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    Summary
    EudraCT Number:2011-005049-11
    Sponsor's Protocol Code Number:AAA-III-01
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-01-31
    Trial results View 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 number2011-005049-11
    A.3Full title of the trial
    A multi-centre, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive, midgut carcinoid tumours.
    Estudio en fase III abierto, aleatorizado, multicéntrido, estratificado, de comparador activo y de grupos paralelos para comparar el tratamiento con 177Lu-DOTA0-Tyr3-acetato de octreotida frente a octreotida de acción prolongada en pacientes con tumores carcinoides del intestino medio irresecables, progresivos, positivos para receptores de somatostatina.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter, stratified, open, randomized, comparator-controlled, parallelgroup phase III study. In this study, treatment with 177Lu-DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide LAR) will be compared to treatment with high dose (60 mg) Octreotide LAR in patients with inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumours.
    A.4.1Sponsor's protocol code numberAAA-III-01
    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 SponsorAdvanced Accelerator Applications
    B.1.3.4CountryFrance
    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 supportAdvanced Accelerator Applications
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPierrel Research Italy SPA
    B.5.2Functional name of contact pointPiergiorgio Galletti
    B.5.3 Address:
    B.5.3.1Street AddressVia Alberto Falck, 15
    B.5.3.2Town/ citySesto San Giovanni (MI)
    B.5.3.3Post code20099
    B.5.3.4CountryItaly
    B.5.4Telephone number+390224134 208
    B.5.5Fax number+390224862 961
    B.5.6E-mailp.galletti@pierrelgroup.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/07/523
    D.3 Description of the IMP
    D.3.1Product nameLutathera
    D.3.4Pharmaceutical form 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 INN[177Lu]-DOTA0-Tyr3-Octreotate
    D.3.10 Strength
    D.3.10.1Concentration unit MBq/ml megabecquerel(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number370
    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 Yes
    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 Sandostatin LAR
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameSandostatin LAR
    D.3.4Pharmaceutical form Powder and solvent for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 79517-01-4
    D.3.9.3Other descriptive nameOCTREOTIDE ACETATE
    D.3.9.4EV Substance CodeSUB03490MIG
    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: 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 Sandostatin LAR
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameSandostatin LAR
    D.3.4Pharmaceutical form Powder and solvent for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 79517-01-4
    D.3.9.3Other descriptive nameOCTREOTIDE ACETATE
    D.3.9.4EV Substance CodeSUB03490MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    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 Sandostatin LAR
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameSandostatin LAR
    D.3.4Pharmaceutical form Powder and solvent for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 79517-01-4
    D.3.9.3Other descriptive nameOCTREOTIDE ACETATE
    D.3.9.4EV Substance CodeSUB03490MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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
    Patients with inoperable, progressive, OctreoScan® positive, well-differentiated neuroendocrine tumours of the small bowel (midgut carcinoid tumours), who are treated with 20 mg or 30 mg Octreotide LAR at a fixed dose for at least 12 weeks prior to enrolment in the study.
    Pacientes con tumores neuroendocrinos del intestino delgado (tumores carcinoides del intestino medio) bien diferenciados progresivos positivos en OctreoScan®, irresecables, tratados con 20 mg ó 30 mg de octreotida de acción prolongada cada 3-4 semanas a una dosis fija durante un mínimo de 12 semanas con anterioridad a su inclusión en el estudio.
    E.1.1.1Medical condition in easily understood language
    Patients with tumours arisen from the small bowel and which cannot be removed completely by surgery.
    Pacientes con tumores surgidos en el intestino medio y que no pueden ser extirpados totalmente mediante cirugía
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10062392
    E.1.2Term Carcinoid tumor of the small bowel
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10052399
    E.1.2Term Neuroendocrine tumour
    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
    To compare Progression Free Survival (PFS) after treatment with 177Lu-DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in patients with inoperable, progressive (as determined by RECIST Criteria), somatostatin receptor positive, well-differentiated neuroendocrine tumours of the small bowel (midgut carcinoid tumours).
    Comparar la supervivencia libre de enfermedad (SLE) tras el tratamiento con 177Lu-DOTA0-Tyr3-acetato de octreotida y el mejor tratamiento complementario (30 mg de octreotida LAR) con el tratamiento a dosis altas (60 mg) de octreotida LAR en pacientes con tumores neuroendocrinos del intestino delgado (tumores carcinoides del intestino medio) y bien diferenciados, irresecables, progresivos (según los criterios RECIST Versión 1.1, Eisenhauer EA y cols., 2009; Apéndice 2), positivos para receptores de somatostatina.
    E.2.2Secondary objectives of the trial
    1.To compare the Overall Response Rate (ORR) between the two study arms;
    2.To compare the Overall Survival (OS) between the two study arms;
    3.To compare the Time to Tumour Progression (TTP) between the two study arms;
    4.To evaluate the safety and tolerability of 177Lu-DOTA0-Tyr3-Octreotate;
    5.To evaluate the health related quality of life (QoL) as measured by the EORTC QLQ-G.I.NET21 questionnaire;
    6.To explore the correlation of toxicity outcomes and administered radiation doses corrected for body weight and body surface area;
    7.To explore the correlation of clinical efficacy outcomes with the levels of the biomarkers Chromogranin-A (CgA) in the serum and 5-Hydroxyindoleacetic acid (5-HIAA) in the urine;
    8. To evaluate dosimetry, pharmacokinetics (PK) and ECG in a subset of 20
    patients;
    9.To explore the correlation of clinical efficacy outcomes with OctreoScan® tumour uptake score;
    10.To explore the correlation of clinical outcomes with serum levels of Alkaline Phosphatase (AP).
    1.Comparar tasa de respuesta objetiva entre grupos; 2.Comparar supervivencia global entre grupos; 3.Comparar el tiempo hasta la progresión tumoral entre grupos; 4.Evaluar seguridad y tolerabilidad de 177Lu-DOTA0-Tyr3-acetato de octreotida (según los criterios RECIST Versión 1.1); 5.Evaluar calidad de vida relacionada con la salud según cuestionario EORTC QLQ-G.I.NET21; 6.Estudiar correlación existente entre resultados de toxicidad y dosis de radiación administradas corregidas respecto al peso corporal y el área de superficie corporal; 7.Estudiar correlación existente entre eficacia clínica y concentraciones de biomarcadores cromogranina-A en suero y ácido 5-hidroxindolacético en orina; 8.Evaluar dosimetría, farmacocinética y ECG en un subgrupo de 20 pacientes; 9.Estudiar correlación existente entre resultados de eficacia clínica con puntuación de captación tumoral de OctreoScan®; 10.Estudiar correlación existente entre desenlaces clínicos y concentraciones séricas de FA
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    This study is the first controlled comparative study with a radiolabelled versus non-radioactive somatostatin analogue. In this study safety and efficacy of treatment with 177Lu-DOTA0-Tyr3-
    Octreotate versus Octreotide LAR will be investigated in patients with inoperable, progressive, somatostatin receptor positive midgut carcinoid tumours.

    Primary Objective:
    Calculate whole body and organ radiation dosimetry of 177Lu-DOTA0-Tyr3-Octreotate to determine the dose to critical organs (e.g., kidney and bone marrow) and correlate with findings of the Erasmus MC Phase I/II Clinical study.

    Secondary Objectives:
    - Define the pharmacokinetic profile (ADME) of 177Lu-DOTA0-
    Tyr3-Octreotate;
    - Correlate safety, dosimetry, and pharmacokinetic data obtain in
    this study with the Erasmus MC phase I/II Clinical study to
    confirm previous findings;
    - Evaluate cardiac safety: determine the acute
    electrophysiological changes during treatment with 177Lu-
    DOTA0-Tyr3-Octreotate (through 24-hour continuous ECG
    recording via 12-lead Holter machine).
    Este estudio es el primer estudio controlado de comparación de un análogo de somatostatina radiomarcado y un análogo no radioactivo. En este trabajo, se determinarán la seguridad y la eficacia del tratamiento con 177Lu-DOTA0-Tyr3-acetato de octreotida en comparación con octreotida LAR en sujetos con tumores carcinoides del intestino medio positivos para receptores de somatostatina, progresivos e irresecables.

    Objetivo primario:
    Calcular la dosimetría de la radiación corporal total y orgánica de 177Lu-DOTA0-Tyr3-acetato de octreotida para definir la dosis recibida por órganos críticos (p. ej., riñón y médula ósea) y relacionarla con los hallazgos del estudio clínico Erasmus MC de fase I/II.

    Objetivos secundarios:
    - Definir el perfil farmacocinético (ADME) de 177Lu-DOTA0-Tyr3-acetato de octreotida ;
    - Establecer correlaciones entre los datos de seguridad, dosimetría y farmacocinética obtenidos en este estudio con el estudio clínico Erasmus MC de fase I/II con el fin de confirmar los hallazgos previos;
    - Evaluar la seguridad cardíaca: determinar las variaciones electrofisiológicas agudas a lo largo del tratamiento con 177Lu-DOTA0-Tyr3-acetato de octreotida (mediante el registro electrocardiográfico continuo de 24 horas con un dispositivo Holter de 12 derivaciones).


    E.3Principal inclusion criteria
    1. Presence of inoperable (curative intent) at enrolment time, histologically proven, midgut carcinoid tumour.

    2. Ki67 index ≤ 20%.

    3. Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to enrolment in the study.

    4. Patients ≥18 years of age.

    5. Patients must have progressive disease based on RECIST Criteria, Version 1.1 (Appendix 2) evidenced with CT scans/MRI obtained within 3 years from enrolment; previous images must be centrally evaluated to confirm the disease progression under previous therapy: for the purpose of determining disease progression the oldest CT/MRI scan must not be older than 3 years and the most recent scan must not be older than 4 weeks from the projected randomization date. The CT scan/MRI scan should be one that was performed while the patient was on a fixed dose of Sandostatin LAR.

    6. Confirmed presence of somatostatin receptors on all technically evaluable tumour lesions documented by CT/MRI scans, based on positive OctreoScan® imaging within 24 weeks prior to enrolment in the study.

    7. The tumour uptake observed using OctreoScan® should be ? normal liver uptake observed on planar imaging (Appendices 5 and 6).

    8. Karnofsky Performance Score (KPS) ≥60

    9. Presence of at least 1 measurable site of disease.
    1. Presencia de tumor carcinoide del intestino medio confirmado histológicamente e irresecable (intención curativa) en el momento de la inclusión..
    2. Índice Ki67 ≤ 20%.
    3. Pacientes tratados con octreotida de acción prolongada a una dosis fija de 20 mg ó 30 mg a intervalos de 3-4 durante, al menos, 12 semanas antes de la inclusión en el estudio.
    4. Pacientes ≥18 años de edad.
    5. Pacientes con enfermedad progresiva según los criterios RECIST, versión 1.1 (Apéndice 2) demostrada en las TC/RM realizadas a lo largo de los 3 años siguientes a la inclusión en el estudio; las imágenes obtenidas previamente se someterán a una evaluación central con el objeto de confirmar la progresión de la enfermedad durante el tratamiento previo: para determinar el estado de la enfermedad, la prueba de TC/RM más antigua no superará los 3 años y la más reciente no se habrá realizado más de 4 semanas antes de la fecha prevista de aleatorización. La TC/RM se habrá efectuado mientras el paciente recibía una dosis fija de Sandostatin LAR.
    6. Presencia confirmada de receptores de somatostatina en todas las lesiones tumorales susceptibles de valoración técnica y documentadas mediante TC/RM, basada en resultados positivos en las pruebas de la imagen OctreoScan® a lo largo de las 24 semanas previas a la inclusión en el estudio.
    7. La captación tumoral medida mediante OctreoScan® será ≥ captación hepática normal observada en las imágenes planares (Apéndices 5 y 6).
    8. Puntuación de rendimiento según la escala de Karnofsky (KPS) ≥60
    9. Presencia de, al menos, un foco cuantificable de enfermedad.
    E.4Principal exclusion criteria
    1. Serum creatinine >150 µmol/L or 1.7 mg/dL, or a measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) of <50 mL/min.

    2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x10^9/L (2000/mm3); platelets <75x10^9/L (75x10^3/mm3).

    3. Total bilirubin >3 x ULN.

    4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.

    5. Pregnancy (see protocol Appendix 7).

    6. For female patients of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male patients, who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) as defined in Appendix 7.

    7. Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to enrolment in the study.

    8. Peptide receptor radionuclide therapy (PRRT) at any time prior to enrolment in the study.

    9. Targeted surgery, radiotherapy (external beam), chemotherapy, embolization, interferons, mTOR-inhibitors or other investigational therapy within 12 weeks prior to enrolment in the study.

    10. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrolment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to enrolment in the study.

    11. Uncontrolled congestive heart failure (NYHA II, III, IV).

    12. Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.

    13. Any patient who has both OctreoScan® positive and negative tumours.

    14. Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTA0-Tyr3-Octreotate, unless the tumour uptake observed by OctreoScan® imaging during continued Octreotide treatment is at least as high as normal liver uptake observed by planar imaging (Appendices 5 and 6).

    15. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study.

    16. Prior external beam radiation therapy to more than 25% of the bone marrow.

    17. Urinary incontinence.

    18. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.

    19. Patients who have not provided a signed an informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
    1. Creatinina sérica >150 µmol/l ó 1,7 mg/dl, o bien aclaramiento de creatinina cuantificado (o Tasa de filtración glomerular cuantificada (TFG) mediante métodos de aclaramiento plasmático, pero no basados en cámara gamma) de <50 ml/min.
    2. Concentración de Hb <5,0 mmol/l (<8,0 g/dl); FL <2x109/l (2.000/mm3); plaquetas <75x109/l (75x103/mm3).
    3. Bilirrubina total >3 x LSN.
    4. Albúmina sérica <3,0 g/dl excepto cuando el tiempo de protrombina se encuentre dentro del intervalo normal.
    5. Embarazo (véase Apéndice 7 del Protocolo).
    6. En mujeres en edad fértil (definidas como < 2 años tras la última menstruación y no sometidas a esterilización quirúrgica) y hombres que no se hayan sometido a esterilización quirúrgica y cuyas parejas femeninas se encuentren en edad fértil: ausencia de anticonceptivos no hormonales eficaces (dispositivo intrauterino, método anticonceptivo de barrera acompañado de gel espermicida) como se detalla en el Apéndice 7.
    7. Tratamiento con >30 mg octreotida de acción prolongada a intervalos de 3-4 semanas a lo largo de las 12 semanas anteriores a la inclusión en el estudio.
    8. Tratamiento con radionúclidos del receptor del péptido (PRRT) en cualquier momento previo a la inclusión en el estudio.
    9. Cirugía dirigida, radioterapia (haz externo), quimioterapia, embolización, interferones, inhibidores de mTOR u otros tratamientos en fase de investigación a lo largo de las 12 semanas anteriores a la inclusión en el estudio.
    10. Metástasis cerebrales detectadas, a no ser que se hayan tratado y estabilizado durante un mínimo de 24 semanas con anterioridad a la inclusión en el estudio. Los pacientes con antecedentes de metástasis cerebrales deberán someterse a una TC con contraste, de la cabeza, con el fin de documentar la estabilidad de la enfermedad con anterioridad a su inclusión en el estudio.
    11. Insuficiencia cardíaca congestiva no controlada (NYHA II, III, IV).
    12. Diabetes mellitus no controlada definida como una glucemia en ayunas >2 LSN.
    13. Pacientes portadores de tumores tanto positivos como negativos en la prueba OctreoScan®.
    14. Pacientes en tratamiento con octreotida de acción corta que no pueda interrumpirse durante las 24 h anteriores y siguientes a la administración de 177Lu-DOTA0-Tyr3-acetato de octreotida, o cualquier paciente en tratamiento con octreotida LAR que no pueda suspenderse durante, al menos, 6 semanas antes de la administración de 177Lu-DOTA0-Tyr3-acetato de octreotida, a no ser que la captación tumoral observado en las imágenes de OctreoScan® durante el tratamiento continuado con octreotida sea, al menos, equivalente a la captación hepática normal observada en las imágenes planares (Apéndices 5 y 6).
    15. Pacientes afectados por cualquier otro trastorno médico, psiquiátrico o quirúrgico significativo no controlado mediante tratamiento que pudiera repercutir en la finalización del estudio.
    16. Radioterapia de haz externo previa en más del 25% de la médula ósea.
    17. Incontinencia urinaria.
    18. Otras neoplasias malignas coexistentes conocidas, salvo cáncer de piel de tipo no melanoma y carcinoma cervicouterino in situ, a no ser que se haya completado un tratamiento definitivo y existan indicios demostrativos de la ausencia de recurrencia durante 5 años.
    19. Pacientes que no hayan firmado un documento de consentimiento informado para participar en el estudio, obtenido con anterioridad al inicio de cualquier actividad relacionada con el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable of this study is PFS.
    La variable principal de eficacia es la SLE
    E.5.1.1Timepoint(s) of evaluation of this end point
    The median point estimate and 95% Confidence Interval (CI) for the PFS will be provided using the Kaplan-Meier method, and the log-rank test will be used to compare the PFS between the two treatment groups.
    Se determinarán la mediana de la estimación puntual y el intervalo de confianza al 95% (IC) de la SLE mediante el método de Kaplan-Meier y se aplicará la prueba de rangos logarítmicos para comparar la SLE entre ambos grupos de tratamiento.
    E.5.2Secondary end point(s)
    The secondary efficacy variables are: Objective Response Rate (ORR), Time to Tumour Progression (TTP) and OS.
    Las variables secundarias de eficacia son: tasa de respuesta objetiva (TRO), tiempo hasta la progresión tumoral (TPT) y SG.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response rates and 95% CIs will be calculated for the ORR by treatment group. Frequencies in the two treatment groups will be compared by Fisher?s exact test.
    Se calcularán las tasas de respuesta y los IC al 95% para la TRO en cada grupo de tratamiento. Se compararán las frecuencias en ambos grupos de tratamiento por medio de la prueba exacta de Fisher.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Dosimetry
    Dosimetría
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Belgium
    France
    Germany
    Italy
    Portugal
    Spain
    Switzerland
    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 is defined as the moment that the last enrolled patient has completed 72 weeks of assessments (unless early termination) after the patient?s first treatment in either arm of the study.
    El Final del Estudio se define como el momento en el que el último paciente reclutado haya completado 72 semanas de evaluaciones (salvo que se produzca una finalización anticipada) después de la primera dosis administrada en cualquiera de los grupos de estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    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: 200
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 200
    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)
    Long-term toxicity to critical organs (bone marrow and kidney) suspected in relationship to the study drug (including haematology, biochemistry, urine analyses) will be monitored every 6 months for 3 years after the End of Study.
    PFS (based on local assessments) and OS data will be recorded every 6 months for 3 years after the End of Study.
    Phone contacts or visits at site can be performed during the 3 years follow-up after end of the study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-04-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-01-18
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