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    Summary
    EudraCT Number:2013-000726-66
    Sponsor's Protocol Code Number:GETNE1206
    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:2014-06-09
    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 number2013-000726-66
    A.3Full title of the trial
    Randomized open label study to compare the efficacy and safety of everolimus followed by chemotherapy with STZ-5FU upon progression or the reverse sequence, chemotherapy with STZ-5FU followed by everolimus upon progression, in advanced progressive pNETs
    Estudio abierto aleatorizado para comparar la eficacia y la seguridad de everolimus seguido de quimioterapia con STZ-5FU tras la progresión o la secuencia invertida, quimioterapia con STZ-5FU seguida de everolimus tras la progresión, en tumores neuroendocrinos pancreáticos (TNEP) avanzados y progresivos (estudio SEQTOR).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized not blinded clinical trial to compare two sequences of treatment: STZ-5FU followed by everolimus or everolimus followed buy STZ-5FU upon progression.
    Ensayo clínico abierto aleatorizado para comparar la eficacia de dos secuencias de tratamiento: STZ-5FU seguido de everolimus o everolimus seguido de STZ-5FU.
    A.3.2Name or abbreviated title of the trial where available
    SEQTOR
    A.4.1Sponsor's protocol code numberGETNE1206
    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 SponsorGrupo Español de Tumores Neuroendocrinos (GETNE)
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGrupo Español de Tumores Neuroendocrinos (GETNE)
    B.5.2Functional name of contact pointTrial Lead Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressC/ Mare de Deu del Coll 75 1º-2ª
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08023
    B.5.3.4CountrySpain
    B.5.4Telephone number+34932134478
    B.5.5Fax number+34932134478
    B.5.6E-mailcvidal@needsandaims.com
    D. IMP Identification
    D.IMP: 1
    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.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical 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 INNEVEROLIMUS
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNSTREPTOZOCIN
    D.3.9.1CAS number 18883-66-4
    D.3.9.4EV Substance CodeSUB10658MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for 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 INN5-FLOUROURACIL
    D.3.9.3Other descriptive name5-FLOUROURACIL
    D.3.9.4EV Substance CodeSUB27520
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN5 FLUOROURACIL
    D.3.9.3Other descriptive name5 FLUOROURACIL
    D.3.9.4EV Substance CodeSUB31782
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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
    Advanced Pancreatic Neuroendocrine Tumours
    Tumores Neuroendocrinos Pancreáticos Avanzados
    E.1.1.1Medical condition in easily understood language
    Advanced Pancreatic Neuroendocrine Tumours
    Tumores Neuroendocrinos Pancreáticos Avanzados
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10067517
    E.1.2Term Pancreatic neuroendocrine tumour
    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 17.0
    E.1.2Level PT
    E.1.2Classification code 10068909
    E.1.2Term Pancreatic neuroendocrine tumour metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 the efficacy of the combination STZ-5FU chemotherapy followed by Everolimus 10 mg/day upon progression versus the reverse sequence in the treatment of advanced pancreatic neuroendocrine tumours (pNET), in terms of rate of patients with second progression free survival at 84 weeks of treatment, assessed by local investigator using RECIST criteria 1.0.
    Comparar la eficacia de la quimioterapia con la combinación STZ-5FU seguida de 10 mg/día de everolimus tras la progresión frente a la secuencia invertida en el tratamiento de los tumores neuroendocrinos pancreáticos (TNEP) avanzados en cuanto a la tasa de pacientes con supervivencia sin segunda progresión a las 84 semanas de tratamiento, evaluada por el investigador local utilizando los criterios RECIST 1.0.
    E.2.2Secondary objectives of the trial
    - To describe the efficacy of the two sequences of treatment as a continuous variable Hazard Ratio (HR), in advanced pNETs.
    - To determine whether the overall survival of patients could be modified by the upfront administration of each other treatment, upon progression.
    - To compare the clinical activity of STZ-5FU and everolimus 10 mg/day given in 1st or 2nd place, in terms of time to first and second progression, response rate (RR), and early biochemical response (CgA levels), Quality of Life , cost-efficacy of each sequence, and radiologic assessments that correlates better with overall survival.
    - To compare the safety and tolerability of treatment with STZ-5FU and everolimus 10 mg/day, given upfront each other upon progression, in patients with advanced pNET.
    - To compare the cost-efficacy of each treatment given upfront each other upon progression.
    • Describir eficacia de dos secuencias de tratamiento, STZ-5FU y everolimus, como cociente de riesgos instantáneos de variable continua
    • Determinar si supervivencia global se modifica con administración inicial de un tratamiento u otro, tras progresión
    • Comparar actividad clínica de tratamientos con STZ-5FU y everolimus administrados en primer o segundo lugar, en cuanto al tiempo hasta primera y segunda progresión, tasa de respuesta (TR) y la respuesta bioquímica precoz (niveles de CgA a las 4semanas), calidad de vida y relación coste/eficacia de cada secuencia, e investigar los criterios para medir supervivencia sin progresión que mejor correlación guarda con supervivencia global
    • Comparar seguridad y tolerabilidad de tratamientos STZ-5FU y everolimus administrados uno u otro en primer lugar tras la progresión
    • Comparar relación coste/eficacia de tratamientos STZ-5FU y everolimus, administrados uno u otro en primer lugar tras la progresión
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Detection of predictive markers
    Versión 2.0 of date 30th of January 2014
    The objective of this sub-study is the detection of predictive markers of pNET and patients? outcome, on paraffin embedded tumour blocks from patients included in SEQTOR clinical trial.
    Detección de marcadores productivos
    Versión 2.0 de 30 de enero de 2014
    El objetivo de este suestudio es la detección de marcadores productivos de TNEP y los resultados de los pacientes, en bloques tumorales de parafina procedentes de pacientes incluidos en el ensayo clínico SEQTOR.
    E.3Principal inclusion criteria
    1. Adult patients ? 18 years old.
    2. Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic NET.
    3. Documented confirmation of pancreatic NET G1 or G2 as per ENETS classification system:
    G1: <2 mitoses per 2 mm2 and/or Ki-67 index ? 2%
    G2: 2?20 mitoses per 2 mm2 and/or Ki-67 index >2% and ? 20%
    4. Patients from whom a paraffin-embedded primary tumour or metastasis block is available and sent by courier (Section 7.2.10). Patient should give his/her consent for its use in future investigations.
    5. Before study inclusion, patients must show progressive disease documented by radiology within 12 months prior to study inclusion. If patient received anti-tumour therapy during the past 12 months, he/she must have radiological documentation of progressive disease while on or after receiving that anti-tumour therapy. Naive patients can be also included if, under investigator?s judgement, the patient needs active treatment with either chemotherapy or everolimus.
    6. Before starting with the second treatment in sequence, patients must show documented disease progression by RECIST 1.0 (local assessment) while on anti-tumour therapy or in case of toxicity caused by the first treatment period.
    7. ECOG Performance status score 0 - 2.
    8. Life expectancy > 12 months.
    9. Presence of measurable disease as per RECIST criteria 1.0, documented by a Triphasic Computed Tomography (CT) scan or multiphase MRI radiological assessment.
    10. Previous treatment with somatostatin (SS) analogues is allowed. Only those patients with active functioning syndrome at entry can continue with SS analogues during the study.
    11. Adequate bone marrow function, documented by ANC > 1.5 x 109/L, platelets > 100 x 109/L, haemoglobin > 9 g/dL.
    12. Adequate liver function documented by: serum bilirubin ? 2.0 mg/dL, INR ? 2, ALT and AST ? 2.5 x ULN (? 5 x ULN in patients with liver metastasis).
    13. Adequate renal function documented by: serum creatinine < 1.5 x ULN.
    14. Fasting serum cholesterol < 300 mg/dL or < 7.75 mmol/L and fasting triglycerides < 2.5 x ULN. If one or both thresholds are exceeded, the patient may only be included after starting treatment with an adequate lipid-lowering agent.
    15. Women with child-bearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and/or a urine pregnancy test 48 hours before the administration of the first study treatment.
    16. Written Informed Consent obtained according to local regulations.
    1. • Pacientes adultos de ≥ 18 años de edad.
    2. • Diagnóstico comprobado histológicamente de TNE pancreático avanzado, no resecable o metastásico.
    3. • Confirmación documentada de TNE pancreático G1 o G2 según el sistema de clasificación de la ENETS:
    • G1: <2 mitosis por 2 mm2 y/o índice de Ki-67 ≤ 2 %
    • G2: 2–20 mitosis por 2 mm2 y/o índice de Ki-67 > 2 % y ≤ 20 %
    4. • Pacientes de quienes se disponga de un bloque de tumor primario o metástasis incluido en parafina que se envíe por mensajería (Sección 7.2.10). El paciente deberá otorgar su consentimiento para que se utilice en futuras investigaciones.
    5. • Antes de su inclusión en el estudio, los pacientes deben presentar una progresión de la enfermedad comprobada radiológicamente en los 12 meses anteriores a la inclusión en el estudio. Si el paciente ha recibido un tratamiento antitumoral durante los 12 meses anteriores, debe tener documentación radiológica de la progresión de la enfermedad mientras recibía el tratamiento antitumoral o después de recibirlo. También se podrá incluir a pacientes sin tratamiento previo si, en opinión del investigador, necesitan tratamiento activo con quimioterapia o con everolimus.
    6. • Antes de iniciar el segundo tratamiento en secuencia, los pacientes deben presentar una progresión documentada de la enfermedad conforme a RECIST 1.0 (evaluación local) mientras recibían tratamiento antitumoral o en caso de toxicidad causada por el primer período de tratamiento.
    7. • Puntuación del estado funcional en la escala ECOG de 0 - 2.
    8. • Esperanza de vida > 12 meses.
    9. • Presencia de enfermedad medible conforme a los criterios RECIST 1.0, documentada con una exploración por tomografía computarizada (TC) trifásica o con una evaluación radiológica por resonancia magnética (RM) de fase múltiple.
    10. • Se permite el tratamiento previo con análogos de somatostatina (SS). Solo los pacientes con un síndrome funcional activo en el momento de la inclusión podrán continuar recibiendo análogos de SS durante el estudio.
    11. • Función adecuada de la médula ósea, demostrada por: recuento absoluto de neutrófilos (RAN) > 1,5 x 109/l, plaquetas > 100 x 109/l, hemoglobina > 9 g/dl.
    12. • Función hepática adecuada, demostrada por: bilirrubina sérica ≤ 2,0 mg/dl, razón normalizada internacional (RNI) ≤ 2, ALT y AST ≤ 2,5 x límite superior de la normalidad (LSN) (≤ 5 x LSN en pacientes con metástasis hepáticas).
    13. • Función renal adecuada, demostrada por: creatinina sérica < 1,5 x LSN.
    14. • Colesterol sérico en ayunas < 300 mg/dl o < 7,75 mmol/l y triglicéridos en ayunas < 2,5 x LSN. Si se sobrepasa uno de los umbrales o ambos, solo se podrá incluir al paciente después de que inicie un tratamiento con un fármaco hipolipemiante adecuado.
    15. • Las mujeres potencialmente fértiles deberán tener una prueba de embarazo con resultado negativo en los 14 días anteriores a la inscripción y/o o someterse a una prueba de embarazo en orina 48 horas antes de la administración del primer tratamiento del estudio.
    16. • Consentimiento informado por escrito obtenido conforme a la normativa local.
    E.4Principal exclusion criteria
    1. Patients with poorly differentiated pancreatic neuroendocrine tumor; this is, pNET G3 as per ENETS classification system:
    G3: 21 or more mitoses per 2 mm2 and/or Ki-67 index >20%
    2. Previous treatment with chemotherapy and/or mTOR inhibitors (sirolimus, temsirolimus, everolimus, deforolimus) or tirosyne kinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
    3. Immune therapy or radiation therapy within 4 weeks prior to the patient entering the study.
    4. Hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/radiofrequency ablation of hepatic metastasis within 2 months of enrolment.
    5. Previous treatment with Peptide-Receptor Radionuclide Therapy (PRRT) within the last 6 months and/or without progression following PRRT.
    6. Uncontrolled diabetes mellitus defined as: fasting serum glucose > 1.5 x ULN.
    7. Patients with any severe and/or uncontrolled medical conditions such as:
    a. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ? 6 months prior to randomization, serious uncontrolled cardiac arrhythmia,
    b. active or uncontrolled severe infection,
    c. severe hepatic impairment (Child Pugh C) is not allowed; moderate hepatic impairment (Child Pugh B and A) requires a reduced dose of everolimus (5mg and 7.5 mg daily respectively). Positive HBV-DNA and or HBsAg patients at screening should receive prophylaxis treatment.
    d. severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air),
    e. active, bleeding diathesis
    8. Treatment with potent inhibitors or inducers of CYP3A isoenzyme (rifabutin, rifampicin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, telithromycin) within 5 days immediately before the start of treatment (a list of clinically significant drug interactions is shown in section 6. Concomitant Medication).
    9. Patients on chronic treatment with corticosteroids or any other immunosuppressive agent.
    10. Patients known to be HIV seropositive.
    11. Known intolerance or hypersensitivity to everolimus or its excipients or other rapamycin analogues. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
    12. Known intolerance or hypersensitivity to 5FU or STZ or its excipients.
    13. Participation in any other clinical trial or concomitant treatment with any other investigational drug.
    14. No other prior or concurrent malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for ? 3 years.
    15. Pregnant, lactating women or fertile adults not using effective birth control methods. If barrier contraceptives are used, these must be continued to be used throughout the trial by both sexes and for up to 8 weeks after the end of treatment.
    16. For administrative matters (insurance) patients ? 95 are not allowed.
    1. • Pacientes con tumor neuroendocrino pancreático poco diferenciado; esto es, TNEP G3 según el sistema de clasificación de la ENETS:
    • G3: 21 o más mitosis por 2 mm2 y/o índice de Ki-67 > 20 %
    2. • Tratamiento anterior con quimioterapia y/o inhibidores de mTOR (sirolimus, temsirolimus, everolimus, deforolimus) o inhibidores de la tirosina quinasa (sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
    3. • Inmunoterapia o radioterapia en las 4 semanas anteriores a la entrada del paciente en el estudio.
    4. • Embolización de la arteria hepática en los últimos 6 meses (1 mes si existen otras áreas de enfermedad medible) o crioablación/ablación por radiofrecuencia de metástasis hepáticas en los 2 meses antes de la inscripción.
    5. • Tratamiento anterior con terapia radionucleídica de receptores peptídicos (Peptide-Receptor Radionuclide Therapy, PRRT) en los últimos 6 meses y/o sin progresión después de la PRRT.
    6. • Diabetes mellitus incontrolada, definida como: glucosa sérica en ayunas > 1,5 x LSN.
    7. • Pacientes con cualquier patología médica grave y/o incontrolada, como:
    a. • angina de pecho inestable, insuficiencia cardíaca congestiva sintomática, infarto de miocardio ocurrido ≤ 6 meses antes de la aleatorización, arritmia cardíaca grave e incontrolada,
    b. • infección grave activa o incontrolada,
    c. • no se permite la insuficiencia hepática grave (Child Pugh C); la insuficiencia hepática moderada (Child Pugh B y A) requiere una dosis reducida de everolimus (5 mg y 7,5 mg al día, respectivamente). Los pacientes positivos para HBV-DNA y/o HBsAg en el momento de la selección deberán recibir tratamiento profiláctico.
    d. • reducción importante de la función pulmonar (espirometría y capacidad de difusión del pulmón para el monóxido de carbono (Diffusing Capacity of the Lung for Carbon Monoxide, DLCO) de 50 % o menos de lo normal, y saturación de O2 del 88 % o menos en reposo en la cámara de aire),
    e. • diátesis sangrante activa
    8. • Tratamiento con inhibidores o inductores potentes de la isoenzima CYP3A (rifabutina, rifampicina, claritromicina, ketoconazol, itraconazol, voriconazol, ritonavir, telitromicina) en los 5 días inmediatamente anteriores al inicio del tratamiento (se puede ver una lista de interacciones farmacológicas clínicamente significativas en la Sección 6. Medicación concomitante).
    9. • Pacientes en tratamiento crónico con corticosteroides u otros fármacos inmunosupresores.
    10. • Pacientes de quienes se sabe que son seropositivos para VIH.
    11. • Intolerancia o hipersensibilidad conocidas a everolimus o sus excipientes o a otros análogos de rapamicina. Los pacientes con problemas poco frecuentes de intolerancia hereditaria a galactosa, insuficiencia de lactasa de Lapp o problemas de absorción de glucosa o galactosa no deben recibir este medicamento.
    12. • Intolerancia o hipersensibilidad conocidas a 5FU o a STZ o a sus excipientes.
    13. • La participación en cualquier otro ensayo clínico o el tratamiento concomitante con cualquier otro fármaco en fase de investigación.
    14. • No se permite ninguna otra neoplasia maligna anterior ni concurrente, con las siguientes excepciones: cáncer de piel de células escamosas o basocelular tratado adecuadamente, cualquier otro cáncer in situ tratado adecuadamente o cualquier otro cáncer sufrido por el paciente y del que haya estado libre durante ≥ 3 años.
    15. • Mujeres embarazadas o lactantes o adultos fértiles que no utilicen métodos anticonceptivos efectivos. Si se emplean métodos anticonceptivos de barrera, los dos sexos deberán continuar utilizándolos durante todo el ensayo y hasta 8 semanas después de finalizar el tratamiento.
    16. • Por razones administrativas (seguros) no se permiten pacientes de ≥ 95 años.
    E.5 End points
    E.5.1Primary end point(s)
    Rate of second progression free survival is defined as: PFS of Course 1 + interval between treatments + PFS of Course 2, where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2.
    Tasa de supervivencia sin segunda progresión, definida como: SSP del curso 1 + intervalo entre tratamientos + SSP del curso 2, donde SSP1 representa la supervivencia sin progresión del curso 1 y SSP2 la supervivencia sin progresión del curso 2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At LVLS.
    UVUP (última visita último paciente)
    E.5.2Secondary end point(s)
    1. HR of second progression free survival (PFS of Course 1 + interval between treatments + PFS of course 2).
    2. Time to first progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    3. Time to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    4. Time from first progression to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    5. Response rate of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    6. Quality of life score.
    7. CgA levels.
    8. Correlation between the four criteria for second progression free survival (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) and Kendall tau variables.
    9. Overall survival (OS) of patients on treatment with the combination STZ-5FU chemotherapy followed by Everolimus 10 mg/day upon progression or the reverse sequence, in the treatment of advanced pancreatic neuroendocrine tumours (pNET).
    10. Number of adverse events, dose reductions, and total dose administered on patients treated with STZ-5FU followed by everolimus 10 mg/day or the reverse sequence, in advanced pNETs.
    11. Ratio of Incremental cost-efficacy (ICER) of the differential of costs incurred on by each treatment arm (A and B): ICER= (Arm A costs ? Arm B costs)/(Arm A 2nd PFS ? Arm B 2nd PFS).
    1. Cociente de riesgos instantáneos (hazard rate HR) de supervivencia hasta segunda progresión (SSP del curso 1 + intervalo entre tratamiento + SSP curso 2)
    2. Tiempo hasta primera progresión de STZ-5FU y everolimus 10mg/día o la secuencia inversa en TNEP avanzados.
    3. Tiempo hasta segunda progresión de STZ-5FU y everolimus 10mg/día o la secuencia inversa en TNEP avanzados.
    4. Tiempo desde primera progresión hasta segunda progresión de STZ-5FU y everolimus 10mg/día o la secuencia inversa en TNEP avanzados.
    5. Ratio de respuesta de STZ-5FU y everolimus 10mg/día o la secuencia inversa en TNEP avanzados.
    6. Resultado de Calidad de Vida
    7. Niveles CgA
    8. Correlación entre los cuatro criterios de supervivencia hasta segunda progresión (RECIST 1.0, RECIST 1.1, compuesto RECIST 1.0 y RECIST 1.1 compuesto) y variables Kendall tau.
    9. Supervivencia global (SG) de pacientes en tratamiento con la combinación de STZ-5FU seguido de Everolimus 10 mg/día hasta progresión o la secuencia inversa, en el tratamiento de tumores neuroendocrinos pancreáticos (TNEP) avanzados.
    10. Número de acontecimientos adversos, reuniones de dosis, y dosis total administrada en pacientes tratados con STZ-5FU seguido de everolimus 10 mg/día o la secuencia inversa, en TNEP avanzados.
    11.Ratio de coste-eficacia incremental (RCEI) del diferencial de costes incurrimos por cada brazo de tratamiento (A y B): RCEI = (Brazo A costes ? Brazo B costes)/(Brazo A SSP2 ? Brazo B SSP2).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. At LVLS.
    2. At First visit of second treatment.
    3. At LVLS.
    4. At LVLS.
    5. Every 12 weeks.
    6. aAt baseline, upon progression and 30 days after the last dose of study treatment.
    7. At baseline and at 4 weeks of treatment start.
    8. At every tumor assessment (every 12 weeks)
    9. At LVLS.
    10. At every cycle.
    11. At LVLS.
    1. UVUP (última visita último paciente)
    2. Primera visita del segundo tratamiento
    3. UVUP (última visita último paciente)
    4. UVUP (última visita último paciente)
    5. Cada 12 semanas
    6. Basal, hasta progresión y 30 días después de la última dosis del tratamiento del estudio
    7. Basal y a las 4 semanas de comenzar el tratamiento
    8. En cada valoración tumoral (cada 12 semanas)
    9. UVUP (última visita último paciente)
    10. En cada ciclo
    11. UVUP (última visita último paciente)
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other 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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 180
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation European Neuroendocrine Tumours Society (ENETS)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-07-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-10
    P. End of Trial
    P.End of Trial StatusOngoing
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