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    Summary
    EudraCT Number:2011-005049-11
    Sponsor's Protocol Code Number:AAA-III-01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-03-05
    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 ConcernedItaly - Italian Medicines Agency
    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.
    Studio multicentrico di fase III, stratificato, randomizzato, in aperto, a gruppi paralleli, verso trattamento di controllo, per confrontare il trattamento con 177Lu-DOTA0-Tyr3-Octreotate verso Octreotide LAR in pazienti con tumore carcinoide dell'™intestino medio, inoperabile, progressivo e con positivita' per i recettori della somatostatina.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multi-centre, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with a new radiopharmaceutical drug to Octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive, midgut carcinoid tumours.
    Studio che coinvolge piu' centri, stratificato, in aperto, a gruppi paralleli, di fase III, per comparare il trattamento con un nuovo radiofarmaco rispetto al trattamento con Octreotide-LAR in pazienti con tumore all'intestino medio che esprimoro positivita' per la presenza di recettori della somatostatina.
    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 supportAsdvanced 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+39 0224134208
    B.5.5Fax number+39 0224862961
    B.5.6E-mailp.galletti@pierrel-research.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.3.2Product code NA
    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.3.9.1CAS number NA
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeNA
    D.3.10 Strength
    D.3.10.1Concentration unit MBq/ml megabecquerel(s)/millilitre
    D.3.10.2Concentration typeup to
    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 SANDOSTATINA LAR*FL 30MG+SIR+2
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS FARMA SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 and solvent for solution for infusion
    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.3.8INN - Proposed INNNA
    D.3.9.1CAS number 79517-01-04
    D.3.9.2Current sponsor codeNA
    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 typeup to
    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 SANDOSTATINA LAR*FL 20MG+SIR+2
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS FARMA SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 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.3.8INN - Proposed INNNA
    D.3.9.1CAS number 79517-01-4
    D.3.9.2Current sponsor codeNA
    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 typeup to
    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 SANDOSTATINA LAR*FL 10MG+SIR+2
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS FARMA SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 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.3.8INN - Proposed INNNA
    D.3.9.1CAS number 79517-01-04
    D.3.9.2Current sponsor codeNA
    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 typeup to
    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.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 every 3-4 weeks at a fixed dose for at least 12 weeks prior to enrolment in the study.
    Soggetti affetti da tumori neuroendocrini ben differenziati dell’intestino tenue (tumori carcinoidi dell’intestino medio) positivi all’OctreoScan, progressivi e non operabili, in trattamento con 20 mg o 30 mg di Octreotide LAR ogni 3-4 settimane a dose fissa per almeno 12 settimane prima del reclutamento nello studio.
    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
    Pazienti con tumore carcinoide dell'intestino medio, inoperabile, progressivo, con positività per i recettori della somatostatina.
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. 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).
    Confronto della Sopravvivenza Libera da Progressione (PFS) in seguito a trattamento con 177Lu-DOTA0-Tyr3-Octreotate e miglior terapia di supporto(30 mg Octreotide LAR) verso trattamento con dose elevata (60 mg) di Octreotide LAR in soggetti affetti da tumori neuroendocrini ben differenziati dell’intestino tenue (tumori carcinoidi dell’intestino medio) positivi ai recettori per la somatostatina, progressivi e non operabili (secondo i criteri RECIST).
    E.2.2Secondary objectives of the trial
    1. To compare the Objective 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
    1. Confronto della Percentuale di Risposta Obiettiva tra i due bracci dello studio; 2. Confronto della Sopravvivenza Globale tra i due bracci dello studio; 3. Confronto del Tempo alla Progressione (TTP) tra i due bracci dello studio; 4. Valutazione di sicurezza e tollerabilità del 177Lu-DOTA0-Tyr3-Octreotate; 5. Valutazione della Qualità di Vita legata alla salute, con questionario EORTC QLQ-G.I.NET21; 6. Studio della correlazione tra tossicità e dosi radianti somministrate, corrette in funzione del peso corporeo e dell’area di superficie corporea (BSA); 7. Studio della correlazione dell’efficacia clinica vs livelli sierici di Cromogranina-A (CgA), e dei livelli urinari dell’acido 5-idrossindolacetico (5-HIAA); 8. Valutazione dosimetrica, farmacocinetica ed ECG in un sottogruppo di 20 pazienti; 9 Outcome di efficacia tramite octreoscan tumor uptake score; 10_outcome clinici vs AP
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PHARMACOKINETIC/PHARMACODYNAMIC:
    Vers:1.0
    Date:2011/11/14
    Title:Pharmacokinetics
    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).
    E.3 PRINCIPAL INCLUSION CRITERIA (list the most important)
    English 1. Presence of inoperable (curative intent) at

    OTHER SUBSTUDIES:
    Dosimetry_1.0_dated 14 Nov 2011

    FARMACOCINETICA/FARMACODINAMICA:
    Vers:1.0
    Data:2011/11/14
    Titolo:Farmacocinetica
    Obiettivi:Questo è il 1 studio comparativo controllato con un radiofarmaco VS analogo non-radiattivo della somatostatina. In questo studio saranno esaminati sicurezza ed efficacia del trattamento con 177Lu-DOTA0-Tyr3-Octreotate vs Octreotide LAR in pazienti con tumore carcinoide dell'intestino medio inoperabile, progressivo e con positività per i recettori della somatostatina.
    Obiettivo Primario:
    -Calcolare la dosimetria di radiazioni per l'intero corpo e organo di 177Lu-DOTA0-Tyr3-
    Octreotate per determinare la dose per gli organi critici (reni e midollo osseo)e correlarli ai risultati ottenuti dagli studi clinici di Fase I/II Erasmus MC
    Obiettivi secondari:
    -Definire il profilo di farmacocinetica (ADME) di 177Lu-DOTA0-Tyr3-
    Octreotate
    -Correlare i dati di sicurezz; dosimetria e farmacocinetica ottenuti in questo studio con quelli dello studio clinico Erasmus Fase I/II per confermare le valutaziopne precedenti;
    -Valutare la sicurezza cardiaca: determinare le modifiche elettrofisiologiche acute durante il trattamento con 177Lu-DOTA0-Tyr3-
    Octreotate (tramite ECG continuo per 24 H registrato con l'apparecchio Holter a 12 elettrodi).

    ALTRI SOTTOSTUDI:
    Dosimetria_1.0_datato 14 Nov 2011

    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 within 3 years from enrolment; previous images must be centrally evaluated to confirm the disease progression under previous therapy: 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 must 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. Presenza di tumore carcinoide dell’intestino medio, istologicamente diagnosticato, non operabile (con intento terapeutico) al momento del reclutamento. 2. Indice Ki67 &lt;/= 20%. 3. Soggetti in trattamento con Octreotide LAR a dose fissa di 20 mg o 30 mg, con intervalli di 3-4 settimane, per almeno 12 settimane prima del reclutamento nello studio. 4. Soggetti di età ≥18 anni. 5. I soggetti dovranno mostrare progressione del tumore secondo i Criteri RECIST, Version 1.1 evidenziata da una TAC/RMN entro 3 anni dal reclutamento; la precedente diagnostica per immagini dovrà essere attentamente valutata al fine di confermare la progressione del tumore nel corso della precedente terapia; la TAC/RMN più remota non dovrà risalire a più di 3 anni e l’indagine più recente a non più di 4 settimane dalla data prevista per la randomizzazione. L’indagine TAC/RMN presentata dovrà essere stata effettuata mentre il soggetto era in trattamento con una dose fissa di Sandostatina LAR. 6. Conferma della presenza di recettori per la somatostatina in tutte le lesioni tecnicamente valutabili del tumore documentate dalle indagini TAC/RMN, in base alla positività del OctreoScan alla diagnostica per immagini, nelle 24 settimane precedenti al reclutamento nello studio. 7. La captazione tumorale osservata con l’utilizzo di OctreoScan dovrà essere maggiore alla normale captazione epatica tramite imaging in modalità planare. 8. Punteggio scala Karnofsky (KPS) &gt;60 9. Presenza di almeno 1 sede misurabile della malattia.
    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 sierica &gt;150 µmol/L o 1,7 mg/dl., o clearance della creatinina misurata (o velocità di filtrazione glomerulare (GFR) misurata con tecniche della clearance plasmatica, non tramite misurazione con gamma-camera) di valore &lt;50 ml/min. 2. Concentrazione di Hb &lt;5,0 mmol/l (&lt;8,0 g/dl.); Conta Leucocitaria &lt;2x10^9/l (2000/mm3); piastrine &lt;75x10^9/l (75x10^3/mm3). 3. Bilirubina totale &gt;3 x ULN. 4. Siero albumina &lt;3,0 g/dl. salvo un tempo di protrombina entro i valori di norma. 5. Gravidanza (vedi Appendice 7 al Protocollo). 6. I soggetti di sesso femminile potenzialmente fertili (ovvero periodo &lt; 2 anni dall’ultima mestruazione e non chirurgicamente sterili) ed i soggetti di sesso maschile, non chirurgicamente sterili o con partner femminili potenzialmente fertili: assenza di validi mezzi contraccettivi, non ormonali (dispositivi intrauterini, metodi contraccettivi di barriera associati a gel spermicidi) come indicato nell’Appendice 7. 7. Trattamento con dosi &gt;30 mg di Octreotide LAR ad intervalli di 3-4 settimane nelle 12 settimane precedenti al reclutamento nello studio. 8. Terapia del recettore radionuclide peptide (PRRT) in qualunque periodo antecedente al reclutamento nello studio. 9. Chirurgia mirata, radioterapia (ad irradiazione esterna), chemioterapia, chemio-embolizzazione, interferoni, inibitori mTOR o altre terapie sperimentali, nelle 12 settimane precedenti il reclutamento nello studio. 10. Metastasi cerebrali note, salvo tali metastasi siano state trattate e stabilizzate da almeno 24 settimane prima del reclutamento nello studio. I pazienti con pregresse metastasi cerebrali dovranno sottoporsi ad una TAC del cranio con mezzo di contrasto per documentare la stabilizzazione della patologia prima del reclutamento nello studio. 11. Insufficienza cardiaca congestizia non controllata (Classe NYHA II, III, IV). 12. Diabete mellito non controllato definito con una glicemia a digiuno &gt;2 valore superiore di norma. 13. Qualsiasi soggetto affetto da tumori con positività o negatività all’OctreoScan. 14. Qualsiasi soggetto in trattamento con Octreotide a breve durata di azione, la cui somministrazione non può essere interrotta nelle 24 h precedenti e nelle 24 h successive alla somministrazione del 177Lu-DOTA0-Tyr3-Octreotate, o qualsiasi soggetto in trattamento con Octreotide LAR, la cui somministrazione non può essere interrotta per almeno 6 settimane prima della somministrazione del 177Lu-DOTA0-Tyr3-Octreotate, salvo la captazione del tumore osservata tramite imaging con l’OctreoScan nel corso del trattamento continuato con Octreotide non risulti inferiore ai normali livelli di captazione epatica osservati tramite imaging in modalità planare (Appendici 5 e 6). 15. I soggetti che presentino qualsiasi altra significativa condizione medica, psichiatrica o chirurgica, non attualmente controllata dal trattamento, la quale possa interferire con il completamento dello studio. 16. Precedente radioterapia ad irradiazione esterna di oltre il 25% del midollo osseo. 17. Incontinenza urinaria. 18. Altre patologie maligne coesistenti documentate, ad eccezione di tumori cutanei maligni non-melanocitici e carcinomi in situ della cervice uterina, salvo se definitivamente trattati ed in assenza documentata di ricorrenza da 5 anni. 19. I soggetti che non abbiano sottoscritto il consenso informato per la partecipazione allo studio, rilasciato prima dell’inizio di qualsiasi attività legata al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable of this tsudy is PFS.
    La variabile primaria di efficacia di questo studio è il PFS.
    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.
    La stima del valore mediano e dell’intervallo di confidenza 95% (CI) per la PFS saranno forniti utilizzando il metodo di Kaplan-Meier mentre il log-rank test sarà utilizzato per il confronto della PFS nei due gruppi di trattamento.
    E.5.2Secondary end point(s)
    The secondary efficacy variables are: Objective Response Rate (ORR), Time to Tumour Progression (TTP) and OS.
    Le variabili secondarie di efficacia sono le seguenti: Percentuale di Risposta Obiettiva (ORR), Tempo alla Progressione del tumore (TTP) e sopravvivenza globale (OS).
    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.
    Le percentuali di risposta e gli intervalli di confidenza 95% verranno calcolati per la ORR per ciascun gruppo di trattamento. Le frequenze nei due gruppi di trattamento verranno messe a confronto con il test esatto di 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
    Dosimetria
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA28
    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
    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 ongoing patient has completed 72 weeks of assessments (unless early termination) after the patient’s first treatment in either arm of the study.
    La fine dello studio corrisponde al momento in cui l'ultimo paziente in corso ha completato 72 settimane di valutazioni (a meno di interruzione prematura)dopo aver ricevuto il primo trattamento in qualsiasi dei 2 bracci di studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months32
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months32
    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.1.1Number of subjects for this age range: 0
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    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
    La sospetta tossicità a lungo termine degli organi critici (midollo osseo e reni)in relazione al farmaco di studio (inclusi ematologia, biochimica e analisi delle urine)sarà monitorata ogni 6 mesi per i 3 ani successivi alla fine dello studio.PFs (analizzato localmente) ed OS saranno raccolti ogni 6 mesi per i 3 anni successivi la fine dellos tudio. Contatti telefonici o visite saranno effettuate ogni 6 mesi durante i 3 anni di follow-up previsiti dalla fine dello studio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-04-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-01-18
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