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    Summary
    EudraCT Number:2011-006097-76
    Sponsor's Protocol Code Number:LOTUS
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-03-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2011-006097-76
    A.3Full title of the trial
    RANDOMIZED PHASE 3 TRIAL EVALUATING THE EFFICACY OF LOCOREGIONAL TREATMENT WITH TRANSARTERIAL EMBOLIZATION (TAE) FOR LIVER METASTASIS, IN COMBINATION WITH OCTREOTIDE LAR, IN PATIENTS WITH NEUROENDOCRINE TUMOR AND INOPERABLE LIVER METASTASIS.
    Studio randomizzato di fase 3 sull'efficacia della terapia locoregionale epatica mediante embolizzazione transarteriosa (TAE) in associazione a terapia medica con octreotide LAR in pazienti affetti da tumore neuroendocrino con metastasi epatiche inoperabili
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    RANDOMIZED PHASE 3 TRIAL EVALUATING THE EFFICACY OF LOCOREGIONAL TREATMENT WITH TRANSARTERIAL EMBOLIZATION (TAE) FOR LIVER METASTASIS, IN COMBINATION WITH OCTREOTIDE LAR, IN PATIENTS WITH NEUROENDOCRINE TUMOR AND INOPERABLE LIVER METASTASIS.
    Studio randomizzato di fase 3 sull’efficacia della terapia locoregionale epatica mediante embolizzazione transarteriosa (TAE) in associazione a terapia medica con octreotide LAR in pazienti affetti da tumore neuroendocrino con metastasi epatiche inoperabili
    A.3.2Name or abbreviated title of the trial where available
    LOTUS
    LOTUS
    A.4.1Sponsor's protocol code numberLOTUS
    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 SponsorISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI - FONDAZIONE "G. PASCALE"
    B.1.3.4CountryItaly
    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 supportNA
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI DI NAPOLI
    B.5.2Functional name of contact pointUnita' Sperimentazione Clinica
    B.5.3 Address:
    B.5.3.1Street AddressVia Mariano Semmola
    B.5.3.2Town/ cityNapoli
    B.5.3.3Post code80131
    B.5.3.4CountryItaly
    B.5.4Telephone number081 5903 571
    B.5.5Fax number081 77029 38
    B.5.6E-mailmariacarmela.piccirillo@usc-intnapoli.net
    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 Yes
    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 for solution 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 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 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 NEUROENDOCRINE TUMOR AND INOPERABLE LIVER METASTASIS
    pazienti affetti da tumore neuroendocrino con metastasi epatiche inoperabili
    E.1.1.1Medical condition in easily understood language
    PATIENTS WITH NEUROENDOCRINE TUMOR AND INOPERABLE LIVER METASTASIS
    pazienti affetti da tumore neuroendocrino con metastasi epatiche inoperabili
    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 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 verify if adding a locoregional treatment of liver metastasis (with trans-arterial embolization–TAE) to a medical treatment (with Octreotide LAR and eventually in combination with other medical treatments of proven efficacy), can prolong the progression free survival of patients affected by NET with inoperable liver metastases
    verificare se l’aggiunta alla terapia medica (con Octreotide LAR, analogo della somatostatina, eventualmente combinata con altri trattamenti medici di provata efficacia) di un trattamento locoregionale epatico (mediante embolizzazione transarteriosa, TAE) è in grado di prolungare la sopravvivenza libera da progressione (PFS) di pazienti affetti da NET, con metastasi epatiche inoperabili
    E.2.2Secondary objectives of the trial
    -overall survival
    -objective response rate
    -quality of life
    -toxicity
    -prognostic factors
    -sopravvivenza globale
    -risposta obiettiva
    -qualità di vita
    -tossicità
    -fattori prognostici
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Diagnosis of gatroenteropancreatic (GEP), pulmonary or unknown primary NET
    2.Unresectable liver metastases, according the judgment of surgeon, (the reasons for the opinion of surgeon should be made explicit)
    3.Hepatic involvement ≤50% volume of the organ
    4.Well (G1) or medium (G2) differentiated histology (according to WHO 2010 classification)
    5.Ki67 ≤ 20% (G1-G2)
    6.Life expectancy > 6 months
    7.Age ≥ 18 and < 80 years

    9. Radiological progression of hepatic localizations, verified during screening phase, or presence of symptoms requiring an immediate treatment with somatostatin analogues (I.E. in case of a functioning tumor, that doesn’t need of a symptomatic therapy with analogues of somatostatin [insulinoma, gastrinoma, ACTHoma], it is necessary to wait for radiological progression)
    1. Pazienti con diagnosi NET di origine gastreoenteropancreatica (GEP) o polmonare o con sede primitiva sconosciuta
    2. Metastasi epatiche non resecabili a giudizio del chirurgo (NB. Le motivazioni del giudizio dovranno essere esplicitate)
    3. Impegno epatico ≤50% del volume dell’organo
    4. Istologia ben differenziata o moderatamente differenziata (sec. classificazione WHO 2010)
    5. Ki67 ≤ 20% (G1-G2)
    6. Attesa di vita &gt; 6 mesi
    7. Età ≥ 18 anni e &lt; 80 anni
    8. Progressione radiologica delle localizzazioni epatiche verificata durante la fase di screening o presenza di sintomi che richiedono trattamento immediato con analoghi della somatostatina (NB se il tumore è funzionante ma non richiede terapia sintomatica con analoghi della somatostatina [insulinoma, gastrinoma, ACTH sec.] è necessario attendere la progressione radiologica)
    E.4Principal exclusion criteria
    1. Previous loco-regional postsurgical treatment
    2. Low differentiated histology
    3. Severe concomitant morbidities such as: severe coagulopathy (to be detailed), severe liver failure (to be detailed), renal failure (creatinine > 2.0 mg/dl) and heart failure (NYHA 3-4 or instable ischemic heart disease), contraindicating the interventional procedure or influencing the general prognosis
    4. Extrahepatic metastasis in critical locations as: brain, spinal cord, lung with respiratory impairment, symptomatic vertebral lesions
    5. Patients with progression disease only on the extra-hepatic localizations during screening phase
    6. Patients with progression disease on critical location such as: brain, spinal cord, lung with respiratory impairment, symptomatic vertebral lesions
    1. Precedenti trattamenti loco-regionali post-chirurgici
    2. Istologia scarsamente differenziata
    3. Comorbidità internistiche severe: alterazioni gravi della coagulazione (da dettagliare), grave insufficienza epatica (da dettagliare), renale (creatininemia &gt; 2.0 mg/dl) e cardiaca (NYHA 3-4 o cardiopatia ischemica in fase instabile), che controindichino la procedura interventistica o condizionino la prognosi generale
    4. Metastasi extraepatiche in sedi critiche: encefalo, midollo spinale, polmone con compromissione respiratoria, vertebrali sintomatiche

    5. Pazienti con progressione di malattia solo extraepatica durante la fase di screening
    6. Pazienti con progressione di malattia in sedi critiche: encefalo, midollo spinale, polmone con compromissione respiratoria, vertebrali sintomatiche
    E.5 End points
    E.5.1Primary end point(s)
    progression free survival
    sopravvivenza libera da progressione
    E.5.1.1Timepoint(s) of evaluation of this end point
    Radiological assessment will be perform, for both arms of study, at following times:
    -just before randomization (this assessment demonstrates liver progression of disease and contribute to define the eligibility of patient for randomization)
    -after 3 months (this assessment have to perform in both arms and, for experimental arm, contributes to orient the second round of TAE)
    -after 6 months from randomization and therefore, every 6 months (in boths arms of trial)
    La rivalutazione radiologica viene fatta ai seguenti tempi in entrambi i bracci dello studio:
    - subito prima della randomizzazione (si tratta della rivalutazione che dimostra la progressione epatica della malattia e concorre a definire l’eleggibilità del paziente per la randomizzazione)
    - dopo 3 mesi (questa rivalutazione va effettuata in entrambi i bracci e, nel braccio sperimentale, concorre a indirizzare il secondo round di TAE)
    - dopo 6 mesi dalla randomizzazione e successivamente ogni 6 mesi (in entrambi i bracci dello studio)
    E.5.2Secondary end point(s)
    -overall survival
    -objective response rate
    -sopravvivenza globale
    -risposta obiettiva
    E.5.2.1Timepoint(s) of evaluation of this end point
    Radiological assessment will be perform, for both arms of study, at following times:
    -just before randomization (this assessment demonstrates liver progression of disease and contribute to define the eligibility of patient for randomization)
    -after 3 months (this assessment have to perform in both arms and, for experimental arm, contributes to orient the second round of TAE)
    -after 6 months from randomization and therefore, every 6 months (in boths arms of trial)
    La rivalutazione radiologica viene fatta ai seguenti tempi in entrambi i bracci dello studio:
    - subito prima della randomizzazione (si tratta della rivalutazione che dimostra la progressione epatica della malattia e concorre a definire l’eleggibilità del paziente per la randomizzazione)
    - dopo 3 mesi (questa rivalutazione va effettuata in entrambi i bracci e, nel braccio sperimentale, concorre a indirizzare il secondo round di TAE)
    - dopo 6 mesi dalla randomizzazione e successivamente ogni 6 mesi (in entrambi i bracci dello studio)
    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 No
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    terapia locoregionale con embolizzazione TAE
    LOCOREGIONAL TREATMENT WITH TAE EMBOLIZATION
    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 No
    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
    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
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state140
    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)
    NA
    NA
    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 Decision2013-01-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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