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    Summary
    EudraCT Number:2013-003713-18
    Sponsor's Protocol Code Number:C14018
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-04-23
    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 number2013-003713-18
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled, Phase 2 Clinical Trial of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC)
    Studio clinico di fase II, randomizzato, in doppio cieco, controllato con placebo sul trattamento con alisertib (MLN8237) in combinazione con paclitaxel rispetto a placebo in combinazione con paclitaxel come terapia di seconda linea nel tumore al polmone a piccole cellule (SCLC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 Trial of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC)
    Studio clinico di fase II su alisertib (MLN8237) in combinazione con paclitaxel rispetto a placebo in combinazione con paclitaxel come terapia di seconda linea nel tumore al polmone a piccole cellule (SCLC)
    A.4.1Sponsor's protocol code numberC14018
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02038647
    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 SponsorMillennium Pharmaceuticals, 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 supportMillennium Pharmaceuticals Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMillennium Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDrug Information Call Center
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne St
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number001510740-2412
    B.5.5Fax number001800881-6092
    B.5.6E-mailmedical@mlnm.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 nameAlisertib
    D.3.2Product code MLN8237
    D.3.4Pharmaceutical form Gastro-resistant tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAlisertib
    D.3.9.1CAS number 1208255-63-3
    D.3.9.2Current sponsor codeMLN8237
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Paclitaxel 6 mg/ml concentrate for solution for infusion Paclitaxel 6 mg/ml concentrato per soluzione per infusione
    D.2.1.1.2Name of the Marketing Authorisation holderHospira UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namepaclitaxel
    D.3.4Pharmaceutical form Concentrate for 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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGastro-resistant tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or Refractory Small cell lung cancer
    tumore al polmone a piccole cellule recidivante o refrattario
    E.1.1.1Medical condition in easily understood language
    Small cell lung cancer
    tumore al polmone a piccole cellule
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10041067
    E.1.2Term Small cell lung cancer
    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 determine whether the combination of alisertib + paclitaxel improves progression-free survival (PFS) compared with placebo + paclitaxel
    Determinare se la combinazione alisertib + paclitaxel migliori la sopravvivenza libera da progressione (progression-free survival, PFS) rispetto a placebo + paclitaxel
    E.2.2Secondary objectives of the trial
    • To evaluate the safety and tolerability of the combination of alisertib + paclitaxel in small cell lung cancer (SCLC) patients

    • To determine whether the combination of alisertib + paclitaxel improves overall survival (OS) compared with placebo + paclitaxel

    • To determine whether the combination of alisertib + paclitaxel improves the overall response rate (ORR) compared with placebo + paclitaxel

    • To determine whether the combination of alisertib + paclitaxel improves the disease control rate (DCR) compared with placebo + paclitaxel

    • To determine whether the combination of alisertib + paclitaxel improves the duration of response (DOR) compared with placebo + paclitaxel

    • To evaluate patient lung cancer associated symptoms of cough, dyspnea, and pain as measured by patient-reported outcome (PRO) instruments

    • To measure plasma alisertib concentrations to contribute to population pharmacokinetic (PK) analysis
    Valutare sicurezza e tollerabilità della combinazione alisertib + paclitaxel in pazienti con SCLC
    Determinare se la combinazione alisertib + paclitaxel migliori la sopravvivenza complessiva (OS) rispetto a placebo + paclitaxel
    Determinare se la combinazione alisertib + paclitaxel migliori il tasso di risposta complessivo (ORR) rispetto a placebo + paclitaxel
    Determinare se la combinazione alisertib + paclitaxel migliori il tasso di controllo della malattia (DCR) rispetto a placebo + paclitaxel
    Determinare se la combinazione alisertib + paclitaxel migliori la durata della risposta (DOR) rispetto a placebo + paclitaxel
    Valutare sintomi di tosse, dispnea e dolore associati al tumore al polmone del paziente, misurandoli tramite gli strumenti di esito riferito dal paziente (PRO)
    Misurare le concentrazioni plasmatiche di alisertib per fornire un contributo all’analisi farmacocinetica (PK) di popolazione
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients ≥ 18 years old.

    2. Have a pathologically (histology or cytology) confirmed diagnosis of SCLC.

    3. Have received and progressed after a platinum based standard chemotherapy regimen for first line treatment of SCLC, either limited stage (LS) or extensive stage (ES). Patients could not have received any prior second-line therapy for relapsed or progressive disease, including re-treatment with original frontline regimen. Patients should have relapsed within < 180 days after their response to first line therapy. At least 3 weeks should have elapsed between the end of first line therapy and the first dose of study drug. No previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression.

    4. Have measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) within ≤ 2 weeks before randomization. Clear radiographic evidence of disease progression after initial therapy should have been documented.

    5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (PS 0 1).

    6. Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed, provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids. Patients should be without neurologic dysfunction that would confound the evaluation of neurological and/or other AEs. Patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (eg, carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study. Use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed. Radiotherapy must have been completed a minimum of 14 days prior to randomization, and patients must have recovered from AEs related to the radiotherapy to < grade 1 (except alopecia).

    7. Patients requiring full systemic anticoagulation are eligible if they have tolerated treatment with a stable dose and schedule without bleeding complications for more than 1 month.

    8. Female patients who:
    • Are postmenopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 30 days after the last dose of study drug, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

    Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)

    9. The patient or the patient’s legal representative is able to provide written informed consent. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

    10. Screening clinical laboratory values as specified below:
    • Absolute neutrophil count (ANC) ≥ 1500/mm3, platelet count ≥ 100,000/mm3, and hemoglobin ≥ 9 g/dL
    • Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN)
    • Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x the institutional ULN (< 5 x if liver function test elevations are due to liver metastases)
    • Serum albumin ≥ the lower limit of normal (LLN)
    • Creatinine < 1.5 x institutional ULN or estimated creatinine clearance using the Cockcroft-Gault formula ≥ 30 mL/minute for patients with creatinine levels above institutional limits

    11. Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before randomization, and otherwise noted in other inclusion/exclusion criteria.

    12. Suitable venous access for the conduct of blood sampling and intravenous administration of study treatments.

    13. Recovered (ie, ≤ Grade 1 toxicity) from the reversible effects of prior anticancer therapy.
    1.sesso maschile e femminile con ≥18 anni d’età
    2.diagnosi di SCLC patologicamente confermata (tramite istologia o citologia)
    3.I pazienti devono aver ricevuto un regime chemioterapico a base di platino, quale trattamento di prima linea per il SCLC e devono aver subito una progressione della malattia, sia verso LS che ES. pazienti non possono aver ricevuto alcuna pregressa terapia di seconda linea per la malattia in progressione o recidivante, compreso nuovo trattamento con regime di prima linea originario. pazienti devono essere in recidiva da <180 giorni dopo risposta alla terapia di prima linea. Tra fine della terapia di prima linea e prima dose del farmaco dello studio devono trascorrere almeno 3 settimane. Non vi deve essere stata precedente irradiazione dell'unico sito di malattia misurabile o valutabile, a meno che il sito non abbia mostrato successiva evidenza di progressione.
    4.pazienti devono presentare malattia misurabile secondo Criteri RECIST 1.1 entro ≤ 2 settimane prima randomizzazione. Chiara evidenza radiografica di progressione dopo terapia iniziale deve essere stata documentata.
    5.pazienti devono presentare PS secondo ECOG di 0 o 1.
    6.pazienti con metastasi cerebrali trattate (chirurgia, irradiazione totale o stereotassica del cervello) sono ammessi, a condizione che le lesioni siano rimaste stabili per almeno 2 settimane e il paziente è fuori steroidi o è su una dose stabile di steroidi. I pazienti non devono presentare disfunzione neurologica che potrebbe creare confusione nella valutazione di eventi avversi neurologici e/o di altri. Pazienti con metastasi cerebrali non richiedono l'uso di enzimi che inducono farmaci antiepilettici (ad esempio, carbamazepina, fenitoina o fenobarbital) entro 14 giorni prima della prima dose e durante lo studio. L’uso di antiepilettici più recenti che non inducono interazioni enzimatiche farmaco-farmaco è consentito. La radioterapia deve essere stata completata un minimo di 14 giorni prima della randomizzazione, e i pazienti devono essersi ripresi da eventi avversi correlati alla radioterapia di <grado 1 (tranne alopecia).
    7.pazienti che necessitano piena anticoagulazione sistemica sono ammissibili se hanno tollerato il trattamento con una dose stabile e un programma senza complicanze emorragiche per più di 1 mese.
    8.Pazienti di sesso femminile che:
    •Sono in menopausa da almeno 1 anno prima della visita di screening, O
    •Sono chirurgicamente sterili, O
    •Se sono in età fertile, accettano di utilizzare 2 metodi efficaci di contraccezione allo stesso tempo, dal momento della firma del ICF, fino a 30 giorni dopo l'ultima dose del farmaco dello studio, O
    •Accettano di praticare vera astinenza, quando questo è in linea con lo stile di vita preferito e abituale del soggetto. (Astinenza periodica [ad esempio, calcolo dei giorni fertili e dell'ovulazione, metodo sintotermico, metodo postovulazione] e coito interrotto non sono ritenuti metodi di contraccezione accettabili.)
    Pazienti di sesso maschile, anche se sterilizzati chirurgicamente (cioè, allo stato di postvasectomia), che:
    •Accettano di utilizzare un efficace metodo contraccettivo a barriera durante l'intero periodo di trattamento dello studio e fino a 4 mesi dopo l'ultima dose di farmaco dello studio, O
    •Accettano di praticare la vera astinenza, quando questo è in linea con lo stile di vita preferito e abituale del soggetto. (Astinenza periodica [ad esempio, calcolo dei giorni fertili e dell'ovulazione, metodo sintotermico, metodo postovulazione per la partner donna] e coito interrotto non sono ritenuti metodi di contraccezione accettabili.)
    9.paziente o rappresentante legale è in grado di fornire consenso informato scritto. Volontario consenso scritto deve essere dato prima dell’esecuzione di qualsiasi procedura relativa allo studio che non fa parte delle procedure standard di cura, con la consapevolezza che il consenso può essere ritirato dal il paziente in qualsiasi momento senza pregiudizio per le sue future cure mediche.
    10.valori clinici di laboratorio allo Screening devono essere:
    •ANC ≥ 1500/mm3, conta piastrinica ≥ 100,000/mm3, emoglobina ≥ 9 g/dl
    •Bilirubina totale ≤ 1,5 volte ULN
    •ALT sierica o AST ≤ 2,5 x ULN (<5 x se l’aumento dei test di funzionalità epatica sono causa di metastasi epatiche)
    •Albumina sierica ≥ LLN
    •Creatinina <1.5 x ULN o clearance della creatinina stimata utilizzando formula di Cockcroft-Gault ≥ 30 ml/min per pazienti con livelli di creatinina superiori ai limiti istituzionali
    11.Condizioni mediche stabili, compresa assenza di gravi riacutizzazioni di malattie croniche, infezioni gravi o chirurgia maggiore entro 4 settimane prima della randomizzazione, e se non diversamente specificato in altre criteri di inclusione/esclusione.
    12.Accesso venoso adatto per effettuare prelievi di sangue e somministrare per via endovenosa i trattamenti dello studio.
    13.Recupero (cioè, ≤ Grado 1 tossicità) dagli effetti reversibili della prima terapia antitumorale.
    E.4Principal exclusion criteria
    1. Any prior therapy for second-line treatment of SCLC.

    2. Patients who relapsed ≥ 180 days after their response to first-line treatment.

    3. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, including alisertib in any setting or any other investigational agent in the relapsed setting.

    4. Prior treatment with paclitaxel or any other taxane agent.

    5. Known hypersensitivity to Cremophor® EL, paclitaxel, or its components.

    6. Any comorbid condition or unresolved toxicity that would preclude administration of alisertib or weekly paclitaxel.

    7. Prior history of ≥ Grade 2 neurotoxicity that is not resolved to ≤ Grade 1.

    8. Patients with symptomatic and/or progressive brain metastases or with carcinomatous meningitis.

    9. Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of alisertib and during study conduct. Major prohibited enzyme inducers include: phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, and St. John’s wort.

    10. Inability to swallow alisertib or other orally administered medications.

    11. Requirement for administration of proton pump inhibitor (PPI), H2 antagonist, or pancreatic enzymes. Use of any PPI in either continued or intermittent use will be prohibited during the conduct of the study and patients must discontinue any use of PPI within 4 days prior to the first dose of alisertib.

    12. Diagnosed with or treated for another malignancy within 3 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type may be enrolled in the study if they have undergone complete resection and no evidence of active disease is present.

    13. Other severe acute or chronic medical or psychiatric condition(s), including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.

    14. History of myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, any ongoing cardiac arrhythmias of Grade > 2, thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy) within 6 months before receiving the first dose of study drug. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed. Patients with a pacemaker may be enrolled in the study upon discussion with the project clinician.

    15. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C. Testing is not required in the absence of clinical findings or suspicion. Patients with prior allogeneic bone marrow or organ transplantation or with an active condition of chronic immune suppression are not eligible.

    16. Infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug.

    17. Patients who are lactating or have a positive serum pregnancy test.

    18. Surgery within 3 weeks (or 2 weeks for a minor surgery) before study enrollment and not fully recovered to baseline or to a stable clinical status. Insertion of a vascular device is allowed.

    19. Unwilling or unable to comply with the protocol or
    cooperate fully with the investigator and site personnel.
    1. Qualsiasi precedente terapia per il trattamento di seconda linea del SCLC.
    2. Pazienti che hanno mostrato recidive ≥ 180 giorni dopo la loro risposta al trattamento di prima linea.
    3. Un precedente trattamento con un agente Aurora A target-specifico o pan-Aurora specifico, compresi alisertib in qualsiasi contesto o qualsiasi altro farmaco sperimentale nel contesto recidiva.
    4. Precedente terapia con paclitaxel o qualsiasi altro agente taxano.
    5. Ipersensibilità nota a Cremophor ® EL, paclitaxel, o ai suoi componenti.
    6. Qualsiasi condizione di comorbidità o tossicità irrisolta che impediscano la somministrazione settimanale di alisertib o paclitaxel.
    7. Precedente storia di neurotossicità di ≥ 2 Grade che non si risolve a ≤ Grado 1.
    8. Pazienti con metastasi cerebrali sintomatiche e/o progressive o con meningite carcinomatosa.
    9. Il trattamento con dosi clinicamente significative di induttori enzimatici entro 14 giorni prima della prima dose di alisertib e durante la conduzione dello studio. Gli induttori enzimatici maggiormente vietati comprendono: fenitoina, carbamazepina, fenobarbital, rifampicina, rifabutina, rifapentina, e iperico.
    10. Incapacità di deglutire alisertib o altri farmaci somministrati per via orale.
    11. Requisiti per la somministrazione di inibitori della pompa protonica (PPI), H2 antagonisti, o enzimi pancreatici. L'uso di PPI continuato o intermittente sarà vietato durante lo svolgimento dello studio e i pazienti devono interrompere qualsiasi uso di PPI entro 4 giorni prima della prima dose di alisertib.
    12. Diagnosi o trattamento di un altro tumore maligno entro 3 anni prima della prima dose del farmaco in studio, o altro tumore maligno precedentemente diagnosticato ed evidenza di malattia residua. Pazienti con tumore della pelle non-melanoma o carcinoma in situ di qualsiasi tipo possono essere arruolati nello studio, se hanno subito una resezione completa e non presentano evidenza di malattia attiva.
    13. Altra grave condizione medica o psichiatrica acuta o cronica, tra cui il diabete non controllato, malassorbimento, resezione del pancreas o intestino tenue superiore, mancanza di enzimi pancreatici, qualsiasi condizione che abbia modificato l’assorbimento di farmaci per via orale da parte dell’intestino tenue, o anomalie di laboratorio che possono aumentare il rischio associato alla partecipazione allo studio o la somministrazione del farmaco sperimentale o che può interferire con l'interpretazione dei risultati dello studio e, a giudizio del medico dello studio, potrebbe rendere il paziente inadeguato per l'arruolamento in questo studio.
    14. Storia di infarto miocardico, instabile ischemica sintomatica, malattie cardiache, ipertensione non controllata nonostante un adeguato trattamento medico, eventuali aritmie cardiache in corso di grado> 2, eventi tromboembolici (ad esempio, trombosi venosa profonda, embolia polmonare, o eventi cerebrovascolari sintomatici) o qualsiasi altra condizione cardiaca (ad esempio, effusione pericardicoa o cardiomiopatia restrittiva) entro 6 mesi prima di ricevere la prima dose di farmaco dello studio. Fibrillazione atriale stabile cronica in terapia anticoagulante stabile è permessa. I pazienti con un pacemaker possono essere arruolati nello studio su valutazione del medico dello studio.
    15. Storia medica di virus dell'immunodeficienza umana (HIV), epatite B o epatite C. Il test non è richiesto in assenza di risultati clinici o sospetto. I pazienti con precedente trapianto allogenico osseo o di organi o di una condizione attiva di soppressione immunitaria cronica non sono ammissibili.
    16. Infezione che richiede una terapia antibiotica endovenosa o altre infezioni gravi entro 14 giorni prima della prima dose del farmaco dello studio.
    17. Pazienti che stanno allattando o hanno un test di gravidanza su siero positivo.
    18. Intervento chirurgico entro 3 settimane (o 2 settimane per un piccolo intervento chirurgico) prima dell’arruolamento e non pienamente recuperato al basale o a uno stato clinico stabile. È consentito l’inserimento di un dispositivo vascolare.
    19. Pazienti non disposti o non in grado di rispettare il protocollo o cooperare pienamente con il medico dello studio e il personale del centro.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS
    sopravvivenza libera da progressione (progression-free survival, PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS will be assessed every cycle of therapy for the first 6 months, and then every 2 cycles between Days 21 and 28

    It is expected that the study will last approximately 22 months to reach the final analysis of the PFS endpoint for the maximum sample size (16 months of enrollment and 6 months of additional follow-up for PFS)
    PFS sarà valutata ad ogni ciclo di terapia per i primi 6 mesi, e poi ogni 2 cicli tra i giorni 21 e 28.
    Si prevede che lo studio durerà circa 22 mesi per raggiungere l’analisi finale dell'endpoint PFS per la dimensione massima del campione (16 mesi di arruolamento e 6 mesi di ulteriore follow-up per PFS).
    E.5.2Secondary end point(s)
    • Safety and tolerability
    • OS
    • ORR, including complete response rate (CRR)
    • Disease control rate (DCR)
    • Duration of response (DOR)
    • Symptom score, time to symptom relief, percentage of patients experiencing symptom relief, and time to symptom progression (cough, dyspnea, and pain)
    • Plasma alisertib concentration (ie, PK)
    • Sicurezza e tollerabilità
    • OS
    • ORR, incluso il tasso di risposta completa (complete response rate, CRR)
    • tasso di controllo della malattia (DCR)
    • durata della risposta (DOR)
    • punteggio dei sintomi, tempo al sollievo dai sintomi, percentuale di pazienti che hanno riscontrato un sollievo dai sintomi, tempo alla progressione dei sintomi (tosse, dispnea e dolore)
    • concentrazione plasmatica di alisertib (cioé PK)
    E.5.2.1Timepoint(s) of evaluation of this end point
    safety- ongoing
    Patients will be followed for OS every 2 months (± 2 weeks) until death events are obtained from approximately 80% of all patients in the ITT population or 14 months after last patient is randomized, whichever occurs first
    sicurezza durante il corso dello studio
    I pazienti saranno seguiti per la OS ogni 2 mesi (±2 settimane) finché non si ottengono eventi di decesso da circa l’80% di tutti i pazienti della popolazione che si intende trattare (intent-to-treat, ITT) oppure 14 mesi dopo la randomizzazione dell’ultimo paziente, a seconda di quale caso si presenti per primo.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life
    qualità della vita
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA 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
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Italy
    Poland
    Spain
    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
    last patient last visit
    ultima visita dell'ultimo paziente
    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 months22
    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 months22
    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: 66
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 89
    F.4.2.2In the whole clinical trial 166
    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)
    not applicable
    non applicabile
    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 Decision2014-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-16
    P. End of Trial
    P.End of Trial StatusOngoing
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