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    Summary
    EudraCT Number:2016-002036-32
    Sponsor's Protocol Code Number:MDV3800-06
    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:2020-12-15
    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 number2016-002036-32
    A.3Full title of the trial
    Talapro-1: a phase 2, open label, response rate study of talazoparib in men with DNA repair defects and metastatic castration resistant prostate cancer who previously received taxane based chemotherapy and progressed on at least 1 novel
    hormonal agent (enzalutamide and/or abiraterone
    acetate/prednisone)
    Talapro-1: studio di fase 2, in aperto, sul tasso di risposta di talazoparib somministrato a uomini con difetti nel riparo del DNA e affetti da carcinoma prostatico metastatico resistente alla castrazione, che hanno già ricevuto la chemioterapia a base di tassani e hanno mostrato progressione durante la somministrazione di almeno 1 nuovo agente ormonale (enzalutamide e/o abiraterone acetato/prednisone)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An international study to evaluate the effectiveness of Talazoparib in men with a genomic defect and metastatic castration-resistant prostate cancer who received previous chemotherapy and progressed on hormonal treatment.
    Uno studio internazionale per valutare l'efficacia di Talazoparib in uomini con un difetto genetico e tumore metastatico alla prostata resistente alla castrazione che hanno già ricevuto chemioterapia e mostrato progressione con trattamento ormonale.
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberMDV3800-06
    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 SponsorMEDIVATION 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 supportMedivation, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trial.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd St
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+120127337900
    B.5.5Fax number+14155433411
    B.5.6E-mailClinicalTrial.gov_Inquiries@pfizer.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 nameTalazoparib
    D.3.2Product code [MDV3800 (BMN 673)]
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.4EV Substance CodeSUB122393
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 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 nameTalazoparib
    D.3.2Product code [MDV3800 (BMN 673)]
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codeMDV3800
    D.3.9.3Other descriptive nameBMN 673
    D.3.9.4EV Substance CodeSUB122393
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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
    Men With DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer Who Previously Received Taxane-Based Chemotherapy and Progressed on at Least 1 Novel Hormonal Agent (Enzalutamide and/or Abiraterone Acetate/Prednisone)
    Uomini con difetti nella riparazione del DNA e cancro alla prostata metastatico resistente alla castrazione cancro che ha già ricevuto chemioterapia a base di tassani e hanno proseguito il trattamento con almeno 1 nuovo agente ormonale (enzalutamide e / o abiraterone acetato /prednisone)
    E.1.1.1Medical condition in easily understood language
    Prostate cancer
    Cancro alla prostata
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate cancer metastatic
    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 evaluate the efficacy of single agent talazoparib in DNA damage repair (DDR) + metastatic CRPC, as measured by best objective response rate (ORR).
    Valutare l’efficacia di talazoparib in monoterapia nel CRPC metastatico positivo a deficit nella riparazione dei danni al DNA (DDR), misurata in base al tasso di risposta obiettiva (ORR) migliore.
    E.2.2Secondary objectives of the trial
    To evaluate efficacy with respect to the following parameters:
    -Time to objective response;
    -Duration of response;
    -Proportion of patients with prostate-specific antigen (PSA) decrease = 50%;
    -Proportion of patients with conversion of circulating tumor cell (CTC) count;
    -Time to PSA progression;
    -Radiographic progression-free survival (PFS);
    -Overall survival.
    To evaluate the safety of talazoparib in this patient population.
    To evaluate the following patient-reported outcomes:
    -Time to deterioration in pain as assessed by the Brief Pain Inventory Short Form (BPI-SF);
    -Change from baseline in pain per BPI-SF;
    -Change from baseline in general health status as assessed by the European Quality of Life 5-Domain 5-Level Scale (EQ-5D-5L).
    To evaluate the pharmacokinetics (PK) of talazoparib
    Valutare l’efficacia in riferimento ai seguenti parametri:
    -tempo alla risposta obiettiva;
    -durata della risposta;
    -percentuale di pazienti con riduzione dell’antigene prostatico specifico (PSA) =50%;
    -percentuale di pazienti con conversione della conta di cellule tumorali circolanti (CTC);
    -tempo alla progressione del PSA;
    -sopravvivenza libera da progressione (PFS) all’esame radiografico;
    -sopravvivenza complessiva.
    Valutare la sicurezza di talazoparib in questa popolazione di pazienti.
    Valutare i seguenti esiti riferiti dal paziente:
    -tempo al deterioramento nel dolore valutato per mezzo del Modulo abbreviato del Breve inventario del dolore (BPI-SF);
    -variazione rispetto al basale nel dolore valutato mediante il BPI-SF;
    -variazione rispetto al basale nello stato di salute generale valutato mediante il Questionario europeo sulla qualità della vita a 5 domini e 5 livelli (EQ 5D 5L).
    Per valutare la farmacocinetica (PK) di talazoparib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.For patients who are at least 18 years of age, there must be evidence of a personally signed and dated informed consent document indicating
    that the patient has been informed of all pertinent aspects of the study.
    2.Histologically or cytologically confirmed adenocarcinoma of the prostate without signet cell, or small cell features. Histologic confirmation may be based on a de novo tumor biopsy obtained for
    purposes of screening. Biopsies of the brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus,
    stomach, or bowel may not be performed for the sole purpose of determining study eligibility.
    3.Patients must have measurable soft tissue disease per RECIST1.1.
    4.DNA damage repair gene alterations likely to sensitize to PARP inhibition (DDR positive) as determined by:
    •Prospective testing of de novo or archival tumor tissue (via central laboratory) or prior historical (with Sponsor preapproval) testing of tumor tissue using the Foundation Medicine, FoundationOne® NGS gene panel test;
    Archival or de novo tumor tissue also should be submitted prior to Day 1 if possible to support concordance analyses and additional molecular
    profiling.
    5.Unless prohibited by local regulations or ethics committee (EC) decision, consent to a saliva sample collection for retrospective sequencing of DDR genes used to assess patient eligibility based on
    tumor tissue, and to serve as a germline control in identifying tumor mutations.
    6.Serum testosterone = 1.73 nmol/L (50 ng/dL) at screening.
    7.Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or
    medical castration).
    8.Progressive disease at study entry defined as 1 or more of the following 3 criteria:
    •A minimum of 3 rising PSA values with an interval of at least 1 week between determinations. The screening central laboratory PSA value must be = 2 µg/L (2 ng/mL) if qualifying solely by PSA progression.
    •Soft tissue disease progression as defined by RECIST 1.1.
    •Bone disease progression defined by PCWG3 with 2 or more new metastatic lesions on bone scan.
    9.Metastatic disease. Patients whose only evidence of metastasis is measurable soft tissue disease below the aortic bifurcation will be acceptable. Neither bone metastases on bone scan nor non- measurable soft tissue disease alone will qualify a patient.
    10.Previous treatment with 1 or 2 chemotherapy regimens including at least 1 taxane based regimen for metastatic (non castrate or castrate) prostate cancer. Patients may have received radium 223 and/or cabazitaxel, or were deemed unsuitable, declined, or did not have access to these therapies.
    11.Documented disease progression (either radiographic or biochemical) on at least 1 novel hormonal therapy (enzalutamide and/or abiraterone
    acetate/prednisone) for the treatment of metastatic CRPC, irrespective of prior NHT treatment for non castrate prostate cancer or nonmetastatic
    (M0) CRPC.
    12.Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before day 1 for patients receiving these therapies.
    13.ECOG performance status of 0 to 2.
    14.Estimated life expectancy of = 6 months as assessed by the investigator. ect
    1.Per i pazienti che hanno almeno 18 anni di età, devono esserci prove di un documento di consenso informato datatao e firmato personalmente che indica che il paziente sia stato informato di tutti gli aspetti pertinenti dello studio
    2.Adenocarcinoma della prostata confermato istologicamente o citologicamente senza cellule con castone o caratteristiche di piccole cellule. La conferma istologica può essere basata su una biopsia tumorale fresca ottenuta per scopi di screening. Biopsie del cervello, polmone / mediastino,pancreas o procedure endoscopiche che si estendono oltre l'esofago, lo stomaco o l’intestino non possono essere eseguite per il solo scopo di
    determinazione dell’idoneità allo studio.
    3. I pazienti dovranno presentare malattia misurabile a livello dei tessuti molli secondo la versione 1.1 dei Criteri di valutazione della risposta nei tumori solidi (RECIST 1.1).
    4. Difetti nel riparo dei danni del DNA che probabilmente rende suscettibili all’inibizione di PARP (DDR positivo), valutato mediante:
    - Test prospettici del tessuto tumorale fresco o tessuto da archivio (dal laboratorio centralizzato) o il il precedente test storico di tessuto tumorale (con preapprovazione dello sponsor) mediante il panello di test di Foundation Medicine, FoundationOne® NGS;
    Il tessuto tumorale d’archivio o quello fresco deve essere presentato prima del Day 1,
    se possibile, per sostenere analisi in accordo e profiling molecolare addizionale.
    5. Consenso alla raccolta del campione di saliva per il sequenziamento retrospettivo dei geni DDR usato per valutare l’eleggibilità del paziente basata sul tessuto tumorale, e a servire come un comparatore di tipo germinale nell’identificazione delle mutazioni tumorali, a meno che non sia proibito dalle normative locali o dalla decisione del comitato etico.
    6.Testosterone sierico = 1,73 nmol/l (50 ng/dl) allo screening.
    7. Orchiectomia bilaterale o terapia di deprivazione androgenica in corso con un agonista/antagonista del GnRH (castrazione chirurgica o medica).
    8. Progressione della malattia al momento dell’ingresso nello studio definita come 1 o più dei 3 criteri seguenti:
    • Un minimo di 3 valori di PSA in aumento con un intervallo di almeno 1 settimana tra le misurazioni. Il valore di PSA ottenuto allo screening dal laboratorio centrale deve essere = 2 µg/l (2 ng/ml) se ammesso soltanto in base alla progressione del PSA.
    • Progressione della malattia dei tessuti molli definita in base ai criteri RECIST 1.1.
    • Progressione della malattia ossea definita in base ai criteri PCWG3 con 2 o più nuove lesioni metastatiche individuate dalla scintigrafia ossea.
    9. Patologia metastatica
    Saranno accettabili i pazienti la cui evidenza di metastasi è una malattia misurabile dei tessuti molli sotto la biforcazione aortica. Nè metastasi ossee nella scansione ossea nè solo la malattia non misurabile dei tessuti molli qualificherà un paziente.
    10.Precedente trattamento con 1 o 2 regimi chemioterapici, compreso almeno 1 regime a base di tassani per il carcinoma prostatico metastatico. I pazienti devono aver ricevuto radio-223 e/o cabazitaxel, oppure essere stati considerati non adatti, aver rifiutato o non aver avuto accesso a queste terapie.
    11.Documentata progressione della malattia (o radiografica o biochimica) con almeno 1 nuova terapia ormonale (enzalutamide e/o abiraterone acetato/prednisone) per il trattamento del CRPC, indipendentemente dal precedente trattamento NHT per cancro alla prostata non castrato o CRPC (M0) non metastatico.
    12. Per i pazienti che ricevono queste terapie, il dosaggio di bifosfonati o denosumab deve essere rimasto stabile per almeno 4 settimane prima del giorno 1.
    13. Stato prestazionale ECOG compreso tra 0 e 2.
    14. Aspettativa di vita stimata = 6 mesi come valutata dallo Sperimentatore. ect
    E.4Principal exclusion criteria
    1.Use of systemic chemotherapeutic (including but not limited to taxanes), hormonal, biologic, or radionuclide therapy for treatment of metastatic prostate cancer (other than approved bone targeting agents and GnRH agonist/antagonist) or any other investigational agent within 4 weeks before day 1.
    2.Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone chemotherapy. Patients who discontinued prior platinum
    based chemotherapy = 6 months prior to screening or whose disease previously progressed on platinum based therapy at any time in the past are also excluded.
    3.Treatment with any concurrent cytotoxic chemotherapy or investigational drug(s) within 4 weeks or 5 half lives of the drug (whichever is longer) before Day 1 and/or during study participation.
    4.Radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) before day 1.
    5.Major surgery within 2 weeks before day 1.
    6.Clinically significant cardiovascular disease, including any of the following:
    •Myocardial infarction or symptomatic cardiac ischemia within 6 months before screening.
    •Congestive heart failure New York Heart Association class III or IV.
    •History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1 year before screening.
    •History of Mobitz II second degree or third degree heart block unless a permanent pacemaker is in place.
    •Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening.
    •Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening electrocardiogram.
    •Uncontrolled hypertension as indicated by systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening.
    7.Significant organ dysfunction as defined by any one of the following laboratory abnormalities:
    •Renal: eGFR < 30 mL/min /1.73 m2 by the MDRD equation (Modification of Diet in Renal Disease [available via www.mdrd.com]).
    •Hepatic:
    •Total serum bilirubin > 1.5 times the upper limit of normal (ULN) (> 3 × ULN for patients with Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation);
    •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) = 2.5 times ULN (if liver test abnormalities are due to hepatic metastasis,
    then AST or ALT = 5 × ULN);•Albumin < 2.8 g/dL.
    •Bone marrow reserve: absolute neutrophil count < 1500/µL, platelets < 100,000/µL, or hemoglobin < 9 g/dL (NOTE: may not have received growth factors or blood transfusions within 14 days before obtaining the hematology values at screening).
    8.Known or suspected brain metastasis or active leptomeningeal disease.
    9.Symptomatic or impending spinal cord compression or cauda equina syndrome.
    10.Diagnosis of myelodysplastic syndrome.
    11.History of another cancer within 3 years before enrollment with the exception of nonmelanoma skin cancers, or American Joint Committee on Cancer stage 0 or stage 1 cancer that has a remote probability of recurrence in the opinion of the investigator and the sponsor.
    12.Gastrointestinal disorder affecting absorption, etc.
    1. Uso di terapia sistemica ormonale, biologica o con radionuclidi per il trattamento del carcinoma prostatico metastatico (a meno che non si tratti di agenti approvati che agiscono in maniera mirata sull’osso e di agonisti/antagonisti di GnRH) o di qualsiasi altro agente sperimentale nelle 4 settimane che precedono il giorno 1.
    2. Trattamento pregresso con un inibitore di PARP, con chemioterapia a base di platino, ciclofosfamide o mitoxantrone. Sono anche esclusi pazienti che hanno interrotto la precendente chemioterapia a base di platino 6 mesi prima dello screening o la cui malattia ha precedentemente mostrato progressione alla terapia a base di platino in qualsiasi momento nel passato.
    3. Terapia con concomitante chemioterapia citotossica o farmaco sperimentale entro 4 settimane o 5 emivite del farmaco (a seconda del periodo più lungo) prima del 1 ° giorno e / o durante la partecipazione allo studio.
    4.Radiazione terapia entro 3 settimane (entro 2 settimane, se singola frazione di radioterapia) prima del giorno 1.
    5. chirurgia maggiore entro 2 settimane prima del giorno 1.
    6. Malattia cardiovascolare clinicamente significativa, compreso uno qualsiasi dei seguenti eventi:
    -Infarto miocardico o ischemia cardiaca sintomatica nei 6 mesi che precedono lo screening.
    - Insufficienza cardiaca congestizia di classe III o IV in base alla New York Heart Association.
    -Anamnesi di aritmie ventricolari clinicamente significative (come tachicardia ventricolare sostenuta, fibrillazione ventricolare o torsioni di punta) entro un anno prima dello screening.
    -Anamnesi di blocco cardiaco di tipo Mobitz II di secondo o terzo grado, a meno che non sia stato impiantato un pacemaker permanente.
    -Ipotensione indicata da una pressione sanguigna sistolica < 86 mmHg allo screening.
    -Bradicardia indicata da battito cardiaco < 45 battiti al minuto sull’elettrocardiogramma di screening.
    -Ipertensione non controllata indicata da una pressione sanguigna sistolica > 170 mmHg o pressione sanguigna diastolica > 105 mmHg allo screening.
    7. Significativa disfunzione d’organo definita da una qualsiasi delle seguenti anomalie di laboratorio:
    Renale: eGFR < 30 ml/min /1,73 m2 secondo l’equazione della Modifica della dieta nella malattia renale (MDRD [disponibile tramite www.mdrd.com]).
    Epatica:
    – Bilirubina sierica totale > 1,5 volte il limite superiore della norma (ULN) (> 3 volte l’ULN per i pazienti con sindrome di Gilbert o nei quali le concentrazioni di bilirubina indiretta suggeriscono una causa extraepatica di incremento)
    – Aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) = 2,5 volte l’ULN (se le anomalie dei test sul fegato sono dovute a metastasi epatica, allora AST o ALT = 5 volte l’ULN)
    – Albumina < 2,8 g/dl
    -Riserva di midollo osseo: conta assoluta dei neutrofili < 1.500/µl, piastrine < 100.000/µl o emoglobina < 9 g/dl (NOTA: i pazienti possono non aver ricevuto fattori di crescita o trasfusioni di sangue nei 14 giorni precedenti l’ottenimento dei valori ematologici allo screening).
    8. Metastasi cerebrale nota o sospetta o malattia leptomeningea attiva.
    9. Compressione della spina dorsale sintomatica o imminente oppure sindrome della cauda equina.
    10. Diagnosi di sindrome mielodisplastica (SMD).
    11. Anamnesi di un altro tumore nei 3 anni precedenti l’arruolamento, ad eccezione di tumori cutanei non melanoma, o tumore di stadio 0 o 1 secondo l’American Joint Committee on Cancer (Lega americana contro il cancro) che, secondo l’opinione dello sperimentatore e dello sponsor, ha una probabilità remota di recidivare.
    12. Disturbo gastrointestinale che comporta conseguenze sull’assorbimento, etc.
    E.5 End points
    E.5.1Primary end point(s)
    Best objective response rate (ORR).The proportion of patients with a best overall soft tissue response of CR or PR per RECIST 1.1
    Miglior tasso di risposta obiettiva.
    La percentuale di pazienti con la migliore risposta complessiva a livello di tessuti molli della RC o RP valutata secondo i criteri RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint analysis will be performed when the last enrolled patient completes at least 6 months of study drug treatment, withdraws consent, discontinues from the study, or dies, whichever occurs first.
    L'analisi endpoint primario sarà eseguita quando l'ultimo paziente arruolato completa di almeno 6 mesi di trattamento il farmaco in studio, ritira il consenso, interrompe dallo studio, o muore, a seconda di quale evento si verifica prima.
    E.5.2Secondary end point(s)
    - Time to objective response
    - Duration of response
    - Proportion of patients with conversion of CTC count
    - Time to PSA progression
    -Tempo di risposta obiettiva
    - La durata della risposta
    - Percentuale di pazienti con conversione della conta delle CTC
    - Tempo alla progressione del PSA
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Time to objective response: time from enrollment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3.
    - Duration of response: time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST 1.1 by independent central review and no evidence of confirmed bone disease
    progression per PCWG3 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occurs first.
    -CTC assessment at weeks 1,9,17,25, safety follow up
    -PSA assessment at weeks 1,9,13,17,21,25, safety follow up
    - Tempo di risposta obiettiva: tempo dall' arruolamento alla prima prova oggettiva della risposta dei tessuti molli con nessuna evidenza di progressione della malattia ossea confermato sulla scintigrafia ossea per PCWG3.
    - La durata della risposta: tempo dalla prima evidenza oggettiva di risposta dei tessuti molli (successivamente confermata) per RECIST 1.1 da revisione centrale indipendente e nessuna evidenza di progressione di malattia ossea confermata per PCWG3 alla prima successiva obiettiva evidenza di progressione radiografica o di morte per qualsiasi causa, a seconda di quale si verifica prima.
    - valutazione CTC alle settimane 1,9,17,25, follow up di sicurezza
    - valutazione PSD alle settimane 1,9,13,17,21,25, follow up di sicurezza
    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
    Exploratory biomarker assessments: Sufficient fresh or archival tumor tissue must be submitted at prescreening (optional) or screening for whole exome sequencing, homologous recombination deficiency (HRD) analysis, and transcriptome studies. Blood samples for germline DNA sequencing will be collected at prescreening (optional) or screening.
    Blood samples for circulating tumor cells (CTC), circulating tumor DNA (ctDNA), and protein biomarker analyses will be collected throughout the study.
    Saliva
    Valutazioni dei biomarker esplorativi: una sufficiente quantità di tessuto tumorale fresco o di archiviazione deve essere presentata al prescreening (opzionale) o lo screening per il sequenziamento dell'intero esoma, l’analisi carenza di ricombinazione omologa (HRD), e studi del trascrittoma. I campioni di sangue per il sequenziamento del DNA germinale saranno raccolti al prescreening (opzionale) o allo screening.
    Nel corso dello studio saranno raccolti i campioni di sangue per le cellule tumora
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA61
    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
    Australia
    Belgium
    Canada
    France
    Germany
    Italy
    Netherlands
    New Zealand
    Spain
    United Kingdom
    United States
    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 years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 100
    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
    nessuno
    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 Decision2016-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-30
    P. End of Trial
    P.End of Trial StatusOngoing
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