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    Summary
    EudraCT Number:2015-000814-23
    Sponsor's Protocol Code Number:CLDK378A2407
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-03-01
    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 number2015-000814-23
    A.3Full title of the trial
    A Phase II, open label, multi-center, multi-arm study of ceritinib in patients with advanced solid tumors and hematological malignancies characterized by genetic abnormalities of anaplastic lymphoma kinase (ALK)
    Studio di Fase II, in aperto, multicentrico, con bracci
    multipli, con ceritinib in pazienti con tumori solidi in stadio avanzato e neoplasie ematologiche caratterizzate da alterazioni genetiche della chinasi del linfoma anaplastico (ALK)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study evaluating ceritinib in tumors with ALK genetic abnormalities
    Studio clinico per valutare ceritinib in tumori caratterizzati da alterazioni genetiche di ALK
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberCLDK378A2407
    A.5.4Other Identifiers
    Name:-Number:-
    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 SponsorNOVARTIS PHARMA SERVICES AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA S.p.A
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityORIGGIO
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number0296541
    B.5.5Fax number029659066
    B.5.6E-mailinfo.studiclinici@novartis.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 Yes
    D.2.1.1.1Trade name Zykadia
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNceritinib
    D.3.9.2Current sponsor codeLDK378
    D.3.9.4EV Substance CodeSUB130802
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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 and hematological malignancies with ALK genetic alteration and/or overexpression
    Tumori solidi in stadio avanzato e neoplasie ematologiche caratterizzate da alterazione genetica e/o sovraespressione di ALK
    E.1.1.1Medical condition in easily understood language
    Specific tumors that are characterized by ALK genetic alteration (and/or overexpression in some diseases)
    Tumori specifici che sono caratterizzati da alterazione genetica (e / o sovraespressione in alcune patologie) di ALK
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067917
    E.1.2Term Inflammatory myofibroblastic tumour
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10006205
    E.1.2Term Breast carcinoma inflammatory
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10018337
    E.1.2Term Glioblastoma multiforme
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073478
    E.1.2Term Anaplastic large-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the antitumor activity of ceritinib as measured by DCR determined by investigators
    Valutare l’attività antitumorale mediante il tasso di controllo della malattia (DCR), in base alla valutazione locale dello sperimentatore.
    E.2.2Secondary objectives of the trial
    - To assess the antitumor activity of ceritinib as measured by ORR, DOR,
    TTR as determined by investigators
    - To assess the antitumor activity of ceritinib as measured by PFS
    determined by investigators
    - To assess the safety and tolerability of ceritinib.
    - Valutare l’attività antitumorale di ceritinib, misurata mediante ORR, DOR, TTR, determinati dagli sperimentatori. - Valutare l’attività antitumorale di ceritinib misurata mediante la PFS determinata dagli sperimentatori. - Valutare la sicurezza d’impiego e la tollerabilità di ceritinib.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Written informed consent for the main study obtained prior to any screening procedure.
    - Patient must have a histologically or cytologically confirmed diagnosis of one of the tumors that is ALK positive (ALK+). The ALK test results must be available at the investigator site before the first dose of the study drug. The tumor types are described below:
    Anaplastic Large Cell Lymphoma (ALCL), local confirmation of diagnosis of ALK+ ALCL is sufficient for eligibility.
    Inflammatory Myofibroblastic Tumor locally documented translocation involving the ALK gene,
    Glioblastoma, Inflammatory breast cancer Any other locally documented ALK+ tumor. Must carry a locally documented genetic alteration of ALK including any of the following (ALK overexpression is also acceptable in Gliobalstoma):
    - A known activating mutation in the kinase domain of ALK or a point mutation in the kinase domain of ALK that results in an amino acid change that has not been reported in normal germline DNA, or any other mutation (e.g. insertion or deletion) which results in a change in the amino acid sequence of the kinase domain of ALK, as long as the alteration does not clearly result in inactivation of the kinase activity, such as deletion of the kinase domain, or a stop codon preventing translation of the kinase
    domain.
    - An amplification of the ALK gene, defined as ≥ 6 copies per cell, or 3 copies per haploid genome. When assessed by FISH, ALK amplification must be observed in focal clusters of tumor cells (not only single cells) or in more than one-third of the tumor cells.
     - A translocation involving the ALK gene.
    - Glioblastoma patients only, overexpression of ALK protein documented locally is also acceptable for eligibility
    - Patient must provide an archival or fresh tumor tissue before the first dose of the study drug for potential retrospective ALK testing at a Novartis designated central laboratory by a comparative technology: the confirmation of ALK positivity is not required for enrollment if other inclusion and exclusion criteria are fulfilled
    - Patient is 18 years or older at the time of informed consent.
    - Patient has WHO performance status ≤ 2.
    - Patient has at least one measurable lesion as defined by appropriate guidelines. A lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation
    Other protocol related inclusion criteria may apply
    - Consenso informato scritto dello studio principale ottenuto prima di qualsiasi procedura di screening.
    - Pazienti con diagnosi confermata dall’esame istologico o citologico, di uno dei tumori che sia ALK positivo (ALK+). I risultati della valutazione di ALK devono essere disponibili per lo sperimentatore presso il centro prima della somministrazione della prima dose del farmaco in studio. I tipi di tumore sono descritti di seguito:
    Linfoma anaplastico a grandi cellule (ALCL): la conferma locale della diagnosi di ALCL ALK+ è sufficiente per l’eleggibilità.
    Tumore infiammatorio miofibroblastico: traslocazione che coinvolge il gene ALK documentata a livello locale.
    Glioblastoma multiforme, carcinoma mammario infiammatorio, qualsiasi altro tumore ALK+ documentato a livello locale devono presentare un’alterazione genetica di ALK documentata a livello locale che comprende qualsiasi dei seguenti (nel glioblastoma multiforme è anche accettabile la sovraespressione di ALK):
    • Una mutazione nota nel dominio della chinasi di ALK o una mutazione puntiforme nel domino della chinasi di ALK che risulti in una modifica di un aminoacido che non è stata riportata nel normale DNA germinale o qualsiasi altra mutazione (per esempio inserzione o delezione) che risulti in una modifica di una sequenza amminoacidica del dominio della chinasi di ALK, fino a quando l’alterazione non risulti chiaramente in inattivazione dell’attività della chinasi, quale delezione del dominio della chinasi o un codone di terminazione che previene la traslazione del dominio della chinasi.
    • Un’amplificazione del gene ALK, definita come ≥ 6 copie per cellula o 3 copie per genoma aploide. Quando valutata mediante FISH, l’amplificazione di ALK deve essere osservata in cluster focali di cellule tumorali (non solamente in cellule singole) o in più di 1/3 delle cellule tumorali.
    • Una traslocazione che coinvolge il gene ALK.
    • Solamente nei pazienti con glioblastoma multiforme, una sovraespressione della proteina ALK (per l’eleggibilità è anche accettabile la documentazione locale).
    - I pazienti devono fornire un campione di tessuto tumorale archiviato o fresco prima della somministrazione della prima dose del trattamento in studio per una possibile valutazione retrospettiva di ALK presso un laboratorio centralizzato designato da Novartis, mediante una tecnologia comparativa:
    • La conferma della positività di ALK non è richiesta per l’arruolamento se altri criteri di esclusione e inclusione sono soddisfatti.
    - Pazienti con età uguale o superiore a 18 anni al momento del consenso informato.
    - World Health Organization (WHO) performance Status ≤ 2.
    - I pazienti devono presentare almeno una lesione misurabile, definita in base alle linee guida appropriate. Una lesione a una sede precedentemente irradiata può essere calcolata solo come una lesione target se vi è un chiaro segno di progressione dal momento dell’irradiazione.
    Vedere il protocollo per ulteriori criteri
    E.4Principal exclusion criteria
    1. Patient with ALK+ lung cancer.
    2. Patient with known hypersensitivity to any of the excipients of LDK378.
    3. Patient with symptomatic CNS metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
    4. History of carcinomatous meningitis.
    5. Patient with diarrhea CTCAE ≥ grade 2; or patients with neuropathy CTCAE ≥ grade 2
    Other protocol related exclusion criteria may apply.
    1. Pazienti con carcinoma polmonare ALK+.
    2. Pazienti con ipersensibilità nota a qualsiasi degli eccipienti di LDK378.
    3. Pazienti con metastasi sintomatiche del sistema nervoso centrale (SNC) che non sono stabili dal punto di vista neurologico o che hanno richiesto dosi crescenti di corticosteroidi entro le 2 settimane precedenti l’ingresso nello studio, per gestire i sintomi del SNC.
    4. Evidenza pregressa di meningite carcinomatosa.
    5. Pazienti con diarrea di grado CTCAE ≥ 2 oppure pazienti con neuropatia di grado CTCAE ≥ 2.
    Vedere il protocollo per ulteriori criteri
    E.5 End points
    E.5.1Primary end point(s)
    DCR, defined as the proportion of patients with best overall response of CR, PR, or SD ≥ 16 weeks
    DCR viene definita come la percentuale di pazienti con miglior risposta globale di CR, PR, o SD a 16 settimane dall’inizio del trattamento
    E.5.1.1Timepoint(s) of evaluation of this end point
    at week 16
    a 16 settimane
    E.5.2Secondary end point(s)
    1. ORR, defined as the proportion of patients with a best overall response defined as CR or PR; (CR+PR)
    2. The following endpoints will be evaluated by investigator assessment:
    – DOR, defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause
    - TTR, defined as the time from date of the first dose to date of first documented response (CR or PR)
    – PFS, defined as time from date of the first dose to date of first documented disease progression or date of death due to any cause
    3. ECG, Performance status, Vital signs, Physical examination; AEs, and laboratory (hematology, biochemistry, urinalysis, coagulation,pregnancy test and hormones (males only)
    1. ORR, definita come la percentuale di pazienti con miglior risposta globale definita come CR o PR
    2. I seguenti endpoints saranno valutati sulla base della valutazione dello sperimentatore:
    - DOR definita come il tempo dalla data della prima CR o PR documentata alla data della prima progressione di malattia documentata o la data del decesso dovuto a ogni causa
    -TTR, definita come il tempo dalla data della prima dose alla data delle prima risposta (CR o PR) documentata
    - PFS, definita come il tempo dalla data della prima dose alla data della prima progressione di malattia o la data del decesso dovuto ad ogni causa.
    3. • Eventi avversi seri
    • Profilo degli esami di laboratorio
    • Ematologia
    • Biochimica
    • Esame urine
    • Test di coagulazione
    • Test di gravidanza (femmine)
    • Valutazioni ormonali (solo maschi)
    • Esame obiettivo
    • Segni vitali
    • Elettrocardiogrammi (ECG)
    • WHO Performance status
    E.5.2.1Timepoint(s) of evaluation of this end point
    at week 16
    a 16 settimane
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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 trial5
    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 EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belgium
    Czech Republic
    Denmark
    France
    Germany
    Israel
    Italy
    Korea, Democratic People's Republic of
    Netherlands
    Spain
    Sweden
    Switzerland
    Thailand
    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
    The study will end approximately 38 weeks after the last patient treated in the study or once at least 75% of patients have died or have been lost to follow-up.

    Novartis may continue to supply ceritinib to patients who may benefit from continued treatment as per the Investigator’s opinion.
    Lo studio si concluderà circa 38 settimane dopo l'ultimo paziente trattato nello studio o quando almeno il 75% dei pazienti sarà deceduto o perso al follow-up.
    Novartis può continuare a fornire ceritinib per i pazienti che possono trarre beneficio dal trattamento continuato secondo il parere dello sperimentatore.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    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 months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 31
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 106
    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 Decision2017-04-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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