante de la dosis (dose-limiting toxicities, DLTs)

    Fase 2:
    Tasa de respuesta global (overall response rate, ORR), en su evaluación mediante el porcentaje de pacientes con mejor respuesta global confirmada de respuesta completa (complete response, CR) o respuesta parcial (partial response, PR) según los criterios adecuados de evaluación de la respuesta en el marco de la enfermedad, a juicio del investigador.”
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 meses
    E.5.2Secondary end point(s)
    Phase 1b:
    • ORR as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or partial response (PR) according to the appropriate tumor response criteria as assessed by Investigator
    • DOR in patients with best overall response of CR or PR as determined by the treating Investigator [from time of first tumor response to progression or date of data analysis, whichever occurs earlier]
    • Duration of progression-free survival (PFS) following initiation of study treatment to disease progression, death, or date of analysis, whichever occurs earlier
    • Duration of overall survival (OS) following initiation of study treatment to time of death
    • Time to response (TTR) in patients with best overall response of CR or PR as determined by treating Investigator [from initiation of study treatment to date of first response]
    • Comparing the DOR in patients with CR or PR as determine by treating Investigator with the DOR observed with the immediate prior line of anticancer treatment
    • Plasma concentration of DAY101 at specified time points in order to define PK parameters
    • Measured by downstream MAPK pathway signaling, including pERK and other relevant pathway signaling using appropriate assay(s) on tumor biopsies obtained at baseline and on Cycle 1 Day 1 and Cycle 2 Day 1 (± 3 days)

    Phase2:
    • Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5
    • Change from baseline in targeted vital signs
    • Change from baseline in targeted clinical laboratory test result
    • ORR as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or PR according to the appropriate tumor response criteria as assessed by Investigator
    • DOR in patients with best overall response of CR or PR as determined by the treating Investigator [from time of first tumor response to progression or date of data analysis, whichever occurs earlier]
    • Duration of progression-free survival (PFS) following initiation of study treatment to disease progression, death, date of analysis, whichever occurs earlier
    • Duration of OS following initiation of study treatment to time of death
    • Time to response (TTR) in patients with best overall response of CR or PR as determined by treating Investigator [from initiation of study treatment to date of first response]
    • Comparing the DOR in patients with CR or PR as determine by treating Investigator with the DOR observed with the immediate prior line of anticancer treatment]
    • Measure plasma concentration of DAY101 at specified time points in order to define population PK parameters
    • Measured by downstream MAPK pathway signaling and other relevant pathway signaling using appropriate assay(s) on tumor biopsies obtained at baseline and while on-treatment
    • Measured by the relationship between PK and PD biomarkers
    Fase 1b:
    • ORR en su evaluación mediante el porcentaje de pacientes con mejor respuesta global confirmada de respuesta completa (CR) o respuesta parcial (PR) según los criterios adecuados de respuesta tumoral, a juicio del investigador
    • Duración de la respuesta (duration of response, DOR) en los pacientes con mejor respuesta global de CR o PR, determinada por el investigador responsable [medida desde el momento de la primera respuesta del tumor hasta la progresión o la fecha de análisis de los datos, eligiéndose la primera de estas situaciones que tenga lugar]
    • Duración de la supervivencia sin progresión (progression-free survival, PFS), medida desde el inicio del tratamiento del estudio hasta la progresión de la enfermedad, la muerte o la fecha de análisis de los datos, eligiéndose la primera de estas situaciones que tenga lugar
    • Duración de la supervivencia global (overall survival, OS), medida desde el inicio del tratamiento del estudio hasta la muerte
    • Tiempo hasta la respuesta (time to response, TTR) en los pacientes con mejor respuesta global de CR o PR, determinado por el investigador responsable [medido desde el inicio del tratamiento del estudio hasta la fecha de la primera respuesta]
    • Comparación de la DOR en pacientes con CR o PR, determinada por el investigador responsable, frente a la DOR observada con la línea inmediatamente anterior de tratamiento antitumoral
    • Concentración plasmática de DAY101 en determinados puntos de tiempo, a fin de definir los parámetros farmacocinéticos
    • Medición de la señalización de la vía MAPK anterógrada, incluidas pERK y otras señales de vías relevantes, utilizando el método o métodos adecuados en biopsias tumorales obtenidas en el basal y en el Ciclo 1 Día 1 y en el Ciclo 2 Día 1 (± 3 días)

    Fase 2:
    • Incidencia y severidad de los acontecimientos adversos, con determinación de su severidad según los NCI CTCAE v5
    • Cambio frente al basal en las constantes vitales de interés
    • Cambio frente al basal en el resultado de las determinaciones de laboratorio de interés
    • ORR en su evaluación mediante el porcentaje de pacientes con mejor respuesta global confirmada de respuesta completa (CR) o respuesta parcial (PR) según los criterios adecuados de respuesta tumoral, a juicio del investigador
    • DOR en los pacientes con mejor respuesta global de CR o PR, determinada por el investigador responsable [medida desde el momento de la primera respuesta del tumor hasta la progresión o la fecha de análisis de los datos, eligiéndose la primera de estas situaciones que tenga lugar]
    • Duración de la supervivencia sin progresión (PFS), medida desde el inicio del tratamiento del estudio hasta la progresión de la enfermedad, la muerte o la fecha de análisis de los datos, eligiéndose la primera de estas situaciones que tenga lugar
    • Duración de la supervivencia global (OS) medida desde el inicio del tratamiento del estudio hasta la muerte
    • Tiempo hasta la respuesta (TTR) en los pacientes con mejor respuesta global de CR o PR, determinado por el investigador responsable [medido desde el inicio del tratamiento del estudio hasta la fecha de la primera respuesta]
    • Comparación de la DOR en pacientes con CR o PR, determinada por el investigador responsable, frente a la DOR observada con la línea inmediatamente anterior de tratamiento antitumoral
    • Medición de la concentración plasmática de DAY101 en determinados puntos de tiempo, a fin de definir los parámetros farmacocinéticos poblacionales
    • Medición de la señalización de la vía MAPK anterógrada y otras señales de vías relevantes, utilizando el método o métodos adecuados en biopsias tumorales obtenidas en el basal y durante el tratamiento
    • Medición de la relación entre biomarcadores farmacocinéticos y farmacodinámicos”
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months
    6 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 No
    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
    tolerabilidad
    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
    Phase 1b will only apply to sub-studies of DAY101 in combination with other therapies
    La fase Ib solo se aplicará a los subestudios de DAY101 en combinación con otros tratamientos
    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
    multicéntrico, en paraguas
    multi-center, umbrella
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Korea, Republic of
    Spain
    United States
    France
    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
    LPLV
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    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 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 33
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Young children not of age to provide consent. Parents/guardians may give consent on behalf of their children.
    Niños pequeños sin edad de dar su consentimiento. Los progenitores/tutores legales pueden otorgar el consentimiento en nombre de los menores a su cargo.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 11
    F.4.2.2In the whole clinical trial 43
    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
    ninguno
    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 Decision2022-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-30
    P. End of Trial
    P.End of Trial StatusOngoing
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