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    Summary
    EudraCT Number:2016-003616-13
    Sponsor's Protocol Code Number:TPX-0005-01
    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:2020-11-23
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-003616-13
    A.3Full title of the trial
    A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients with Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
    Uno studio multicentrico, in aperto, di fase 1/2, condotto per la prima volta sugli esseri umani per valutare la sicurezza, la tollerabilità, la farmacocinetica e l’attività antitumore di TPX-0005 in pazienti con tumori solidi in stadio avanzato che ospitano riarrangiamenti dei geni ALK, ROS1 o NTRK1-3 (TRIDENT-1)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1/2 Open Label solid tumor Safety and Tolerability study.
    Studio di fase 1/2 in aperto per valutare la sicurezza e la tollerabilità nei pazienti con tumori solidi
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberTPX-0005-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03093116
    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 SponsorTurning Point Therapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTurning Point Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTurning Point Therapeutics, Inc.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address10628 Science Center Dr #200
    B.5.3.2Town/ citySan Diego
    B.5.3.3Post codeCA 92121
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018589255857
    B.5.6E-mailmelissa.langston@tptherapeutics.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 nameRepotrectinib
    D.3.2Product code [TPX-0005]
    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.3.8INN - Proposed INNrepotrectinib
    D.3.9.1CAS number 1802220-02-5
    D.3.9.2Current sponsor codeTPX-0005
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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
    advanced solid tumors
    tumori solidi in stadio avanzato
    E.1.1.1Medical condition in easily understood language
    Cancer
    tumore
    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 10065252
    E.1.2Term Solid tumor
    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
    Phase 2 Study
    • To determine the confirmed Objective Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
    Studio di fase 2
    • Determinare e confermare il tasso di risposta oggettiva (ORR) di repotrectinib per tutte le popolazioni di soggetti con tumori a uno stadio avanzato, con riarrangiamento dei geni ALK, ROS1, NTRK1, NTRK2, NTRK3, in ogni coorte di espansione, valutato mediante revisione centrale indipendente in cieco (BICR).
    E.2.2Secondary objectives of the trial
    Phase 2 Study
    •To determine the Duration of Response (DOR), time to response (TTR), and clinical benefit rate (CBR) of repotrectinib, as assessed by BICR.
    • To estimate the progression-free survival (PFS) and overall survival (OS) of subjects treated with repotrectinib with advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
    • To evaluate the safety and tolerability of repotrectinib when administered at the RP2D in subjects with advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
    • To determine the intracranial objective response rate (IC-ORR) of repotrectinib and Central Nervous System PFS (CNS-PFS) in subjects presenting with measurable brain metastases at baseline, using modified RECIST v1.1 assessment.
    • To confirm PK of repotrectinib at the RP2D.
    • To assess treatment-related symptoms and general health status using validated instruments
    Studio di fase 2
    •DetermLaDurataDellaRisp(DOR),ilTempoDiRisp(TTR)EIlTassoDiRispDelBenefClinico(CBR)diRepotrectinib,PerTutteLePopDiSoggConTumInStadioAvanz,conRiarrDeiGeniALK,ROS1,NTRK1,NTRK2,NTR3,inOgniCoorteDiEspans,valutatiMedianteBICR.
    •StimareLaSopravvSenzaProgrDiMalattia(PFS)eLaSopravvComplessiva(OS)deiSoggTrattatiCon RepotrectinibConTumSolidiInStadioAvanz,conRiarrDeiGeniALK,ROS1.NTRK1,NTRK2,NTRK3.
    •ValutareLaSicELaTollerabDelDosaggioDiRepotrectinibRaccomPerLaFase2(RP2D)suSoggConTumSolidiInStadioAvanz,conRiarrangiamDeiGeniALK,ROS1,NTRK1,NTRK2,NTRK3.
    •DetermIlTassoDiRispObiettivaIntracranica(IC-ORR)DiRepotrectinibELaSopravvivSenzaProgrDiMalattiaDelSistNervCentrale(CNS-PFS)suSoggChePresentanoMetastasiCerebraliMisurabiliAllaVisitaBasale,valutateSecICriteriRECISTv1.1aggiornat.
    •ConfermLaPKDiRepotrectinibAllaRP2D.
    •ValutareISintomiRelativiAlTrattamELoStatoDiSaluteGeneraleDeiSoggTrattatiConRepotrectinib,misurando i risultati ottenuti con strum approv (EORTC-QLQ-C30 e LC-13, se appl).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) that harbors a ROS1, ALK or NTRK1-3 gene fusion.
    - Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either:
    a) a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibility.
    b) a fluorescence in situ hybridization (FISH) test AND prospective confirmation of fusion status by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment will be accepted to determine molecular eligibility.
    - Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all inclusion and exclusion criteria are met:
    EXP-1: ROS1 TKI-naïve ROS1+ NSCLC (n=55).
    • No prior exposure to a ROS1 TKI is allowed.
    • Up to one prior line of chemotherapy OR immunotherapy is allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment).
    EXP-2: 1 Prior ROS1 TKI ROS1+ NSCLC (n=100).
    • Disease progression, unresponsive, or intolerant to one prior line of a ROS1 TKI.
    • ROS1 TKIs used in a prior line of treatment are limited to crizotinib, ceritinib, entrectinib, or lorlatinib. Note: Any previous exposure to a ROS1 TKI is considered as one prior line of TKI treatment (e.g., if the same ROS1 TKI was given before and after a chemotherapy or other systemic therapy, it is considered as 2 prior TKIs and the subject would not be eligible for EXP-2).
    • Up to one prior line of chemotherapy OR immunotherapy before or after a ROS1 TKI is allowed (chemo- or immunotherapy-based ombination regimen is considered as one line of treatment).

    EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (n=40).
    • Disease progression, unresponsive, or intolerant to 2 prior lines of a ROS1 TKI treatment.
    • ROS1 TKIs used in prior lines of treatment are limited to crizotinib, ceritinib, entrectinib, lorlatinib, brigatinib, ensartinib, or cabozantinib. Other prior ROS1 TKI agents that are not listed may be allowed after discussion with the Sponsor Medical Monitor. Note: Any previous exposure to a ROS1 TKI is considered as one prior line of TKI treatment (e.g., if 2 different ROS1 TKIs are utilized, or the same ROS1 TKI was given before and after a chemotherapy or other systemic therapy, it is considered as 2 prior TKIs and the subject would be eligible).
    • Up to one prior line of chemotherapy OR immunotherapy pre-TKI or post-TKI is allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment).
    EXP-4: ROS1 or ALK TKI-naïve ROS1+ or ALK+ solid tumors (non-NSCLC) (n=12-26).
    • No prior exposure to a ROS1 or ALK TKI is allowed.
    • Up to 2 prior lines of chemo or immunotherapy are allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment).
    EXP-5: TRK TKI-naïve NTRK+ solid tumors (n=55).
    • No prior exposure to a TRK TKI is allowed.
    • Any number of prior lines of chemo or immunotherapy is allowed.
    EXP-6: TRK TKI-pretreated NTRK+ solid tumors (n=40).
    • Disease progression, unresponsive, or intolerant to 1 or 2 prior TRK TKIs.
    • TRK TKIs used in prior lines of treatment are limited to entrectinib, larotrectinib, or LOXO-195. Other prior TRK TKIs that are not listed may be allowed after discussion with the Sponsor Medical Monitor. Note: Any previous exposure of a TRK TKI is considered as one prior line of TKI treatment, (e.g., if 2 different TRK TKIs are utilized or the same TRK TKI was used before and after a chemo- or other systemic therapy, it is counted as 2 prior TKIs and the subject would be eligible).
    • Any number of prior lines of chemo- or immunotherapy are allowed.

    please see protocol page 83 for the full inclusion criteria.
    Criteri di inclusione per la Fase 2:
    -Diagnosi citologica o istologica che confermi la presenza di un tumore solido locale in stadio avanzato o metastatico (inclusi tumori del Sistema nervoso centrale) con fusione genica di ROS1, ALK o NTRK1-3.
    -I soggetti devono presentare una fusione genica di ROS1 o NTRK1-3 determinata
    da test locali basati sui tessuti utilizzando:
    a) un test di sequenziamento di prossima generazione (NGS) o di reazione quantitativa a catena della polimerasi (qPCR) sarà accettato per determinare l'idoneità molecolare.
    b) sarà accettato un test di ibridazione in situ a fluorescenza (FISH) E sarà confermata l'eventuale conferma dello stato di fusione mediante un test di laboratorio diagnostico centrale selezionato dallo sponsor PRIOR per l'iscrizione per determinare l'idoneità molecolare.
    - I soggetti con tumori solidi in stadio avanzato, con riarrangiamento dei geni ROS1, NTRK1, NTRK2, NTRK3 verranno assegnati a 6 diverse coorti di espansione (ESP), purché soddisfino tutti i requisiti necessari:
    ESP-1: ROS1 TKI-naïve ROS1+ NSCLC (n=55).
    •Non è ammessa alcuna precedente esposizione a ROS1 TKI.
    •Sono ammessi i soggetti che si siano sottoposti a un ciclo di chemioterapia O immunoterapia (i regimi di chemioterapia o immunoterapia combinati vengono considerati come un ciclo unico).
    ESP-2: 1 Precedente ROS1 TKI ROS1+ NSCLC (n=100).
    •Progressione della malattia, mancata responsività o intolleranza a un precedente ciclo di trattamento di ROS1 TKI.
    •ROS1 TKI utilizzato in un precedente ciclo di trattamento limitato a crizotinib, ceritinib, entrectinib o lorlatinib. Nota: Qualsiasi precedente esposizione a ROS1 TKI viene considerata come un ciclo di trattamento con TKI (per esempio, se il soggetto ha già ricevuto ROS1 TKI prima e dopo la chemioterapia o un’altra terapia sistemica, si considerano due cicli di TKI e pertanto il soggetto non è idoneo a ESP-2).
    •Sono ammessi i soggetti che si siano sottoposti a un ciclo di chemioterapia O immunoterapia prima o dopo l’assunzione di ROS1 TKI (i regimi di chemioterapia o immunoterapia combinati vengono considerati come un ciclo unico).
    ESP-3: 2 Precedenti ROS1 TKI ROS1+ NSCLC (n=40).
    •Progressione della malattia, mancata responsività o intolleranza a due precedenti cicli di trattamento con ROS1 TKI.
    •ROS1 TKI utilizzati in due precedenti cicli di trattamento limitati a crizotinib, ceritinib, entrectinib, lorlatinib, brigatinib, ensartinib o cabozantinib. Potrebbero essere ammessi altri trattamenti con ROS1 TKI non elencati in precedenza, previa discussione con il Medical Monitor del Promotore.
    •Sono ammessi i soggetti che si siano sottoposti a un ciclo di chemioterapia O immunoterapia pre o post TKI (i regimi di chemioterapia o immunoterapia combinati vengono considerati come un ciclo unico).
    ESP-4: ROS1 o ALK TKI-naïve ROS1+ or ALK+ tumori solidi (non-NSCLC) (n=12-26).
    •Non è ammessa alcuna precedente esposizione a ROS1 o ALK TKI.
    •Sono ammessi i soggetti che si siano sottoposti a un massimo di 2 cicli di chemioterapia o immunoterapia (i regimi di chemioterapia o immunoterapia combinati vengono considerati come un ciclo unico).
    ESP-5: TRK TKI-naïve NTRK+ tumori solidi (n=55).
    •Non è ammessa alcuna precedente esposizione a TRK TKI.
    •Sono ammessi i soggetti che si siano sottoposti a un numero qualsiasi di cicli di chemio o immunoterapia.
    ESP-6: TRK TKI-pre trattati NTRK+ tumori solidi (n=40).
    •Progressione della malattia, non responsività o intolleranza a 1 o 2 trattamenti precedenti con TRK TKI.
    •TRK TKI utilizzati in precedenti cicli di trattamento limitati a entrectinib, larotrectinib o LOXO-195. Potrebbero essere ammessi altri trattamenti precedenti con TRK TKI non elencati in precedenza, previa discussione con il Medical Monitor del Promotore.
    •Sono ammessi i soggetti che si siano sottoposti a un numero qualsiasi di cicli di chemio o immunoterapia.
    Si prega di vedere la pagina 83 del protocollo per la lista completa dei criteri di inclusione
    E.4Principal exclusion criteria
    1. Concurrent participation in another therapeutic clinical trial.
    2. Symptomatic brain metastases or leptomeningeal involvement.
    3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the skin, or any in situ carcinoma that has been completely resected, requiring therapy within the previous 2 years.
    4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative radiation (=10 fractions) must have been completed at least 48 hours prior to study entry.
    5. Clinically significant cardiovascular disease (either active or within 6 months prior to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class = II), cerebrovascular accident or transient ischemic attack, symptomatic
    bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of CTCAE grade =2.
    6. Any of the following cardiac criteria:
    • Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec)
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
    7. Known active infections requiring ongoing treatment (bacterial, fungal, viral including human immunodeficiency virus positivity).
    8. Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
    9. Peripheral neuropathy, paresthesia, dizziness, dysgeusia, muscle weakness, ataxia grade =2.
    10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior radiation pneumonitis are not excluded.
    11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study, or could compromise protocol objectives in the opinion of the Investigator and/or Turning Point Therapeutics.
    12. Current use or anticipated need for drugs that are known to be strong CYP3A inhibitors or inducers as listed in Appendix 5 of the protocol.
    1. Partecipazione a un altro studio clinico terapeutico concomitante.
    2. Metastasi cerebrali sintomatiche o coinvolgimento leptomeningeo.
    3. Precedenti di cancro che abbiano richiesto un trattamento terapeutico nei 2 anni precedenti, fatta eccezione per i carcinomi della pelle a cellule squamose o a cellule basali, o di qualsiasi altro carcinoma in situ rientrato completamente.
    4. Intervento chirurgico nelle prime 4 settimane di trattamento con repotrectinib. Radioterapia (ad eccezione della terapia palliativa del dolore da metastasi ossee) nelle prime 2 settimane dall’arruolamento nello studio. Le radiazioni palliative (=10 frazioni) devono essere state completate entro le 48 ore precedenti l’inizio dello studio.
    5. Malattie importanti a carico del sistema cardiovascolare (in corso o verificatesi entro i 6 mesi precedenti all’arruolamento): Infarto miocardico, angina instabile, bypass aorto-coronarico o periferico, insufficienza cardiaca congestizia sintomatica (classificazione della New York Heart Association Classification: Classe = II), accidente cerebrovascolare o attacco ischemico transitorio, brachicardia sintomatica, necessità di assumere farmaci antiaritmici. Disritmia cardiaca in corso con CTAE di grado = 2.
    6.Uno dei seguenti criteri cardiaci di esclusione:
    •Intervallo QT medio corretto a riposo (intervalli misurati con ECG dall'inizio del complesso QRS al termine dell’onda T) con frequenza cardiaca (QTc) > 470 ms, ottenuto con 3 ECG, con l’utilizzo del valore QTc ottenuto dall’ECG dello screening clinico.
    • Qualsiasi anomalia clinicamente rilevante del ritmo, della conduzione cardiaca o morfologia con ECG a riposo (per esempio: blocco di branca sinistro, blocco atrioventricolare di II o III grado, intervallo PR > 250 ms)
    • Qualsiasi fattore che aumenti il rischio del prolungamento del QTc o il rischio di aritmie, insufficienza cardiaca, ipokalemia, sindrome congenita del QT lungo, precedenti familiari di sindrome congenita del QT lungo o terapie farmacologiche concomitanti che causino allungamento dell’intervallo QT.
    7. Infezioni in corso note e in trattamento (batteriche, fungine, virali, inclusi soggetti HIV positivi).
    8. Malattia gastrointestinale (morbo di Crohn, colite ulcerosa o sindrome dell’intestino corto) o altre sindromi da malassorbimento che potrebbero influenzare l’assorbimento del farmaco.
    9. Neuropatia periferica, parestesia, vertigine, disgeusia, debolezza muscolare, atassia di grado =2.
    10. Precedenti di fibrosi interstiziale diffusa, disseminata, bilaterale con grado = 3 o 4 del CTCAE, interstiziopatia polmonare con precedenti di polmonite, polmonite ipersensibile, polmonite interstiziale, interstiziopatia polmonare, bronchiolite obliterante e fibrosi polmonare. Sono ammessi i soggetti con precedenti di polmonite da radiazioni.
    11. Altri disturbi clinici o psichiatrici cronici gravi o anomalie di laboratorio che concorrano ad aumentare i rischi associati alla partecipazione allo studio o alla somministrazione del farmaco in studio, o che potrebbero interferire con l’interpretazione dei risultati dello studio e che, a giudizio dello Sperimentatore, renderebbero il soggetto non idoneo all’arruolamento in questo studio o che, secondo il parere dello Sperimentatore o di Turning Point Therapeutics, potrebbero compromettere il raggiungimento degli obiettivi del protocollo.
    12. Utilizzo presente o passato di medicinali noti come forti inibitori o induttori di CYP3A, tra cui quelli elencati nell’ Appendice 5 del protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint for Phase 2:
    • Objective Response Rate (ORR) assessed by BICR using RECIST v1.1.
    Endpoint primario della Fase 2:
    • Tasso di risposta oggettiva (ORR) valutato con BICR utilizzando RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    The ORR will be defined as the proportion of subjects with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat-imaging performed at least 4 weeks after initial documentation of response. Subjects with a confirmed objective response (CR or PR) will be referred to as responders. Non-responders will include subjects without a confirmed objective response, SD, or PD.
    The ORR will be reported as the proportion of responders along with the corresponding 2-sided 95% Clopper-Pearson exact CI.
    For the EXP-4 cohort using Simon’s two -stage design, the confidence interval will be calculated using exact confidence interval based on method proposed by Shan (Shan, 2018).
    Il tasso di risposta oggettiva (ORR) sarà definito come la proporz di sogg con una risposta completa (CR) o risposta parziale (PR) confermata. Una risposta confermata è una risposta che persiste su un imaging ripetuto eseguito almeno 4 settimane dopo la docum iniziale della risposta. I soggetti con una risp obiettiva confermata (CR o PR) saranno indicati come responder. I non-responder includeranno i sogg senza una risp obiettiva conferm, SD o PD.
    La proporz dei paz rispondenti e l'interv di confidenza bilaterale al 95% usando il metodo di Clopper-Pearson verranno usati per descrivere l'ORR.
    Per la coorte EXP-4 che utilizza il design a due stadi di Simon, l'intervallo di confidenza sarà calcolato utilizzando l'interv di confidenza esatto basato sul metodo proposto da Shan (Shan, 2018).
    E.5.2Secondary end point(s)
    Secondary Endpoints for Phase 2:
    • Duration of Response (DOR), Time to Response (TTR), and Clinical Benefit Rate (CBR)
    • Intracranial tumor response in subjects with measurable brain metastases, as determined by BICR using modified RECIST v1.1
    • CNS Progression-Free Survival (CNS-PFS) in subjects with measurable brain metastases using modified RECIST v1.1
    • Progression-Free Survival (PFS), and OS
    • Type, incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities
    • Pharmacokinetic parameters of repotrectinib
    • Pharmacokinetic parameters of midazolam (midazolam DDI sub-study only)
    • Changes in Quality-of-life and health status during repotrectinib treatment
    Endpoint secondario della Fase 2:
    • Durata della risposta (DOR), Tempo di risposta (TOR) e tasso di risposta del beneficio clinico (CBR)
    • Risposta del tumore intracranico in soggetti con metastasi cerebrali misurabili, valutate con BICR utilizzato il RECIST v1.1 aggiornato.
    • Sopravvivenza senza progressione del CNS in soggetti con metastasi cerebrali misurabili, utilizzando RECIST v1.1 aggiornato
    • Sopravvivenza senza progressione (PFS) e sopravvivenza totale (OS)
    • Tipo, incidenza, acutezza, tempo di manifestazione, gravità e interdipendenza tra EA e anomalie di laboratorio.
    • Parametri farmacocinetici di repotrectinib
    • Parametri farmacocinetici di midazolam (solo sottostudio sull’interazione farmaco-farmaco (DDI) di Midazolam)
    • Cambiamenti nella qualità della vita e nello stato di salute durante il trattamento con repotrectinib
    E.5.2.1Timepoint(s) of evaluation of this end point
    13.2.2.2.1 Duration of Response (DOR)
    The DOR will be defined from the first date of objective response (either CR or PR) to first documentation of radiographic disease progression, as assessed by RECIST v1.1. The DOR will be censored at the last tumor assessment date for subjects without disease progression who have not died within 28 days of the last dose of study treatment.
    The DOR will only be calculated for the subgroup of subjects with a confirmed objective tumor response. The DOR will be summarized in the populations of subjects with a confirmed CR or PR using the Kaplan-Meier method and will be displayed graphically where appropriate. The median event time (if appropriate) and 2-sided 95% CI for the median will be provided.

    see protocol page 185-186 for more details.
    13.2.2.2.1 Durata della risposta (DOR)
    La DOR sarà definita dalla prima data della risp obiettiva (CR o PR) alla prima docum della progr radiografica della malattia, come da RECIST v1.1. La DOR sarà censurata all'ultima data di valut del tumore per i sogg senza progr della malattia che non sono deceduti entro 28 giorni dall'ultima dose del trattamento in studio.
    La DOR verrà calcolata solo per il sottogruppo di sogg con una risp obiettiva del tumore confermata. La DOR sarà riassunta nelle popolaz di sogg con CR o PR confermate utilizzando il metodo Kaplan-
    Meier e verrà visualizzata graficamente liddove applic. Saranno forniti il tempo mediano dell'evento (se applic) e l'interv di confidenza bilaterale al 95% per la mediana.
    Si prega di vedere il prot pagina 185-186 per maggiori dettagli.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    This is phase I /phase II study but only Phase II will be conducted in Italy. Phase I was not conduc
    Questo è uno studio di fase I/II, ma solo la fase II sarà condotta in Italia. La fase I non è stata
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    China
    Denmark
    France
    Germany
    Hong Kong
    Hungary
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Singapore
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 320
    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)
    Standard clinical practice
    Pratica clinica standard
    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 Decision2020-02-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-29
    P. End of Trial
    P.End of Trial StatusOngoing
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