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    Summary
    EudraCT Number:2019-001025-28
    Sponsor's Protocol Code Number:NuTide:121
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-26
    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 number2019-001025-28
    A.3Full title of the trial
    A Phase III Open-Label, Multi-Centre, Randomised Study Comparing NUC-1031 plus Cisplatin to Gemcitabine plus Cisplatin in Patients with Previously Untreated Locally Advanced or Metastatic Biliary Tract Cancer
    Estudio en fase III, abierto, multicéntrico, aleatorizado para comparar NUC-1031 más cisplatino con gemcitabina más cisplatino en pacientes con cáncer de vías biliares localmente avanzado o metastásico sin tratamiento previo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of NUC-1031 plus Cisplatin versus Gemcitabine plus Cisplatin in Previously Untreated Biliary Tract Cancer
    Estudio de NUC-1031 más cisplatino frente a gemcitabina más cisplatino en cáncer de vías biliares sin tratamiento previo
    A.4.1Sponsor's protocol code numberNuTide:121
    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 SponsorNuCana plc
    B.1.3.4CountryUnited Kingdom
    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 supportNuCana plc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNuCana plc
    B.5.2Functional name of contact pointNuCana Clinical Study Information
    B.5.3 Address:
    B.5.3.1Street Address3 Lochside Way
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH12 9DT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number349133030003133
    B.5.6E-mailinfo@nucana.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 nameAcelarin
    D.3.2Product code NUC-1031
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFosgemcitabine palabenamide
    D.3.9.1CAS number 1562406-27-2
    D.3.9.2Current sponsor codeNUC-1031
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number725
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Gemcitabine
    D.2.1.1.2Name of the Marketing Authorisation holderSun Pharmaceutical Industries Europe B.V
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameGemcitabine
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGemcitabine
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cisplatin
    D.2.1.1.2Name of the Marketing Authorisation holderEBEWE Pharma Ges.m.b.H Nfg. KG
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    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 nameCisplatin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCisplatin
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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
    Histologically- or cytologically-confirmed adenocarcinoma of the biliary tract (including gallbladder, intra and extra-hepatic biliary ducts and ampullary cancers) that is locally advanced, unresectable or metastatic.
    Adenocarcinoma biliar confirmado histológica o citológicamente (incluido el colangiocarcinoma, conductos biliares intra y extra-hepáticos y el cáncer ampular) que está localmente avanzada o metastásica.
    E.1.1.1Medical condition in easily understood language
    Cancer of the biliary tract
    Cáncer de conductos biliares
    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
    To compare NUC-1031/cisplatin (Arm A) to the gemcitabine/cisplatin standard of care (Arm B) and to detect a clinically meaningful improvement in Overall Survival and Objective Response Rate.
    Comparar NUC-1031/cisplatino (grupo A) con gemcitabina/cisplatino
    tratamiento estándar (grupo B) y detectar una mejora clínica significativa en la supervivencia general y en la tasa de respuesta objetiva.
    E.2.2Secondary objectives of the trial
    To compare the following between the two treatment arms:
    - Progression-free survival (PFS) based on BICR
    - Duration of response (DoR) based on BICR
    - 18- and 12-month survival
    - Disease control rate (DCR)
    To assess the safety and tolerability of NUC-1031
    To explore the pharmacokinetics of NUC-1031
    To assess changes in patient-reported quality of life
    Comparar lo siguiente entre los dos grupos de tratamiento:
    - Supervivencia sin progresión (SSP) basada en RCIE
    - Duración de la respuesta (DoR) basada en RCIE
    - Supervivencia a los 12 y 18 meses
    - Tasa de control de la enfermedad (TCE)
    Evaluar la seguridad y tolerabilidad de NUC-131
    Investigar la farmacocinética de NUC-1031
    Evaluar los cambios en la calidad de vida notificada por el paciente
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A robust QT substudy will be carried out to assess any potential effects of the NUC-1031 + cisplatin combination on QT interval prolongation.
    Se realizará un subestudio con un análisis exhaustivo para evaluar el efecto de la combinación de NUC-1031 + cisplatino en la prolongación del intervalo QT.
    E.3Principal inclusion criteria
    1. Written informed consent and authorisation to use and disclose health information.

    2. Ability to comprehend and willingness to comply with the requirements of this protocol, including the QoL questionnaires.

    3. Female or male patients aged ≥18 years.

    4. Histologically- or cytologically-confirmed adenocarcinoma of the biliary tract (including gallbladder, intra and extra-hepatic biliary ducts and ampullary cancers) that is locally advanced, unresectable or metastatic. Patients with measurable (as per RECIST v1.1 criteria) or non-measurable disease are permitted.

    5. Life expectancy ≥16 weeks.

    6. ECOG performance status 0 or 1.

    7. Adequate biliary drainage with no evidence of ongoing infection. If applicable, treatable and clinically-relevant biliary duct obstruction has been relieved by internal endoscopic drainage/stenting at least 2 weeks previously or by palliative bypass surgery or percutaneous drainage prior to study entry, and the patient has no active or suspected uncontrolled infection. Patients fitted with a biliary stent should be clinically stable and free of signs of infection for ≥2 weeks prior to study entry. Patients with improving biliary function who meet all other inclusion criteria may be re-tested during the screening window.

    8. Adequate bone marrow, hepatic, and renal function, as evidenced by:
    • Absolute neutrophil count (ANC) ≥1,500/μL without colony-stimulating factor support.
    • Platelet count ≥100,000/μL.
    • Haemoglobin ≥10 g/dL without need for haematopoietic growth factor or transfusion
    support in prior 2 weeks.
    • Total bilirubin <2 × upper limit of normal (ULN); does not apply to patients with Gilbert's
    syndrome. Consistent with inclusion criterion 7, patients whose whole bilirubin and biliary
    function is recovering may be re-tested during the screening period.
    • ALT and/or AST <5 × ULN
    • Serum creatinine ≤1.5 × ULN or creatinine clearance ≥45 mL/min actual or calculated by
    the Cockcroft-Gault method.
    • International normalised ratio (INR) <1.5 and partial thromboplastin time (PTT)
    <1.5 × ULN; does not apply to patients on an anti-coagulant with stable dose 28 days prior to first dose.

    9. QTc interval <450 msec (males) or <470 msec (females), in the absence of bundle branch block. In the presence of bundle branch block with consequent QTc prolongation, patients may be enrolled based on a careful risk-benefit assessment.

    10. Human Immunodeficiency Virus-infected patients who are healthy and have a low risk of Acquired Immune Deficiency Syndrome-related outcomes may be included in this study.

    11.Female patients of child-bearing potential (i.e., all women except those who are post-menopausal for ≥1 year or who have a history of hysterectomy or surgical sterilisation) must have a negative pregnancy test within 3 days prior to the first study drug administration. All patients of child-bearing potential must agree to practice true abstinence or to use two highly effective forms of contraception, one of which must be a barrier method of contraception, from the time of screening until 6 months after the last dose of study medication.

    12. Male patients with a female partner must either have had a successful vasectomy or they and their female partner meet the criteria above (not of childbearing potential or practicing highly effective contraceptive methods).
    1. Consentimiento informado por escrito y autorización para usar y divulgar información médica.

    2. Capacidad para comprender y voluntad para cumplir con los requisitos de este protocolo, incluidos los cuestionarios de CdV.

    3. Pacientes hombres o mujeres de ≥18 años de edad.

    4. Adenocarcinoma del tracto biliar (incluidos el cáncer de vesícula biliar, de conductos biliares intra y extrahepáticos y ampular) histológica o citológicamente confirmado, localmente avanzado, irresecable o metastásico. Se permiten pacientes con enfermedad medible (según los criterios RECIST v1.1) o no medible.

    5. Esperanza de vida ≥16 semanas.

    6. Estado general de 0 a 1 según el ECOG.

    7. Función adecuada de drenaje biliar sin indicios de infección en curso. Si procede, obstrucción del conducto biliar tratable y clínicamente relevante, resuelta mediante drenaje endoscópico interno/colocación de stent al menos 2 semanas antes, o mediante cirugía de derivación paliativa o drenaje percutáneo antes de la entrada en el estudio, y el paciente no tiene ni se sospecha infección activa sin controlar. Los pacientes con stent biliar, deben estar clínicamente estables y sin signos de infección durante ≥2 semanas antes de la entrada en el estudio. Los pacientes con función biliar en fase de mejora que cumplan todos los demás criterios de inclusión pueden volver a realizar las pruebas durante el periodo de selección.

    8. Función hepática, renal y de la médula ósea adecuadas demostrada mediante:
    • Recuento absoluto de neutrófilos (RAN) ≥1.500/μL sin apoyo de factor estimulante de colonias
    • Recuento de plaquetas ≥100 000/μL
    • Hemoglobina ≥10 g/dL sin necesidad de factores de crecimiento hematopoyético ni de transfusión de rescate en las 2 semanas anteriores.
    • Bilirrubina total <2 veces el límite superior de la normalidad (LSN); no se aplica a los pacientes con síndrome de Gilbert. En coherencia con el criterio de inclusión n.º 7, los pacientes cuya bilirrubina total y función biliar se estén recuperando pueden volver a realizar las pruebas durante el periodo de selección.
    • ALT y/o AST <5 veces el LSN
    • Creatinina sérica ≤1,5 veces el LSN o aclaramiento de creatinina ≥45 mL/min real o calculado según el método de Cockcroft y Gault
    • Índice internacional normalizado (INR) <1,5 y tiempo de tromboplastina parcial (TTP) <1,5 veces el LSN; no se aplica a pacientes que tengan una dosis estable de anticoagulantes 28 días antes de la primera dosis.

    9. Intervalo de QTc <450 ms (varones) o <470 ms (mujeres), en ausencia de bloqueo de rama. En la presencia de bloqueo de rama con la consecuente la prolongación del intervalo QTc, los pacientes pueden inscribirse en función de una cuidadosa evaluación de riesgos y beneficios.

    10. Los pacientes con infección por virus de la inmunodeficiencia humana que estén saludables y presenten un riesgo bajo de desenlaces clínicos relacionados con el síndrome de inmunodeficiencia adquirida pueden ser incluidos en este estudio.

    11. Las pacientes en edad fértil (es decir, todas las mujeres, excepto aquellas posmenopáusicas durante ≥1 año o que tienen antecedentes de histerectomía o esterilización quirúrgica) deben tener una prueba de embarazo negativa de los 3 días previos a la primera administración del fármaco del estudio. Todos las pacientes en edad fértil deben aceptar la práctica de una abstinencia verdadera o utilizar dos métodos anticonceptivos altamente eficaces, uno de los cuales debe ser un método anticonceptivo de barrera, desde el momento de la selección hasta 6 meses después de la última dosis de la medicación del estudio.

    12. Los pacientes varones con pareja de sexo femenino deben haber tenido una vasectomía satisfactoria o ellos y su pareja de sexo femenino deben cumplir con los criterios anteriores (no estar en edad fértil o utilizar métodos anticonceptivos altamente eficaces).
    E.4Principal exclusion criteria
    1. Combined or mixed hepatocellular/cholangiocarcinoma.

    2. Prior systemic therapy for advanced or metastatic biliary tract cancer. However, prior chemotherapy in the adjuvant setting or low-dose chemotherapy given in conjunction with radiotherapy in the adjuvant setting and completed at least 6 months prior to enrolment is permitted. The following prior interventions are allowed provided the patient has fully recovered:
    • Surgery: non-curative resection with macroscopic residual disease or palliative bypass surgery. Patients who have previously undergone curative surgery must now have evidence of non-resectable disease requiring systemic chemotherapy.
    • Radiotherapy: prior radiotherapy (with or without radio-sensitising low-dose chemotherapy) for localised disease and there is now clear evidence of disease progression requiring systemic chemotherapy.
    • Photodynamic therapy: prior photodynamic therapy for localised disease with no evidence of metastatic disease or for localised disease to relieve biliary obstruction in the presence of metastatic disease provided there is now clear evidence of disease progression requiring systemic chemotherapy.
    • Palliative radiotherapy: palliative radiotherapy provided that all AEs have resolved and the patient has measurable disease outside the field of radiation.

    3. Prior treatment with or known hypersensitivity to NUC-1031, gemcitabine, cisplatin or other platinum-based agents or history of allergic reactions attributed to the excipients contained in NUC-1031 or diluent solution (dimethylacetamide [DMA], Kolliphor ELP, Tween 80).

    4. Symptomatic central nervous system or leptomeningeal metastases.

    5. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, low grade prostate cancer not requiring treatment or other solid tumours curatively treated with no evidence of disease for ≥3 years.

    6. Concurrent serious (as deemed by the Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation.

    7. Other acute or chronic medical, neurological, or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

    8. Prior exposure to another investigational agent within 28 days prior to randomisation.

    9. Major surgery within 28 days prior to randomisation; patient must have completely recovered from any prior surgical or other procedures.

    10. Pregnant or breastfeeding.

    11. Residual toxicities from prior treatments or procedures which have not regressed to Grade ≤1 severity (CTCAE v5.0), except for alopecia or ≤Grade 1 peripheral neuropathy.

    12. Concomitant use of drugs at doses known to cause clinically relevant prolongation of QT/QTc interval.

    13. Administration of a live vaccination within 28 days prior to randomisation.

    14. Ongoing or recent (≤6 months) hepatorenal syndrome.
    1. Carcinoma hepatocelular/colangiocarcinoma mixto o combinado.

    2. Tratamiento sistémico previo para cáncer de vías biliares avanzado o metastásico. Sin embargo, está permitida la quimioterapia previa en un contexto adyuvante o una dosis baja de quimioterapia administrada junto con radioterapia en el contexto de tratamiento adyuvante y finalizadas al menos 6 meses antes de la inscripción. Las siguientes intervenciones previas están permitidas siempre que el paciente se haya recuperado por completo:
    • Cirugía: resección no curativa con enfermedad macroscópica residual o cirugía de derivación paliativa. Los pacientes que previamente se hayan sometido a intervención quirúrgica curativa deben presentar ahora indicios de enfermedad irresecable que requiera quimioterapia sistémica.
    • Radioterapia: radioterapia previa (con o sin dosis bajas de quimioterapia que sensibilice a la radiación) para enfermedad localizada y existen ahora claros indicios de progresión de la enfermedad que requieren quimioterapia sistémica.
    • Fototerapia dinámica: terapia fotodinámica previa para enfermedad localizada sin indicios de enfermedad metastásica, o para enfermedad localizada con el fin de aliviar una obstrucción biliar en la presencia de enfermedad metastásica, siempre que existan ahora claros indicios de progresión de la enfermedad que requieren quimioterapia sistémica.
    • Radioterapia paliativa: radioterapia paliativa siempre que todos los acontecimientos adversos se hayan resuelto y el paciente presente enfermedad medible fuera del campo de radiación.

    3. Tratamiento previo con o hipersensibilidad conocida a NUC-1031, gemcitabina, cisplatino u otros fármacos a base de platino o antecedentes de reacciones alérgicas atribuidas a los excipientes que contiene NUC-1031 o a la solución diluyente (dimetilacetamida [DMA], Kolliphor ELP, Tween 80).
    4. Metástasis del sistema nervioso central o leptomeníngea sintomáticas.

    5. Antecedentes de otras neoplasias malignas, excepto cáncer de piel no melanoma tratado de manera adecuada, cáncer de cuello uterino tratado y curado in situ, cáncer de próstata de grado bajo que no requiere tratamiento u otros tumores sólidos tratados y curados y sin indicios de enfermedad durante ≥3 años.

    6. Patologías médicas concomitantes graves (según el criterio del investigador), incluidas, entre otras, insuficiencia cardíaca congestiva clase III o IV de la NYHA, antecedentes de síndrome de QT prolongado congénito, infección no controlada, hepatitis B o C activa, u otras patologías concomitantes que, en opinión del investigador, dificultarían la participación o cooperación en el estudio.
    7. Otras patologías médicas, neurológicas o psiquiátricas agudas o crónicas, o alteraciones en la analítica que puedan aumentar el riesgo asociado a la participación del estudio o a la administración del producto en investigación o que puedan interferir con la interpretación de los resultados del estudio y, a juicio del investigador, hagan que el paciente resulte inadecuado para su entrada en este estudio.

    8. Exposición previa a otro fármaco en investigación en los 28 días previos a la aleatorización.

    9. Intervención quirúrgica mayor en los 28 días previos a la aleatorización; el paciente debe haberse recuperado completamente de cualquiera de los procedimientos quirúrgicos anteriores o de otros procedimientos.

    10. Estar embarazada o en periodo de lactancia.

    11. Toxicidad residual de tratamientos o procedimientos previos que no haya remitido hasta un grado ≤1 de intensidad (CTCAE v5.0), salvo alopecia o neuropatía periférica de grado ≤1.

    12. Uso concomitante de fármacos en dosis clínicamente relevantes conocidos por provocar prolongación del intervalo QT/QTc.

    13. Administración de vacuna viva en los 28 días previos a la aleatorización.

    14. Síndrome hepatorrenal actual o reciente (≤6 meses).
    E.5 End points
    E.5.1Primary end point(s)
    OS, defined as the time from randomisation to the time of death from any cause.

    ORR, defined as the percentage of patients achieving a confirmed complete or partial response to treatment as assessed by BICR according to RECIST v1.1 criteria. This will be assessed only in patients with measurable disease at baseline.
    La SG, definida como el tiempo desde la aleatorización hasta la muerte por cualquier causa.

    La TRO, definida como el porcentaje de pacientes que logran una respuesta completa o parcial confirmada al tratamiento evaluada por la RCIE de acuerdo con los criterios RECIST v1.1. Esta se evaluará solo en pacientes con enfermedad medible al inicio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Interim Analysis 1 - approx 25.5 months or 418 patients with measurable disease randomised. This will assess ORR for demonstration of efficacy, and assess OS for futility.

    Interim Analysis 2 - approx 33.1 months or approx 425 deaths. This will assess ORR and OS for demonstration of efficacy.

    Interim Analysis 3 - approx 40 months or 541 deaths. This will assess OS for efficacy.

    Final Analysis - approx 48 months or 637 deaths.
    1º análisis provisional - 418 pacientes aleatorizados con enfermedad medible o en aproximadamente 25,5 meses. Se evaluará TRO para demostrar la eficacia y SG para la futilidad.

    2º análisis provisional - 425 muertes o en aproximadamente 33,1 meses. Se evaluará TRO y SG para demostrar la eficacia.

    3º análisis provisional - 541 muertes o en aproximadamente 25,5 meses. Se evaluará SG para la eficacia.

    Análisis final - 637 muertes o en aproximadamente 48 meses.
    E.5.2Secondary end point(s)
    Progression Free Survival
    • PFS, based on BICR according to RECIST v1.1 criteria, defined as the time from randomisation to the first observation of objective tumour progression or death from any cause. For patients with non-measurable disease at baseline, refer to the protocol criteria for disease progression.

    Efficacy
    • DoR, as assessed by BICR, defined as the time from initial clinical response (partial response [PR] or complete response [CR] that is subsequently confirmed) to the first observation of tumour progression or death from any cause
    • 18-month survival
    • 12-month survival
    • DCR, based on BICR according to RECIST v1.1 criteria, defined as the percentage of patients demonstrating CR, PR, or stable disease (SD)

    Safety
    Safety and tolerability will be assessed by evaluation of the following:
    • Treatment-emergent AEs (TEAEs), including TEAEs by severity grade using Common Terminology Criteria for Adverse Events (CTCAE) v5.0
    • Serious TEAEs (SAEs)
    • Deaths due to TEAEs
    • Treatment discontinuations due to TEAEs
    • Clinically-significant changes in laboratory parameters
    • Changes in Eastern Cooperative Oncology Group (ECOG) status, physical exam, electrocardiogram (ECG) and vital signs

    A robust QT analysis substudy will be carried out to assess the effect of the NUC-1031 + cisplatin combination on QT interval prolongation in a subset of patients.

    Pharmacokinetics of NUC-1031
    Sparse PK sampling will be taken on Cycle 1 Day 1 at the end of infusion, 2 hours after the end of infusion, and 6 hours after the end of infusion, to capture Ctrough and Cmax plasma levels.

    Patient-Reported Quality of Life
    Patient-reported quality of life will be assessed using the European Organisation for Research and Treatment (EORTC) Quality of Life Questionnaire (QLQ-C30) with the QLQ-BIL21 module and the 5-level EuroQol five-dimension scale (EQ-5D-5L).
    Supervivencia sin progresión
    • La SSP, basada en la RCIE de acuerdo con los criterios RECIST v1.1, y definida como el tiempo desde la aleatorización hasta la primera observación de la progresión objetiva del tumor o de muerte por cualquier causa. Para los pacientes con enfermedad no medible al inicio, consulte los criterios del protocolo sobre la progresión de la enfermedad

    Eficacia
    • La DoR, evaluada por la RCIE, se define como el tiempo desde la respuesta clínica inicial (respuesta parcial [RP] o respuesta completa [RC] que se haya confirmado posteriormente) hasta la primera observación de progresión del tumor o de muerte por cualquier causa
    • 18 meses de supervivencia
    • 12 meses de supervivencia
    • La TCE, basada en la RCIE de acuerdo con los criterios RECIST v1.1, definida como el porcentaje de pacientes con RC, RP, o enfermedad estable (EE)

    Seguridad
    La seguridad y la tolerabilidad se evaluarán mediante la evaluación de los siguientes criterios:
    • Los AA surgidos durante el tratamiento (AAST), incluidos los AAST por grado de intensidad usando los Criterios terminológicos comunes para acontecimientos adversos (CTCAE) v5.0
    • Los AAST graves (AAG)
    • Las muertes debidas a AAST
    • Las interrupciones de tratamiento debidas a AAST
    • Cambios clínicamente significativos en los parámetros de laboratorio
    • Cambios en el estado general según el ECOG (Eastern Cooperative Oncology Group), la exploración física, el electrocardiograma (ECG) y las constantes vitales.

    Se realizará un subestudio con un análisis exhaustivo del QT para evaluar el efecto de la combinación de NUC-1031 + cisplatino en la prolongación del intervalo QT en un subconjunto de pacientes.

    Farmacocinética de NUC-1031
    El día 1 del ciclo 1 se realizará una recogida de muestras aisladas para FC al final de la infusión, 2 horas después del final de la infusión y 6 horas después de finalizar la infusión, para capturar los niveles en plasma Cmín y Cmáx.

    Calidad de vida notificada por el paciente
    La calidad de vida según la notificación del paciente se evaluará mediante el cuestionario de calidad de vida QLQ-C30 del EORTC (European Organisation for Research and Treatment) con el módulo QLQ-BIL21 y la escala EuroQol de 5 dimensiones de 5 niveles (EQ-5D-5L).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Progression Free Survival - end the end of the study.

    Efficacy (DoR, 18/12-month survival, DCR) - at the end of the study.

    Safety - after 50 patients have been randomised in total, at every 6 months and at the end of the study.

    QTc analysis - after 40 patients have been enrolled into the QT substudy.

    Pharmacokinetics of NUC-1031 - end of the study.

    Patient-Reported Quality of Life - at the end of the study.
    Supervivencia sin progresión - fin del final del estudio.

    Eficacia (DoR, 18/12- meses de supervivencia, DCR) - al final del estudio.

    Seguridad - después de que 50 pacientes hayan sido aleatorizados en total, cada 6 meses y al final del estudio.

    Análisis de QTc -
    Después de que 40 pacientes hayan sido incluidos en el subestudio QT.

    Farmacocinética de NUC-1032 - final del estudio.

    Calidad de vida notificada por el paciente - al final del estudio.
    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 Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Assessment of archival tumour sample characteristics that may further an understanding of the mechanism(s) through which the clinical activity of NUC-1031 is achieved.
    Evaluación de las características de las células tumorales que pueda mejorar la comprensión de los mecanismos a través de los que se consigue la actividad clínica de NUC-1031.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Russian Federation
    Spain
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study date is defined as the time when 637 deaths have occurred, unless the results for OS meet the specified criterion at an interim analysis to stop for early demonstration of efficacy, or unless the study is terminated early on safety grounds on the recommendation of the IDMC. Patients who are still receiving benefit from study treatment at the end of study may continue study treatment until disease progression
    La fecha de finalización del estudio se define como el momento en que 637 muertes hayan ocurrido, a menos que los resultados para SG cumplan con el criterio establecido de un análisis provisional para parar la demostración temprana de eficacia, o a al menos que el estudio finalice anticipadamente por motivos de seguridad recomendados por IDMC. Pacientes que tengan beneficios del tratamiento del estudio al final del estudio podrán seguir recibiendo tratamiento hasta la progresión de la enfermedad
    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: 704
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 124
    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 state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 392
    F.4.2.2In the whole clinical trial 828
    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)
    Following participation in the NuTide:121 study patients will be referred back to their oncologist and GP, according to local practice.

    Patients who are still receiving benefit from study treatment at the end of study date may continue study treatment until disease progression.
    Los pacientes, después de su participación en el estudio NuTide: 121, serán remitidos a su oncólogo y médico de cabecera, según la práctica habitual.

    Los pacientes reciban beneficios del tratamiento del estudio al final de la fecha final del estudio podrán continuar el tratamiento hasta la progresión de la enfermedad.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR Clinical Research Network Portfolio
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-10-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-04
    P. End of Trial
    P.End of Trial StatusOngoing
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