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    Summary
    EudraCT Number:2016-000089-45
    Sponsor's Protocol Code Number:OT-15-001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2018-04-20
    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 number2016-000089-45
    A.3Full title of the trial
    A Phase 3, Randomized, Open-Label Study To Evaluate the Efficacy and Safety of Eflornithine with Lomustine Compared to Lomustine Alone in Patients with Anaplastic Astrocytoma That Progress/Recur After Irradiation and Adjuvant Temozolomide Chemotherapy
    Studio di fase 3, randomizzato, in aperto, per valutare l’efficacia e la sicurezza di eflornitina in aggiunta a lomustina rispetto a lomustina in monoterapia in pazienti affetti da astrocitoma anaplastico progredito/recidivato dopo irradiazione e chemioterapia adiuvante a base di temozolomide
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to measure how well and how safe eflornithine is in combination with lomustine, compared to lomustine taken alone, in treating patients whose anaplastic astrocytoma has got worse or come back after radiation and chemotherapy.
    Uno studio per misurare quanto sia buono e quanto sia sicuro eflornitina in combinazione con lomustina, rispetto a lomustina preso da solo, nel trattamento di pazienti in cui astrocitoma anaplastico è peggiorato o ritorna dopo trattamento di radiazione e chemioterapia
    A.3.2Name or abbreviated title of the trial where available
    STELLAR Study
    Studio STELLAR
    A.4.1Sponsor's protocol code numberOT-15-001
    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 SponsorORBUS THERAPEUTICS INC.
    B.1.3.4CountryUnited States
    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 supportOrbus Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOrbus Therapeutics, Inc.
    B.5.2Functional name of contact pointMarietta Franco
    B.5.3 Address:
    B.5.3.1Street Address2479 East Bayshore Road
    B.5.3.2Town/ citySuite 105, Palo Alto
    B.5.3.3Post codeCA 94303
    B.5.3.4CountryUnited States
    B.5.4Telephone number0016506569428
    B.5.5Fax number0016506008595
    B.5.6E-mailmarietta.franco@orbustherapeutics.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEflornitina
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEFLORNITINA CLORIDRATO
    D.3.9.1CAS number 96020-91-6
    D.3.9.2Current sponsor codeNa
    D.3.9.3Other descriptive nameEFLORNITINA CLORIDRATO
    D.3.9.4EV Substance CodeSUB01861MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Lomustine 'Medac'
    D.2.1.1.2Name of the Marketing Authorisation holdermedac - Gesellschaft fuer klinische Spezialpraeparate mbH
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLOMUSTINA
    D.3.9.2Current sponsor codeNa
    D.3.9.3Other descriptive nameLOMUSTINA
    D.3.9.4EV Substance CodeSUB08567MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Gleostine
    D.2.1.1.2Name of the Marketing Authorisation holderCorden Pharma Latina S.p.A.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLOMUSTINA
    D.3.9.2Current sponsor codena
    D.3.9.3Other descriptive nameLOMUSTINA
    D.3.9.4EV Substance CodeSUB08567MIG
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Anaplastic Astrocytoma
    astrocitoma anaplastico
    E.1.1.1Medical condition in easily understood language
    Brain tumour.
    Tumore al cervello
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002224
    E.1.2Term Anaplastic astrocytoma
    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
    The primary objective of this study is to demonstrate superiority in overall survival (OS) and comparable safety when eflornithine is added to lomustine compared to lomustine alone in patients with anaplastic astrocytoma (AA) that progress/recur after irradiation and adjuvant temozolomide chemotherapy.

    L’obiettivo primario di questo studio consiste nel dimostrare la superiorità in termini di sopravvivenza globale (Overall survival, OS) e sicurezza comparabile quando eflornitina viene aggiunta a lomustina rispetto a lomustina in monoterapia nei/nelle pazienti affetti/e da astrocitoma anaplastico (AA) progredito/recidivato dopo l’irradiazione e la chemioterapia adiuvante a base di temozolomide.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are intended to determine:
    • Progression Free Survival (Progression-free survival, PFS)
    • objective response rate (Objective response rate, ORR)
    Gli obiettivi secondari di questo studio sono finalizzati a determinare:
    • Sopravvivenza senza progressione (Progression-free survival, PFS)
    • Tasso di risposta obiettiva (Objective response rate, ORR)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following inclusion criteria to be eligible for participation in this study:
    1. The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
    2. Age ≥ 18 years.
    3. Surgical or biopsy-proven diagnosis of WHO grade 3 AA.
    4. Unequivocal evidence of first AA tumor progression or recurrence ≤ 3 months prior to randomization based on MRI criteria for tumor progression using enlarging Gd-contrast enhancement and/or T2 hypersensitivity (Appendix 4). Patients with non-measurable Gd-contrast enhancing tumors will only be eligible if there is no necrosis seen on MRI and/or histopathological confirmation of AA per standard of care procedures is obtained within 4 weeks prior to randomization.
    5. First tumor progression or recurrence following surgical resection or biopsy, if resection is not feasible, EBRT and temozolomide chemotherapy.
    6. Completion of EBRT ≥ 6 months prior to randomization.
    7. Stained, unstained slides or tumor tissue block(s) are available from their most recent tumor surgery are available for central histological confirmation.
    8. A patient whose AA tumor has progressed or recurred and has had another surgical resection prior to randomization will be eligible if a) pathology review confirms AA, b) post-surgical MRI demonstrates measurable tumor on T2/FLAIR, and c) MRI performed after surgery is within 4 weeks prior to randomization.
    9. If taking corticosteroids, must be on a stable or decreasing dose for at least 5 days prior to the screening MRI.
    10. Karnofsky Performance Status (KPS) score of > 70.
    11. Off anticancer therapy for at least 4 weeks and recovered from any significant treatment-related toxicities to Grade ≤ 1 prior to randomization.
    12. Adequate recovery from any major surgery is required; at least 4 weeks must have elapsed from the time of any major surgery and must have recovered from all surgery-related toxicities to Grade ≤ 1 prior to randomization.
    13. Adequate hematologic function (ANC ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 10.5 gm/dL) within 14 days prior to randomization.
    14. Total bilirubin ≤ 1.5x upper limit of normal (ULN) within 14 days prior to randomization.
    15. Hepatic transaminases (AST and ALT) ≤ 2x ULN within 14 days prior to randomization.
    16. Adequate renal function (serum creatinine ≤ 1.5x ULN) within 14 days prior to randomization.
    17. Life expectancy ≥ 6 months.
    18. Female patients of childbearing potential must agree to utilize acceptable contraceptive methods from screening throughout the duration of the study period, and for 30 days following the last dose of study drug. Abstinence is an acceptable method of contraception. Otherwise, consistent and current use of 1 of the following methods of birth control is accepted: oral contraceptive, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), tubal sterilization, Essure micro-insert system, or vasectomy in the male partner. Female patients must also refrain from egg donation and in vitro fertilization during treatment and until at least 30 days from the last dose of study drug.
    19. Male patients must agree to abstain from sexual intercourse or use an acceptable contraceptive method (e.g. condoms) from screening throughout the duration of the study period, and for 90 days following the last dose of study drug. Male patients must also refrain from sperm donation during treatment and until at least 90 days from the last dose of study drug.
    Per essere eleggibili a partecipare a questo studio, i/le pazienti devono soddisfare i criteri di inclusione elencati di seguito:
    1. Essere in grado di comprendere e firmare un modulo di consenso informato scritto, che deve essere consegnato prima dell’inizio delle procedure di studio.
    2. Età >/ 18 anni.
    3. Intervento chirurgico o diagnosi comprovata da biopsia di AA di grado 3 della classificazione dell’Organizzazione mondiale della sanità (OMS).
    4. Prova inequivocabile di prima progressione o ricorrenza tumorale dell’AA ≤ 3 mesi precedenti la randomizzazione secondo i criteri di risonanza magnetica per immagini (RMI) per la progressione del tumore utilizzando la captazione con mezzo di contrasto di ingrandimento contenente gadolinio e/o l’ipersensibilità in sequenze T2 (Appendice 4). I/Le pazienti affetti/e da tumori con captazione non misurabile del mezzo di contrasto contenente gadolinio saranno eleggibili solo in assenza di necrosi evidenziate alla RMI e/o di conferma istopatologica di AA secondo le procedure di cura standard entro le 4 settimane precedenti la randomizzazione.
    5. Prima progressione o recidiva tumorale dopo resezione chirurgica o biopsia, se la resezione non è praticabile, EBRT [External beam radiation therapy (radioterapia a fasci esterni)] e chemioterapia a base di temozolomide.
    6. Completamento dell’EBRT ≥ 6 mesi prima della randomizzazione.
    7. Disponibilità di vetrini o di uno o più blocchi di tessuto tumorale con o senza colorazione ottenuti dal più recente intervento chirurgico eseguito sul tumore per la conferma istologica a livello centrale.
    8. Un/a paziente il cui tumore AA sia progredito o recidivato e sia stato/a sottoposto/a a un’ulteriore resezione chirurgica prima della randomizzazione sarà elegibile se a) la revisione patologica conferma l’AA, b) la RMI post-chirurgica del tumore dimostra un tumore misurabile nelle sequenze T2/FLAIR e c) la RMI eseguita dopo l’intervento chirurgico rientri nelle 4 settimane precedenti la randomizzazione.
    9. In caso di assunzione di corticosteroidi, deve trattarsi di trattamento con una dose stabile o decrescente da almeno 5 giorni prima della risonanza magnetica per immagini di screening.
    10. Punteggio dello stato di validità di Karnofsky > 70.
    11. Sospensione della terapia antitumorale da almeno 4 settimane e recupero da qualsiasi tossicità significativa correlata al trattamento di grado ≤ 1 prima della randomizzazione.
    12. Necessità di un recupero adeguato da qualsiasi intervento chirurgico maggiore; devono essere trascorse almeno 4 settimane dal momento di qualsiasi intervento chirurgico maggiore e deve essere sopraggiunto di un recupero da tutte le tossicità correlate all’intervento chirurgico di grado ≤ 1 prima della randomizzazione.
    13. Funzione ematologica adeguata (ANC [Absolute neutrophil count (conta assoluta dei neutrofili)] ≥ 1.500/µL, conta piastrinica ≥ 100.000/µL ed emoglobina ≥ 10,5 g/dl) nei 14 giorni precedenti la randomizzazione.
    14. Bilirubina totale ≤ 1,5 volte il limite superiore della normalità (Upper limit of normal, ULN) entro i 14 giorni precedenti la randomizzazione.
    15. Transaminasi epatiche (AST [Aspartato transaminasi] e ALT [Alanina transaminasi]) ≤ 2 volte l’ULN entro i 14 giorni precedenti la randomizzazione.
    16. Funzione renale adeguata (creatinina sierica ≤ 1,5 volte l’ULN) entro i 14 giorni precedenti la randomizzazione.
    17. Aspettativa di vita di ≥ 6 mesi.
    18. Le pazienti di sesso femminile in età fertile devono accettare di utilizzare metodi contraccettivi accettabili a partire dallo screening per l’intera durata del periodo di studio e nei 30 giorni successivi all’ultima dose del farmaco in studio. L’astinenza è un metodo contraccettivo accettabile. In alternativa, è consentito l’utilizzo costante e continuativo di 1 dei seguenti metodi di contraccezione: contraccettivo orale, dispositivo intrauterino (Intrauterine device, IUD), sistema intrauterino a rilascio ormonale (Intrauterine hormone-releasing system, IUS), sterilizzazione tubarica, sistema Essure di micro-inserti o vasectomia del partner maschile. Le pazienti di sesso femminile devono inoltre astenersi dalla donazione di ovuli e dalla fecondazione in vitro durante il trattamento e fino ad almeno 30 giorni dall’ultima dose del farmaco in studio.
    19. I pazienti di sesso maschile devono accettare di astenersi da rapporti sessuali o di utilizzare un metodo contraccettivo accettabile (ad esempio, preservativi) a partire dallo screening per l’intera durata del periodo di studio e nei 90 giorni successivi all’ultima dose del farmaco in studio. I pazienti di sesso maschile devono inoltre astenersi dalla donazione di sperma durante il trattamento e fino ad almeno 90 giorni dall’ultima dose del farmaco in studio.
    E.4Principal exclusion criteria
    Patients who meet any of the following exclusion criteria are not eligible for study participation:
    1. MRI defining progression is consistent with a diagnosis of glioblastoma or radiation necrosis.
    2. Patients who are considered to be refractory to EBRT and temozolomide but who have not progressed.
    3. Prior systemic therapy for recurrence of AA.
    4. Presence of extracranial or leptomeningeal disease.
    5. Prior lomustine use.
    6. History of other invasive malignancy, unless adequately treated with curative intent and with no known active disease present within 2 years prior to the first dose of study drug. Patients with non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia and organ-confined prostate cancer deemed by the investigator to be at low risk of recurrence are not excluded.
    7. Active infection or serious intercurrent medical illness.
    8. Known to be HIV positive or to have an AIDS-related illness, Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) positive.
    9. Poorly controlled epilepsy.
    10. Unable to undergo an MRI with contrast.
    11. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class III or IV congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.
    12. Malabsorption syndrome, history of resection of the stomach or small bowel, active ulcerative colitis or Crohn’s disease, or partial or complete bowel obstruction or other conditions that would be expected to alter the absorption or PK of study drugs.
    13. Receipt of any other anticancer therapy while receiving protocol-defined therapy.
    14. Concurrent use of any other investigational agent during the study or within 30 days prior to randomization.
    15. Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study.
    16. Pregnant or breastfeeding.
    I/Le pazienti che rispondono a qualsiasi dei seguenti criteri di esclusione non sono eleggibili a partecipare allo studio:
    1. La RMI per la definizione della progressione deve essere coerente con una diagnosi di glioblastoma o necrosi da radiazioni.
    2. I/Le pazienti che sono considerati/e refrattari/e a EBRT e temozolomide, ma che non hanno sviluppato una progressione della malattia.
    3. Terapia sistemica preventiva per recidiva di AA.
    4. Presenza di malattia extracranica o leptomeningea.
    5. Precedente utilizzo di lomustina.
    6. Anamnesi di altri tumori maligni invasivi, se non adeguatamente trattati con intento curativo e assenza di malattia attiva nota entro i 2 anni precedenti la randomizzazione. Non sono esclusi/e pazienti affetti/e da tumore cutaneo non melanomatoso, carcinoma in situ (tra cui, tumore della vescica superficiale), neoplasia cervicale intraepiteliale e tumore della prostata confinato all’organo che lo sperimentatore consideri a basso rischio di recidiva.
    7. Infezione attiva o patologia medica seria intercorrente.
    8. Nota sieropositività o patologia correlata all’AIDS [Acquired immunodeficiency syndrome (sindrome da immunodeficienza acquisita)], positività al virus dell’epatite B (Hepatitis C virus, HBV) o al virus dell’epatite C (Hepatitis C virus, HCV).
    9. Epilessia scarsamente controllata.
    10. Incapacità a sottoporsi a una RMI con mezzo di contrasto.
    11. Malattia cardiovascolare non controllata o grave, tra cui infarto miocardico o angina instabile entro i 6 mesi precedenti la randomizzazione, insufficienza cardiaca congestizia di Classe III o IV secondo la classificazione della New York Heart Association (NYHA [Associazione dei cardiologi di New York]), aritmie serie che richiedono un trattamento farmacologico, malattia pericardica clinicamente significativa o amiloidosi cardiaca.
    12. Sindrome da malassorbimento, anamnesi di resezione gastrica o dell’intestino tenue, colite ulcerosa attiva o malattia di Crohn, ostruzione intestinale parziale o totale o altre condizioni che tendenzialmente alterano l’assorbimento o la farmacocinetica dei farmaci dello studio.
    13. Ricezione di qualsiasi altra terapia antitumorale durante la terapia definita dal protocollo.
    14. Utilizzo concomitante di qualsiasi altro agente sperimentale durante lo studio o entro i 30 giorni precedenti la randomizzazione.
    15. Qualsiasi altra condizione clinica o precedente terapia che, secondo il giudizio dello Sperimentatore, renderebbe il/la paziente non idoneo/a allo studio.
    16. Gravidanza o allattamento al seno.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point is the duration of overall survival as measured from the date of randomization
    L'end point primario è la durata della sopravvivenza globale come misurato dalla data di randomizzazione
    E.5.1.1Timepoint(s) of evaluation of this end point
    Measured from the date of randomization until the date of death. The calendar date of the 194th death will serve as the data cut-off date for the primary analysis.
    Misurato a partire dalla data di randomizzazione fino alla data del decesso. Il 194° decesso servirà come data di cut-off per l'analisi primaria
    E.5.2Secondary end point(s)
    The secondaty end points include :
    Efficacy:
    .PFS
    .ORR
    Safety:
    .Incidence of treatment emergent adverse events
    .Incidence of serious adverse events
    .Changes and shifts from baseline in hematology and serum chemistry values, ECGs, and vital signs
    Gli endpoint secondari includono:
    Efficacia:
    .pfs
    .ORR
    Sicurezza:
    .Incidenza di trattamento di eventi avversi emersi
    .Incidenza di eventi avversi gravi
    Modifiche e spostamenti rispetto al valore basale ematologico e alla chimica del siero, ECG, e segni vitali
    E.5.2.1Timepoint(s) of evaluation of this end point
    the primary analysis of the secondary and exploratory efficacy endpoints and safety will occur at the time of the primary analysis of overall survival
    l'analisi primaria degli endpoint secondari di efficacia e sicurezza sperimentali si verificherà al momento dell'analisi primaria di sopravvivenza globale
    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 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) 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    Italy
    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
    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 months2
    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 months2
    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: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 252
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 280
    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
    Nessuna
    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 Decision2016-07-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-13
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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