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    Summary
    EudraCT Number:2017-004415-39
    Sponsor's Protocol Code Number:TO-TAS0728-101
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-01-31
    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 number2017-004415-39
    A.3Full title of the trial
    A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY TO INVESTIGATE THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF TAS0728, AN ORAL COVALENT BINDING INHIBITOR OF HER2, IN SUBJECTS WITH ADVANCED SOLID TUMORS WITH HER2 OR HER3 ABNORMALITIES
    Estudio multicéntrico, abierto, en fase I/II para investigar la seguridad, farmacocinética y eficacia de TAS0728, un inhibidor oral de la unión covalente de HER2 en sujetos con tumores sólidos avanzados con anomalías en HER2 o HER3.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 1/2, open-label, multicenter study, designed to evaluate the safety, tolerability, the blood concentration values and efficacy of a substance called TAS0728.
    Estudio multicéntrico, abierto, en fase I/II, diseñado para evaluar la seguridad, la tolerabilidad, los valores de concentración en sangre y la eficacia de una sustancia denominada TAS0728.
    A.4.1Sponsor's protocol code numberTO-TAS0728-101
    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 SponsorTaiho Oncology, 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 supportTaiho Oncology, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTaiho Pharma Europe, Ltd. (TPEL)
    B.5.2Functional name of contact pointElvira Klissourska
    B.5.3 Address:
    B.5.3.1Street AddressLakeside House, 1 Furzeground Way, Stockley Park
    B.5.3.2Town/ cityUxbridge
    B.5.3.3Post codeUB11 1BD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0044208 622 3384
    B.5.5Fax number0044208 622 3239
    B.5.6E-maileklissourska@taiho.eu
    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 nameTAS0728
    D.3.2Product code TAS0728
    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 INNTAS0728
    D.3.9.2Current sponsor codeTAS0728
    D.3.9.3Other descriptive nameTAS0728
    D.3.9.4EV Substance CodeSUB190569
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 nameTAS0728
    D.3.2Product code TAS0728
    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 INNTAS0728
    D.3.9.2Current sponsor codeTAS0728
    D.3.9.3Other descriptive nameTAS0728
    D.3.9.4EV Substance CodeSUB190569
    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
    Urothelial cancer with HER2 or HER3 mutation
    Biliary tract cancer with HER2 or HER3 mutation
    Breast cancer with HER2 or HER3 mutation
    Breast cancer with HER2 amplification/overexpression as per ASCO-CAP 2013 guidelines
    Non-small cell lung cancer (NSCLC) with HER2 or HER3 mutation
    Colorectal cancer (CRC) with HER2 mutation or amplification
    Other tumors with HER2 or HER3 mutation, amplification, or overexpression (eg, gastric or gastroesophageal junction (GEJ), endometrial)
    Cáncer urotelial con mutación de HER2/HER3; Cáncer de las vías biliares con mutación de HER2/HER3; Cáncer de mama con mutación de HER2/HER3; Cáncer de mama con amplificación o sobreexpresión de HER2 conforme a directrices de 2013 de la ASCO-CAP; Carcinoma broncopulmonar no microcítico con mutación de HER2/HER3; Cáncer colorrectal con mutación o amplificación de HER2; Otros tumores con mutación, amplificación o sobreexpresión de HER2/HER3 (p. ej., gástrico de unión gastroesofágica, endometrial)
    E.1.1.1Medical condition in easily understood language
    Cancers of urinary tract, Biliary tract, breast, lung, stomach, colon, for which a pathological change in expression of certain genes, named HER2 and HER3, has been proved.
    Cánceres del tracto urinario, de las vías biliares, de mama, de pulmón, de estómago, de colon, para los que se ha demostrado un cambio patológico en la expresión de ciertos genes, llamados HER2 y HER3
    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 PT
    E.1.2Classification code 10061451
    E.1.2Term Colorectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10057654
    E.1.2Term Breast cancer female
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10004593
    E.1.2Term Bile duct cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077840
    E.1.2Term Urothelial cancer of renal pelvis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079440
    E.1.2Term Non-squamous non-small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    For phase I (dose escalation): To determine the maximum-tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of TAS0728 when administered orally twice daily (BID) in 21-day cycles to adult subjects with advanced solid tumors harboring human epidermal growth factor receptor (HER) 2 or HER3 overexpression, amplification, or mutation.
    For phase IIa (proof of concept): To evaluate the preliminary efficacy of TAS0728 as measured by objective response rate (ORR) in subjects with the following tumor types with HER2 or HER3 mutation:
    Urothelial cancer
    Biliary tract cancer
    Breast cancer with
    Breast cancer with
    Non-small cell lung cancer (NSCLC)
    Colorectal cancer (CRC)
    Fase I (aumento escalonado de la dosis): Determinar la dosis máxima tolerada (DMT) y/o la dosis recomendada en fase II (DRFII) de TAS0728 cuando se administra por vía oral dos veces al día (2 v/d) en ciclos de 21 días a sujetos adultos con tumores sólidos avanzados que presentan sobreexpresión, amplificación o mutación del receptor del factor de crecimiento epidérmico humano HER2 o HER3.
    Fase IIa (prueba de concepto): Evaluar la eficacia preliminar de TAS0728 medida mediante la tasa de respuesta objetiva (TRO) en sujetos con los siguientes tipos de tumores con mutación de HER2 o HER3: Cáncer urotelial, Cáncer de las vías biliares, Cáncer de mama, Carcinoma broncopulmonar no microcítico (Non-small cell lung cancer, NSCLC), Cáncer colorrectal (CCR).
    E.2.2Secondary objectives of the trial
    Phase 1 Dose Escalation
    • To evaluate the ORR in subjects receiving TAS0728
    • To assess the safety and tolerability of TAS0728
    • To investigate the clinical pharmacokinetics (PK) of TAS0728
    Phase 2a Proof of Concept
    • To assess the safety and tolerability of TAS0728
    Fase I Aumento escalonado de la dosis:
    • Evaluar la TRO en sujetos que reciben TAS0728
    • Evaluar la seguridad y la tolerabilidad de TAS0728
    • Investigar la farmacocinética (FC) clínica de TAS0728
    Fase IIa Prueba de concepto:
    • Evaluar la seguridad y la tolerabilidad de TAS0728
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or females with an age >= 18 years.
    2. Subjects with histological- or cytological-confirmed, advanced cancer, who have progressed on (or not been able to tolerate) standard therapy or for whom no standard anticancer therapy exists. Subjects may have received two different forms of specific anti-HER2 therapy for their cancer except for breast cancer where receipt of up to four lines of anti-HER2 therapy is allowed prior to enrollment.
    a. For Phase 1, only subjects with the following molecular/genetic alterations will be enrolled:
    i. HER2+ determined by local laboratory, for example: immunohistochemistry (IHC) 3+ and/or fluorescence in situ hybridization (FISH)+ by an accurate and validated assay, or potentially actionable HER2 or HER3 mutation or amplification by next generation sequencing.
    b. For Phase 2a, subjects with one of the following tumor types will be enrolled as determined by local laboratory:
    I. Urothelial cancer with HER2 or HER3 mutation
    ii. Biliary tract cancer with HER2 or HER3 mutation
    iii. Breast cancer with HER2 or HER3 mutation
    iv. Breast cancer with HER2 amplification or overexpression as per ASCO-CAP 2013 guidelines
    v. NSCLC with HER2 or HER3 mutation
    vi. CRC with HER2 mutation or amplification
    vii. Other tumors with HER2 mutation/amplification/overexpression or HER3 mutation (gastric/GEJ, endometrial).
    c. For Phase 2a, subjects should also meet the following criteria:
    i. Radiological progression on the last line of therapy before entering this trial must be documented
    ii. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
    3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
    4. Subjects must have the following laboratory values:
    a. ANC >= 1.5 × 109/L
    b. Hemoglobin >= 8.0 g/dL
    c. Platelet count >= 75 × 109/L
    d. Albumin >= 3 g/dL
    e. Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for serum albumin) or ionized calcium within institutional normal limits
    f. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase and alanine aminotransferase/serum glutamic-pyruvic transaminase ≤ 3 × upper limit of normal (ULN) or <= 5.0 × ULN if liver metastases are present
    g. Total serum bilirubin <= 1.5 × ULN
    h. Serum creatinine <= 1.4 × ULN or 24-hour or calculated creatinine clearance (Ccr) >= 50 mL/min (according to Cockcroft Gault formula).* For subjects in Phase 2a with urothelial cancer, a creatinine clearance of >= 40 mL/min is acceptable.
    5. Left ventricular ejection fraction (LVEF) > institutional lower limit of normal.
    *For a calculated Ccr value, the eligibility should be determined using the Cockcroft Gault formula:
    Male Ccr (mL/min) = Body weight (kg) × (140 – age)/[72 × serum creatinine (mg/dL)]
    Female Ccr (mL/min) = male Ccr × 0.85.
    6. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to the first dose and for 6 months after the last dose) if conception is possible during this interval. Female subjects are considered to not be of childbearing potential if they have a history of hysterectomy, or are postmenopausal defined as no menses for 12 months without an alternative medical cause. For both males and females, see Section 5.5 for definitions of contraceptive methods considered effective for this protocol.
    7. Subjects must be able to swallow and retain orally administered medication and not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels.
    8. Able to agree to and sign informed consent and to comply with the protocol.
    1. Hombres o mujeres mayores de 18 años de edad.
    2. Sujetos con cáncer avanzado, confirmado histológica o citológicamente, que haya progresado con el tratamiento estándar (o si este no se puede tolerar) o para el que no exista ningún tratamiento antineoplásico estándar. Los sujetos pueden haber recibido dos formas diferentes de tratamiento antineoplástico específico contra la HER2, excepto para el cáncer de mama para el que se permiten hasta cuatro líneas de tratamiento contra la HER2 antes de la inclusión.
    a. En el caso de la fase I, solo se incluirá a los sujetos con las siguientes alteraciones moleculares/genéticas:
    i. HER2+ determinado por el laboratorio local, por ejemplo: inmunohistoquímica (IHQ) 3+ y/o hibridación in situ con fluorescencia (FISH)+ mediante un ensayo preciso y validado, o mutación o amplificación de HER2 o HER3 potencialmente aprovechable mediante secuenciación de última generación.
    b. En el caso de la fase IIa, se incluirá a los sujetos con uno de los siguientes tipos de tumores, según determine el laboratorio local:
    i. Cáncer urotelial con mutación de HER2 o HER3
    ii. Cáncer de las vías biliares con mutación de HER2 o HER3
    iii. Cáncer de mama con mutación de HER2 o HER3
    iv. Cáncer de mama con amplificación o sobreexpresión de HER2 conforme a las directrices de 2013 de ASCO-CAP
    v. NSCLC con mutación de HER2 o HER3
    vi. CCR con mutación o amplificación de HER2
    vii. Otros tumores con mutación/amplificación/sobreexpresión de HER2 o mutación de FIER3 (gástrico/GEJ/endometrial).
    c. En el caso de la fase IIa, los sujetos también deben cumplir los siguientes criterios:
    i. Debe confirmarse la progresión radiológica en la última línea de tratamiento antes de incorporarse a este ensayo
    ii. Al menos 1 lesión mensurable, según la definición de los Criterios de evaluación de la respuesta en tumores sólidos (RECIST) versión 1.1.
    3.Estado funcional del Grupo Oncológico Cooperativo del Este (Eastern Cooperative Oncology Group, ECOG) de 0 o 1.
    4. Los sujetos deben tener los siguientes valores de laboratorio:
    a. Recuento absoluto de neutrófilos (RAN) >= 1,5 x 109/l
    b. Hemoglobina >= 8,0 g/dl
    c. Recuento de plaquetas >= 75 x 109/l
    d. Albúmina >= 3 g/dl
    e. Potasio, magnesio, fósforo, sodio, calcio total (corregido por la albúmina en suero) o calcio ionizado en suero dentro de los límites institucionales del centro
    f. Aspartato aminotransferasa/transaminasa glutámico-oxaloacética en suero y alanina aminotransferasa/transaminasa glutámico-pirúvica en suero <=3 veces el límite superior de la normalidad (LSN) o <=5,0 veces el LSN si está presente metástasis hepática
    g. Bilirrubina total sérica <= 1,5 veces el LSN
    h. Creatinina sérica <= 1,4 veces el LSN o 24 horas o depuración de la creatinina (Ccr) calculada >= 50 ml/min (de acuerdo con la fórmula de Cockcroft-Gault).* En el caso de los sujetos en la fase IIa con cáncer urotelial, es aceptable una depuración de la creatinina de >= 40 ml/min.
    *Para un valor de Ccr calculada, la idoneidad se debe determinar utilizando la fórmula de Cockcroft-Gault:
    Ccr de los hombres (ml/min) = Peso corporal (kg) x (140 - edad)/[72 x creatinina sérica (mg/dl)] Ccr de las mujeres (ml/min) = Ccr de los hombres x 0,85.
    5. Fracción de eyección del ventrículo izquierdo (FEVI) > límite inferior institucional de lo normal.
    6. Las mujeres con capacidad de procrear deberán obtener un resultado negativo en una prueba de embarazo (en suero u orina) en los 7 días anteriores al inicio de la administración del medicamento del estudio. Tanto los hombres como las mujeres deberán comprometerse a utilizar un método anticonceptivo eficaz durante el estudio (antes de la primera dosis y en los 6 meses siguientes a la última dosis) si existe la posibilidad de que se produzca un embarazo durante este intervalo. Las mujeres se considerarán sin capacidad de procrear si tienen antecedentes de histerectomía o estado posmenopáusico, definido como 12 meses sin menstruación, sin una causa médica alternativa. Tanto en el caso de los hombres como en el de las mujeres, consulte el apartado 5.5 para obtener definiciones de los métodos anticonceptivos considerados eficaces para este protocolo.
    7. Los sujetos deben poder tragar y retener el medicamento administrado por vía oral y no deben tener ninguna anomalía gastrointestinal (GI) importante que pueda alterar la absorción, como síndrome de hipoabsorción o resección importante del estómago o los intestinos.
    8. Deben poder aceptar y firmar el consentimiento informado y cumplir con el protocolo.
    E.4Principal exclusion criteria
    Disease exclusions
    1. Subjects with a history of brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases. Subjects with treated brain metastases that are asymptomatic and have been clinically stable for at least 4 weeks will be eligible.
    Medical condition exclusions
    2. Subjects who have a history of another primary malignancy, other than:
    a. carcinomas in situ, eg, breast, cervix, and prostate
    b. locally excised nonmelanoma skin cancer
    c. A subject who has had no evidence of disease from another primary cancer for 2 or more years.
    3. Any other clinically significant acute or chronic medical or psychiatric condition or any laboratory abnormality that may increase the risk associated with study drug administration, or may interfere with the interpretation of study results such as, but not limited to:
    a. Uncontrolled diabetes mellitus
    b. Liver disease such as decompensated liver disease
    c. Life-threatening autoimmune disease.
    4. Diseases that significantly affect GI absorption of the compound.
    5. Subjects who have impaired cardiac function or clinically significant cardiac disease, including any of the following:
    a. Baseline corrected QT level using Fridericia formula (QTcF) > 480 ms or congenital QT syndrome
    b. History or presence of serious uncontrolled ventricular arrhythmias
    c. Any New York Heart Association Classification of Heart Failure >= Class II Severe/unstable angina, New York Heart Association classification 4 Congestive Heart Failure (Appendix 1)
    d. Echocardiogram or multiple grated acquisition under 50% ejection fraction.
    Prior therapy exclusions
    6. Chemotherapy, biologic therapy, targeted therapy, immunotherapy, extended-field radiotherapy, or investigational agents within 5 half-lives or within 4 weeks (whichever is shorter) prior to administration of first dose of study drug on Day 1 or have not recovered from the side effects of such therapy.
    7. Major surgery/surgical therapy for any cause within 4 weeks of first dose.
    Exclusiones por enfermedades
    1. Los sujetos con antecedentes de metástasis cerebrales o que presenten signos/síntomas atribuibles a metástasis cerebrales y no se hayan sometido a una evaluación con métodos de obtención de imágenes radiológicos para descartar la presencia de metástasis cerebrales. Reunirán los requisitos los sujetos con metástasis cerebrales tratadas que sean asintomáticos y hayan permanecido clínicamente estables durante al menos 4 semanas.
    Exclusiones por afecciones médicas
    2. Sujetos que tengan antecedentes de otra neoplasia maligna primaria distinta de:
    a. carcinomas in situ, p. ej., mama, cuello uterino y próstata
    b. cáncer de piel distinto del melanoma extirpado localmente
    c. Un sujeto que no haya tenido ningún signo de enfermedad de otro cáncer primario durante 2 o más años.
    3. Cualquier otro trastorno médico o psiquiátrico, agudo o crónico, clínicamente significativo o cualquier anomalía de laboratorio que pueda aumentar el riesgo asociado con la administración del medicamento del estudio o interferir en la interpretación de los resultados del estudio como, entre otros, los siguientes:
    a. Diabetes mellitus no controlada.
    b. Enfermedad hepática como la hepatopatía descompensada.
    c. Enfermedad autoinmunitaria potencialmente mortal.
    4. Enfermedades que afecten de modo significativo a la absorción GI del compuesto.
    5. Sujetos que tengan un deterioro de la función cardíaca o una cardiopatía clínicamente significativa, incluidas alguna de las siguientes:
    a. Nivel del intervalo QT inicial corregido utilizando la fórmula de Fridericia (QTcF) > 480 ms o síndrome del intervalo QT congénito.
    b. Antecedentes o presencia de arritmias ventriculares graves no controladas.
    c. Cualquier clasificación de insuficiencia cardíaca de clase >= II según la de la Asociación Neoyorquina del Corazón (Anexo 1).
    d. Fracción de eyección inferior al 50 % en ecocardiograma o ventriculografía nuclear.
    Exclusiones por tratamientos previos
    6. Quimioterapia, tratamiento biológico, tratamiento dirigido, inmunoterapia, radioterapia de campo extendido o agentes en fase de investigación en un plazo de las 5 semividas o las 4 semanas (lo que sea más corto) previas a la administración de la primera dosis del medicamento del estudio el día 1 o si no se han recuperado de los efectos secundarios de dichos tratamientos.
    7. Tratamiento quirúrgico/cirugía mayor por cualquier causa en las 4 semanas previas a la primera dosis.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1 Dose Escalation
    • Incidence rate of dose-limiting toxicities (first cycle only) at each dose level
    Phase 2a Proof of Concept
    • ORR according to Response Evaluation Criteria in Solid Tumors (RECIST guidelines (Version 1.1, 2009) for each tumor type. Objective response rate is defined as the proportion of subjects who had best overall response (BOR) of complete response (CR) or partial response (PR)
    Fase I Aumento escalonado de la dosis
    Tasa de incidencia de toxicidades limitantes de la dosis (primer ciclo solamente) en cada nivel de dosis
    Fase IIa Prueba de concepto
    TRO acorde al “Response Evaluation Criteria in Solid Tumors (RECIST guidelines (Version 1.1, 2009)” para cada tipo de tumor. La tasa de respuesta objetiva se define como la proporción de sujetos que tuvieron la mejor tasa de respuesta para una respuesta completa o parcial.
    E.5.1.1Timepoint(s) of evaluation of this end point
    See table 1, pg 12-14 in Protocol, Schedule of Events
    Refiéranse a la tabla 1, páginas 12-14 del protocolo, Diagrama de actividades
    E.5.2Secondary end point(s)
    • Safety: Type, frequency and severity of adverse drug reactions according to National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03)
    • Disease control rate is defined as the proportion of subjects who achieve a response of CR, PR, or stable disease
    • Progression-free survival is defined as the time from the first dose date to objectively documented disease progression or death
    • Duration of response defined as the time between the date of first response and the subsequent date of objectively documented disease progression or death
    • Overall survival is defined as the time between the first dosing date and the date of death
    •Pharmacokinetics (Phase 1 – dose escalation only): TAS0728 plasma concentrations, urinary concentrations and basic PK parameters
    • Seguridad: Tipo, frecuencia y gravedad de las reacciones adversas del medicamento de acuerdo al “National Cancer Institute Common Terminology Criteria for Adverse Events” (versión 4.03)
    • La tasa de control de la enfermedad se define como la proporción de sujetos que alcanzan una respuesta completa, parcial, o la estabilización de la enfermedad.
    • La supervivencia sin progresión se define como el tiempo desde la fecha de la primera dosis hasta la progresión de la enfermedad documentada objetivamente o el fallecimiento.
    • La duración de la respuesta se define como el tiempo entre la fecha de la primera respuesta y la sucesiva fecha de progresión de la enfermedad documentada objetivamente o el fallecimiento.
    • La supervivencia global se define como el tiempo entre la fecha de la primera dosis y la fecha de fallecimiento.
    • Farmacocinética (Fase I - aumento escalonado de la dosis): concentración de TAS0728 en plasma , orina y parámetros básicos de FC.
    E.5.2.1Timepoint(s) of evaluation of this end point
    See table 1, pg 12-14 in Protocol, Schedule of Events
    Refiéranse a la tabla 1, páginas 12-14 del protocolo, Diagrama de actividades
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic 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) Yes
    E.7.1.1First administration to humans Yes
    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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    France
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Subject Last Visit
    Última visita del ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    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 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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state29
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 87
    F.4.2.2In the whole clinical trial 174
    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)
    After discontinuation due to Dose limiting Toxicity or inefficacy, the Investigator will decide best approved treatment for respective indication.
    Después de la interrupción del tratamiento debido a la toxicidad limitante de la dosis o ineficacia, el investigador decidirá el mejor tratamiento aprobado para la indicación correspondiente.
    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 Decision2018-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-04-15
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