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    EudraCT Number:2015-005117-72
    Sponsor's Protocol Code Number:AG120-C-005
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-01-20
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-005117-72
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects with Nonresectable or Metastatic Cholangiocarcinoma with an IDH1 Mutation
    Studio di Fase 3, multicentrico, randomizzato, in doppio cieco, controllato con placebo su AG-120 in pazienti precedentemente trattati affetti da colangiocarcinoma non resecabile o metastatico con una mutazione di IDH1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study to test for efficacy of an oral investigational drug, AG-120, in patients with nonresectable or metastatic cholangiocarcinoma with an IDH1 mutation
    Studio di Fase 3 per valutare l'efficacia di un farmaco sperimentale per uso orale, AG-120, in pazienti affetti da colangiocarcinoma non resecabile o metastatico con una mutazione di IDH1
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAG120-C-005
    A.5.4Other Identifiers
    Name:IND NumberNumber:131191
    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.1.3.4CountryUnited 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 supportAgios Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAgios Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDirector, Scientific Communications
    B.5.3 Address:
    B.5.3.1Street Address88 Sidney Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018332288474
    B.5.5Fax number0019014323977
    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 nameAG-120
    D.3.2Product code [AG-120]
    D.3.4Pharmaceutical form 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 INNivosidenib
    D.3.9.1CAS number 1448347-49-6
    D.3.9.2Current sponsor codeAG-120
    D.3.9.4EV Substance CodeSUB130391
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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. cell therapy medicinal product Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Nonresectable or Metastatic Cholangiocarcinoma
    Colangiocarcinoma non resecabile o metastatico
    E.1.1.1Medical condition in easily understood language
    Cancer of the bile duct that has metastasized or can't be removed with surgery
    Carcinoma del dotto biliare metastatizzato o che non può essere asportato chirurgicamente
    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 LLT
    E.1.2Classification code 10077846
    E.1.2Term Cholangiocarcinoma metastatic
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10008594
    E.1.2Term Cholangiocarcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of AG-120 based on progression-free survival (PFS) per Independent Radiology Center (IRC) assessment compared to placebo in subjects with nonresectable or metastatic cholangiocarcinoma with an isocitrate dehydrogenase 1 (IDH1) mutation.
    Dimostrare l'efficacia di AG-120 in base alla sopravvivenza libera da progressione (PFS) secondo la valutazione del Centro radiologico indipendente (IRC) rispetto al placebo in soggetti affetti da colangiocarcinoma non resecabile o metastatico con una mutazione dell'isocitrato deidrogenasi 1 (IDH1).
    E.2.2Secondary objectives of the trial
    - To evaluate the safety and tolerability of AG-120 compared to placebo.
    - To evaluate PFS per Investigator assessment.
    - To compare the efficacy of AG-120 with placebo based on overall survival (OS), objective response rate (ORR), duration of response (DOR), and time to response (TTR), with response assessed per the Investigator and by the IRC.
    - To evaluate health related quality of life (HRQOL) with AG-120 compared to placebo as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-BIL21), the Patient Global Impression of Change (PGI-C), and the Patient Global Impression of Severity (PGI-S).
    - To evaluate health economic outcomes as assessed by the EQ-5D-5L instrument.
    - To evaluate the pharmacokinetics (PK) of AG-120.
    - To evaluate the PK/pharmacodynamic (PD) relationship of AG-120 and 2-hydroxyglutarate (2-HG) in blood samples.
    - Stabilire la sicurezza e la tollerabilità di AG-120 rispetto al placebo.
    - Valutare la PFS secondo la valutazione dello sperimentatore.
    - Confrontare l'efficacia di AG-120 con placebo in base alla sopravvivenza globale (OS), il tasso di risposta obiettiva (ORR), la durata della risposta (DOR), e il tempo alla risposta (TTR), con valutazione della risposta da parte dello sperimentatore e dell'IRC.
    - Valutare la qualità della vita correlata allo stato di salute (HRQOL) con AG-120 rispetto al placebo in base ai Questionari sulla qualità della vita redatti dall'Organizzazione europea per la ricerca e il trattamento del cancro (EORTC QLQ-C30 e EORTC QLQ-BIL21), l'Impressione globale di cambiamento del paziente (PGI-C) e l'Impressione globale di gravità del paziente (PGI-S).
    - Valutare gli esiti economico-sanitari in base allo strumento EQ-5D-5L.
    - Valutare la farmacocinetica (PK) di AG-120.
    - Valutare il rapporto PK/PD di AG-120 e 2-idrossiglutarato (2 HG) in campioni di sangue.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Be =18 years of age
    2. Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably collected within the last 3 years) consistent with nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation, or ablative therapies.
    3. Have documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent banked tumor tissue available) based on central laboratory testing (R132C/L/G/H/S mutation variants tested).
    4. Have an ECOG PS score of 0 or 1
    5. Have an expected survival of >=3 months.
    6. Have at least one evaluable and measurable lesion as defined by RECIST v1.1. Subjects who have received prior local therapy (including but not limited to embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or within the field and has shown =20% growth in size since post-treatment assessment.
    7. Have documented disease progression following at least 1 and no more than 2 prior systemic regimens for advanced disease (nonresectable or metastatic), with progression on the treatment that was most recently given at a minimum. Subjects must have received at least 1 gemcitabine- or 5-FU-containing regimen for advanced cholangiocarcinoma. Systemic adjuvant chemotherapy will be considered a line of treatment if there is documented disease progression during or within 6 months of completing the therapy.
    8. Have recovered from toxicities associated with prior anticancer therapy to baseline unless stabilized under medical management.
    9. Have adequate bone marrow function as evidenced by:
    a. Absolute neutrophil count >=1,500/mm^3 or 1.5 ×109/L
    b. Hemoglobin >=8 g/dL
    c. Platelets >=100,000/mm^3 or 100 × 109/L
    10. Have adequate hepatic function as evidenced by:
    a. Serum total bilirubin =2 × upper limit of normal (ULN), unless considered due to Gilbert’s disease
    b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=5 × ULN
    11. Have adequate renal 11. function as evidenced by:
    a. Serum creatinine <1.5 × ULN
    b. Creatinine clearance >=50 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine
    12. Be able to understand and willing and able to sign the informed consent and comply with scheduled visits, treatment plans, procedures and laboratory tests including serial peripheral blood sampling and urine sampling, during the study.
    13. Female subjects with reproductive potential must have a negative serum pregnancy test prior to the start of therapy, or a confirmation from an obstetrician in case of equivocal serum pregnancy results. Females of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated) for at least 24 consecutive months (i.e., have not had menses at any time in the preceding 24 consecutive months). Women of reproductive potential, as well as fertile men and their partners who are female with reproductive potential, must agree to abstain from sexual intercourse or to use a highly 2 effective forms of contraception (including at least one barrier form) from the time of giving informed consent throughout the study and for 90 days (both females and males) following the last dose of study drug. Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone releasing systems, bilateral tubal ligation, condoms with spermicide or male partner sterilization.
    1. Età > =18 anni
    2. Presentare una diagnosi istopatologica (campione di biopsia tumorale archiviato o nuovo, preferibilmente prelevato negli ultimi 3 anni) coerente con colangiocarcinoma non resecabile o metastatico e non essere eleggibili a resezione curativa, trapianto o terapie ablative.
    3. Presentare malattia documentata con mutazione del gene IDH1 (da nuova biopsia del tumore o dal più recente tessuto tumorale archiviato disponibile) sulla base delle analisi del laboratorio centrale (analisi delle varianti della mutazione R132C/L/G/H/S).
    4. Presentare un punteggio di PS ECOG di 0 o 1 (Appendice 15.1 del Protocollo).
    5. Presentare una sopravvivenza prevista >=3 mesi.
    6. Presentare almeno una lesione valutabile e misurabile come definita secondo i criteri RECIST v1.1. I soggetti che hanno ricevuto una precedente terapia locale (inclusa a titolo d'esempio embolizzazione, chemioembolizzazione, ablazione con radiofrequenza, oppure radioterapia) sono eleggibili a condizione che la malattia misurabile sia al di fuori o all'interno dall'ambito del trattamento e abbia presentato una crescita della dimensione di >=20% dalla valutazione post-trattamento.
    7. Presentare progressione della malattia documentata a seguito di almeno 1 e non più di 2 precedenti regimi sistemici per malattia in stadio avanzato (non resecabile o metastatica) con progressione durante il trattamento più recentemente somministrato ad un dosaggio minimo. I soggetti devono aver ricevuto almeno 1 regime contenente gemcitabina o 5-FU per il colangiocarcinoma in stadio avanzato. La chemioterapia adiuvante sistemica sarà considerata una linea di trattamento qualora vi sia progressione della malattia documentata durante o entro 6 mesi dal completamento della terapia.
    8. Essersi ristabiliti dalla tossicità associata alla terapia antitumorale alla baseline, salvo stabilizzazione sotto gestione medica.
    9. Presentare funzionalità del midollo osseo adeguata dimostrata da:
    a. Conta assoluta dei neutrofili >=1.500/mm3 o 1,5×109/L
    b. Emoglobina >=8 g/dL
    c. Piastrine >= 100.000/mm3 o 100 × 109/L
    10. Presentare funzionalità epatica adeguata dimostrata da:
    a. Bilirubina sierica totale <=2 volte il limite superiore della norma (ULN), salvo se si ritiene che sia imputabile alla sindrome di Gilbert
    b. Aspartato aminotransferasi (AST) e alanina aminotransferasi (ALT) <=5 x ULN
    11. Presentare funzionalità renale adeguata dimostrata da:
    a. Creatinina nel siero <1,5 × ULN
    b. Clearance della creatinina >=50 mL/min sulla base del calcolo di stima della filtrazione glomerulare (GFR) mediante la formula di Cockroft-Gault:
    (140 - età) X (peso in kg) X (0,85 per le donne)/72 X creatinina nel siero
    12. Essere in grado di comprendere e avere la volontà ed essere in grado di firmare il consenso informato e di attenersi al programma di visite dello studio, piani di trattamento, procedure e analisi di laboratorio, inclusi prelievo di sangue periferico in serie e raccolta delle urine, durante lo studio. Un rappresentante legalmente autorizzato può esprimere il consenso per conto di un soggetto non in grado di fornire il proprio consenso informato, se ritenuto accettabile e approvato dal Comitato di Revisione Istituzionale (IRB)/Comitato Etico Indipendente (IEC) del centro.
    13. I soggetti di sesso femminile in età fertile devono presentare un test di gravidanza su siero negativo prima di iniziare la terapia, o una conferma da parte di ostetrico in caso di risultati equivoci del test di gravidanza su siero.
    E.4Principal exclusion criteria
    1. Received a prior IDH inhibitor.
    2. Received systemic anticancer therapy or investigational agent <2 weeks prior to Day 1 (washout from prior immune based anticancer therapy is 4 weeks). In addition, the first dose of study treatment should not occur before a period =5 half-lives of the investigational agent has elapsed.
    3. Received radiotherapy to metastatic sites of disease <2 weeks prior to Day 1.
    4. Underwent hepatic radiation, chemoembolization, and radiofrequency ablation <4 weeks prior to Day 1.
    5. Have known symptomatic brain metastases requiring steroids. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, havediscontinued corticosteroid treatment for these metastases for at least 4 weeks and have radiographically stable disease for at least 3 months prior to study entry. Note: up to 10 mg per day of prednisone equivalent will be allowed.
    6. Have a history of another primary cancer, with the exception 6. of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid or liquid tumor with no known active disease present that, in the opinion of the Investigator, will not affect subject outcome in the setting of current cholangiocarcinoma diagnosis.
    7. Underwent major surgery within 4 weeks of Day 1 or have not recovered from postsurgery toxicities.
    8. Are pregnant or breastfeeding.
    9. Are taking known strong CYP3A4 inducers or inhibitors, or sensitive CYP3A4 substrate medications, unless they can be transferred to other medications with a narrow therapeutic window unless they can be transferred to other the medications within =5 half-lives prior to dosing.
    10. Exclusion criterion 10 deleted from Amendment 4 to the protocol, version 5.0
    11. Have an active infection requiring systemic anti-infective therapy or with an unexplained fever >38.5°C within 7 days of Day 1 (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
    12. Have any known hypersensitivity to any of the components of AG-120 or the matched placebo.
    13. Have significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction; unstable angina; and/or stroke.
    14. Have LVEF <40% by ECHO scan (or by other methods according to institutional practice) obtained within 28 days prior to the start of study treatment.
    15. Have a heart-rate corrected QT interval (using Fredericia’s formula) (QTcF) >=450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Bundle branch block and prolonged QTcF interval are permitted with approval of the Medical Monitor.
    16. Are taking medications that are known to prolong the QT interval, unless they can be transferred to other medications within =5 half-lives prior to dosing or unless the medications can be properly monitored during the study. (If equivalent medication is not available, QTcF should be closely monitored.)
    17. Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS) related illness. Subjects with a sustained viral response to HCV or immunity to prior HBV infection will be permitted. Subjects with chronic HBV that is adequately suppressed per institutional practice will be permitted.
    1.Somministrazione di precedente inibitore di IDH.
    2.Somministrazione di terapia sistemica antitumorale o di un agente sperimentale <2 settimane prima del Giorno 1 (il washout dall'immunoterapia antitumorale precedente è di 4 settimane). Inoltre, la prima dose di trattamento in studio non dovrà essere somministrata prima che sia trascorso un periodo di >=5 emivite dell'agente sperimentale.
    3.Essersi sottoposti a radioterapia mirata ai siti metastatici della malattia <2 settimane prima del Giorno 1.
    4.Essersi sottoposti a irradiazione epatica, chemioembolizzazione, ablazione con radiofrequenza <4 settimane prima del Giorno 1.
    5.Presentare metastasi cerebrali sintomatiche note che richiedono steroidi. I soggetti con metastasi cerebrali diagnosticate in precedenza sono eleggibili se hanno completato il loro trattamento e si sono ristabiliti dagli effetti acuti della radioterapia o dell'intervento chirurgico prima dell'ingresso nello studio, hanno interrotto il trattamento con corticosteroidi per tali metastasi da almeno 4 settimane e presentano malattia stabile radiologicamente documentata da almeno 3 mesi prima dell'ingresso nello studio. Nota: saranno ammessi fino a 10 mg al giorno di equivalente di prednisone.
    6.Presentare anamnesi di altro tumore primario, ad eccezione di: a) carcinoma cutaneo non melanomatoso asportato a finalità curative; b) carcinoma cervicale in situ trattato in modo curativo; oppure c) altro tumore solido o liquido primario in assenza di malattia attiva nota che, a giudizio dello sperimentatore, non influenzerà l’esito del paziente in caso di diagnosi attuale di colangiocarcinoma.
    7.Essersi sottoposti a intervento chirurgico importante entro 4 settimane dal Giorno 1 o non essersi ristabiliti dalle tossicità post-intervento.
    8.Essere in gravidanza o in fase di allattamento.
    9.Assumere forti induttori noti del CYP3A4 o farmaci che sono substrati sensibili del CYP3A4 e che hanno una finestra terapeutica ristretta, a meno che non possano essere trasferiti ad altri farmaci entro >=5 emivite prima della somministrazione della dose.
    10. Criterio di esclusione 10 eliminato nell’Emendamento 4 al protocollo, Versione 5.0
    11.Presentare infezione attiva che richiede terapia sistemica anti-infettiva o con febbre ingiustificata >38,5°C entro 7 giorni dal Giorno 1 (a discrezione dello sperimentatore, i soggetti con febbre tumorale possono essere arruolati).
    12.Presentare nota ipersensibilità ad uno dei componenti di AG-120 o al placebo corrispondente.
    13.Presentare malattia cardiaca attiva significativa nei 6 mesi precedenti l'inizio del trattamento in studio, compresi insufficienza cardiaca congestizia di classe III o IV secondo la New York Heart Association (NYHA); infarto miocardico e angina instabile; e/o ictus.
    14.Presentare LVEF <40% misurata mediante ECHO (o altri metodi in base alla prassi istituzionale) ottenuta nei 28 giorni precedenti l'inizio del trattamento in studio.
    15.Presentare un intervallo QT per la frequenza cardiaca corretto (secondo la formula di correzione di Fridericia) (QTcF) >=450 ms o altri fattori che aumentano il rischio di prolungamento dell'intervallo QT o di eventi di aritmia (ad es. insufficienza cardiaca, ipocalcemia, anamnesi familiare di sindrome del QT lungo). Il blocco di branca e un intervallo QTcF prolungato sono ammessi con approvazione del Medical Monitor.
    16.Assumere farmaci che sono noti per prolungare l'intervallo QT , a meno che possano essere trasferiti ad altri farmaci entro >=5 emivite prima dell'inizio della somministrazione o a meno che i farmaci possano essere adeguatamente monitorati durante lo studio. (Se non è disponibile un farmaco equivalente, il QTcF dovrà essere attentamente monitorato.)
    22. Anamnesi medica nota di leucoencefalopatia multifocale progressiva (PML)
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS, the time from date of randomization to date of first documented disease progression (as assessed by the IRC per RECIST v1.1), or date of death due to any cause.
    L'endpoint primario è la PFS, il tempo dalla data di randomizzazione alla data della prima progressione della malattia documentata (come valutato dall'IRC in base ai criteri RECIST v1.1), o alla data del decesso per qualsiasi causa.
    E.5.1.1Timepoint(s) of evaluation of this end point
    ongoing basis from randomization until progression of disease or death
    in modo continuo dalla randomizzazione fino alla progressione della malattia o al decesso
    E.5.2Secondary end point(s)
    AEs, SAEs, AEs leading to discontinuation or death. Safety laboratory parameters, vital signs, 12-lead ECGs, evaluation of left ventricular ejection fraction (LVEF), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and concomitant medications. Secondary efficacy endpoints include: - OS, defined as the time from date of randomization to date of death. - ORR, defined as the proportion of subjects with a best overall response defined as CR or PR - DOR, defined as the time from date of first documented complete response (CR) or partial response (PR) to date of first documented disease progression or death due to any cause - PFS as determined by the Investigator. - TTR, defined as the time from date of randomization to date of first documented CR or PR for responders, as assessed by the Investigator and by the IRC per RECIST v1.1. Quality of Life as assessed by validated instruments. Health economic outcomes as assessed by the EQ-5D-5L instrument. Serial or sparse blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters of AG-120. Blood sampling at specified time points for determination of 2-HG levels to characterize the PD effects of AG-120.
    AE, SAE, AE che portano all'interruzione o al decesso.
    Parametri di laboratorio di sicurezza, funzioni vitali, ECG a 12 derivazioni, valutazione della frazione di eiezione ventricolare sinistra (LVEF), stato di performance (PS) in base all'Eastern Cooperative Oncology Group (ECOG) e farmaci concomitanti.
    Gli endpoint di efficacia secondari comprendono:
    - OS, definita come il tempo dalla data della randomizzazione alla data del decesso.
    - ORR, definito come la percentuale di soggetti che presentano la migliore risposta globale, definita come CR o PR
    - DOR, definito come il tempo trascorso dalla data della prima risposta completa (CR) o risposta parziale (PR) documentata alla data della prima progressione della malattia documentata o decesso per qualsiasi causa
    - PFS come determinata dallo sperimentatore.
    - TTR, definito come il tempo dalla data di randomizzazione alla data della prima CR o PR documentata per i responder, in base alla valutazione dello sperimentatore e dell'IRC secondo i criteri RECIST v1.1.
    Qualità della vita, in base a valutazione condotta mediante strumenti convalidati.
    Esiti economico-sanitari in base a valutazione condotta mediante lo strumento EQ-5D-5L.
    Campionamento di sangue ridotto o in serie in corrispondenza di punti temporali specificati per la determinazione dei profili di tempo-concentrazione plasmatica e dei parametri PK di AG-120.
    Campionamento di sangue in corrispondenza di punti temporali specificati per la determinazione dei livelli di 2-HG per caratterizzare gli effetti di AG-120 sulla PD.
    E.5.2.1Timepoint(s) of evaluation of this end point
    D1, D15 and D28 of each cycle
    end of treatment
    safety follow-up
    G1, G15 e G28 di ciascun ciclo
    fine del trattamento
    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 No
    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 No
    E.6.11Pharmacogenomic Yes
    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. 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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
    Korea, Republic of
    United States
    United Kingdom
    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
    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 months2
    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 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.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 86
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 103
    F.4.2.2In the whole clinical trial 186
    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)
    Patients are released into Standard of Care
    I pazienti iniziano il trattamento standard di cura
    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 Decision2017-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-11
    P. End of Trial
    P.End of Trial StatusCompleted
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