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    Summary
    EudraCT Number:2016-004373-40
    Sponsor's Protocol Code Number:AveNEC
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-05-15
    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 ConcernedGermany - PEI
    A.2EudraCT number2016-004373-40
    A.3Full title of the trial
    A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab in patients with advanced, metastatic high grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after chemotherapy
    Eine offene, multizentrische Phase II-Studie zur Untersuchung der Wirksamkeit und Sicherheit von Avelumab bei Patienten mit fortgeschrittenem, metastasiertem, gering differenziertem Neuroendokrinem Karzinom NEC G3 (WHO), welches nach der Chemotherapie fortschreitet
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the clinical activity and safety of avelumab in patients with neuroendocrine carcinomas
    Eine Studie, mit der untersucht werden soll, welche Effekte der Wirkstoff Avelumab auf die Tumorerkrankung von Patienten mit neuroendokrinem Karzinom hat
    A.4.1Sponsor's protocol code numberAveNEC
    A.5.4Other Identifiers
    Name:Merck trial code Number:MS100070_0075
    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 SponsorUniversity Medical Center of the Johannes Gutenberg-University Mainz
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center of the Johannes Gutenberg-University Mainz
    B.5.2Functional name of contact pointUniv.-Prof. Dr. med. M. M. Weber
    B.5.3 Address:
    B.5.3.1Street AddressLangenbeckstr. 1
    B.5.3.2Town/ cityMainz
    B.5.3.3Post code55131
    B.5.3.4CountryGermany
    B.5.4Telephone number00496131177260
    B.5.5Fax number00496131175608
    B.5.6E-mailmmweber@uni-mainz.de
    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 Bavencio
    D.2.1.1.2Name of the Marketing Authorisation holderMerck KGaA
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameAvelumab
    D.3.2Product code MSB0010718C
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAVELUMAB
    D.3.9.3Other descriptive nameBavencio
    D.3.9.4EV Substance CodeSUB180078
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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, metastatic high grade neuroendocrine carcinomas NEC G3 (WHO 2010)
    fortgeschrittenes, metastasiertes, gering differenziertes Neuroendokrines Karzinom NEC G3 (WHO)
    E.1.1.1Medical condition in easily understood language
    neuroendocrine cancer
    neuroendokriner Krebs
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the clinical activity of avelumab as determined by the disease control rate (DCR) according to RECIST1.1 from start of study drug until documented disease progression (PD), assessed every 8 weeks for the first 6 month and every 12 weeks thereafter.
    Beurteilung der klinischen Aktivität von Avelumab anhand der Krankheitskontrollrate (DCR) nach RECIST1.1 von der ersten Gabe der Studienmediaktion bis zur dokumentierten Tumorprogression (PD), beurteilt alle 8 Wochen innerhalb der ersten 6 Monate und alle 12 Wochen danach
    E.2.2Secondary objectives of the trial
    To assess disease control rate (DCR) on other assessments
    To assess the objective response rate (ORR)
    To assess the best overall response (BOR)
    To assess the duration of disease control.
    To assess the progression-free survival time (PFS).
    To assess the overall survival (OS).
    To assess the time to response (TTR)
    To assess the quality of life (QoL).
    To evaluate the safety and tolerability.
    Exploratory objectives include assessment of subclassification of the NEC according to histomorphological differentiation and proliferation rate Ki67 (20-55 % vs. > 55%), changes from baseline in Chromogranin A (CgA) and Neuron specific enolase (NSE) levels, and evaluation of PD-L1 expression and the potential association of these factors
    with response rate, evaluation of tumor growth rate (TGR), and evaluation of Tumor response according to irRECIST.
    Bestimmung der Krankheitskontrollrate (DCR) zu anderen Einschätzungen
    Bestimmung der Gesamtansprechrate (ORR)
    Bestimmung des besten Ansprechens (BOR)
    Bestimmung der Dauer des Ansprechens
    Bestimmung des Progressionsfreien Überlebens (PFS)
    Bestimmung des Gesamtüberlebens (OS)
    Bestimmung der Zeit bis zum Ansprechen (TTR)
    Bestimmung der Lebensqualität (QoL)
    Bewertung der Sicherheit und Verträglichkeit
    Explorative Ziele beinhalten die Subklassifizierung der NEC anhand der immunhistochemischen Differenzierung und Proliferationsrate von Ki67 (20-55 % vs. > 55%), Änderungen des Gehaltes von Chromogranin A (CgA) und der Neuronenspezifischen Enolayse (NSE), Bestimmung der PD-L1-Expression und Bewertung möglicher Zusammenhänge dieser Faktoren mit der Ansprechrate, Bestimmung der Tumorwachstumsrate (TGR) und Bestimmung des Tumoransprechens nach irRECIST
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Male or female patient ≥ 18 years
    - Histologically proven neuroendocrine neoplasia NEC G3 (WHO 2010)
    - One block or 20 slides (4 microns) of archival tumor tissue to perform central pathological review and biomarker assessment
    - No curative option available
    - Progressive disease within 9 months before study initiation and after prior at least
    one chemotherapy (platinum based chemotherapy or STZ/TEM/DTIC based
    chemotherapy in NET G3)
    - Presence of measurable disease as per RECIST1.1 criteria
    - ECOG Performance Status 0 – 2
    - Written informed consent
    - Männliche oder weibliche Patienten ≥ 18 Jahre
    - Histologisch gesicherte neuroendokrine Neoplasie NEC G3 (WHO 2010)
    - Ein Block oder 20 Schnitte (4 Mikrometer) von Archiv-Tumorgewebe, um Biomarker-Untersuchungen durchzuführen
    - Keine Therapieoption mit Heilungsaussichten verfügbar
    - Progression innerhalb von 9 Monaten vor Studienbeginn und nach vorhergehender Chemotherapie (Platin-basierte Chemotherapie oder STZ/TEM/DTIC-basierte Chemotherapie bei NET (G3)
    - Vorliegen einer messbaren Erkrankung nach RECIST1.1-Kriterien
    - ECOG Performance Status 0 – 2
    - Unterschriebene Einwilligungserklärung
    E.4Principal exclusion criteria
    - Merkel Cell carcinoma (MCC) or small cell lung cancer (SCLC)
    - Typical or Atypical Carcinoid of the lung with a Ki67 < 20%
    - Prior therapy with any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints)
    - Neuroendocrine tumors that are potentially curable by surgery
    - Major surgery within 4 weeks of first dose of study medication.
    - TACE, TAE, SIRT or PRRT within 3 months of starting study treatment
    - Patients pretreated with Interferon as last treatment line prior to study entry
    - Concurrent anticancer treatment
    - active infection requiring systemic therapy including, HIV/AIDS, HBV or HCV
    - Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
    - Pregnancy or lactation
    - Vaccination within 4 weeks of the first dose of avelumab and while on trial
    - Merkelzellkarzinom (MCC) oder kleinzelliges Lungenkarzinom (SCLC)
    - Typisches oder Atypisches Karzinoid der Lunge mit Ki67 < 20%
    - Frühere Therapie mit einem Antikörper/Medikament welches gezielt T-Zell Ko-regulatorische Proteine beeinflußt (Immun-Checkpoint Inhibitoren)
    - Neuroendokrine Tumoren, welche durch eine Operation potentiell heilbar sind
    - Große Operation innerhalb von 4 Wochen vor der ersten Studienmedikationsgabe
    - TACE, TAE, SIRT oder PRRT innerhalb von 3 Monaten vor Start der Studienbehandlung
    - Patienten, welche mit Interferon als letzter Behandlungslinie vor Studienstart vorbehandelt worden sind
    - Andere Tumortherapie
    - Klinisch relevante akute oder chronische Infektionen, inklusive HIV, HBV oder HCV
    - Aktive Autoimmunerkrankung, welche sich verschlechtern könnte, wenn ein immunstimulierendes Agens gegeben wird
    - Schwangerschaft oder Stillen
    - Impfungen innerhalb von 4 Wochen vor der ersten Dosis von Avelumab und während der Studie
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the disease control rate (CR, PR, SD according to RECIST1.1) after 16 weeks of study treatment
    Das primäre Zielkriterium ist die Krankheitskontrollrate (CR, PR, SD nach RECIST) nach 16 Wochen Studienbehandlung
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 16 weeks of study treatment
    nach 16 Wochen Studienbehandlung
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints are:
    - Disease control rate (DCR) on other assessments
    - Objective response rate (ORR) on every assessment according to RECIST1.1
    - Best overall response (BOR) according to RECIST1.1
    - Duration of disease control and time to response (TTR) according to RECIST1.1
    - Median Progression-free survival time (PFS)
    - Overall survival (OS) and survival rate after 1 and 2 years
    - Quality of life (QoL) assessed by EORTC QLQ-C30 on every assessment
    - Number, severity, and duration of treatment-related AEs according to NCICTCAE v4.0
    The exploratory efficacy endpoints are:
    - histomorphological subclassification into NET G3 (differentiated morphology, ki67 20-55%) versus NEC G3 (small cell or large cell undifferentiated morphology and/or Ki67 > 55%)
    - Chromogranin A (CgA) and Neuron specific enolase (NSE) serum levels
    - PD-L1 expression measured by IHC or other established techniques
    - Tumor growth rate (TGR)
    - Disease control rate (DCR) according irRECIST
    Die sekundären Zielkriterien sind:
    - Krankheitskontrollrate (DCR) zu anderen Einschätzungen
    - Gesamtansprechrate (ORR) zu jeder Einschätzung nach RECIST1.1
    - Bestes Ansprechen (BOR) nach RECIST1.1
    - Dauer des Ansprechens und Zeit bis zum Ansprechen (TTR) nach RECIST1.1
    - Progressionsfreies Überleben (PFS)
    - Gesamtüberlebens (OS) und Überlebensrate nach 1 und 2 Jahren
    - Lebensqualität (QoL) ermittelt anhand EORTC-QLQ-C30 zu jeder Visite
    - Anzahl, Schwere und Dauer von behandlungsbedingten unerwünschten Ereignissen nach NCI-CTCAE v4.0
    Explorative Ziele sind:
    - Histomorphologische Unterteilung zwischen NET G3 (differenzierte Morphologie, Ki67 (20-55 %) und NEC G3 (kleinzellige oder großzellige undifferenzierte Morphologie und/oder Ki67 > 55%)
    - Chromogranin A (CgA) und Neuronenspezifischer Enolayse (NSE) Serumlevel
    - PD-L1-Expression gemessen anhand Immunhistochemie oder anderer etablierter Techniken
    - Tumorwachstumsrate TGR)
    - Krankheitskontrollrate (DCR) nach irRECIST
    E.5.2.1Timepoint(s) of evaluation of this end point
    DCR, ORR: on every assessment
    BOR: after 16, 24 weeks and 1 year
    TTR: after 1 year
    PFS: after 1 year
    OS and survival rate: after 1 and 2 year
    QoL: assessed on every assessment
    DCR, ORR: zum jeden Zeitpunkt des Tumorassessments
    BOR: nach 16 Wochen, nach 24 Wochen und 1 Jahr
    TTR: nach 1 Jahr
    PFS: nach 1 Jahr
    OS und Überlebensrate: nach 1 und 2 Jahren
    QoL: zu jeder Visite
    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 Yes
    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.8.3 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 concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Letzter Besuch des Letzten Patienten
    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 months9
    E.8.9.1In the Member State concerned 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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state60
    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)
    After the end of the trial the study drug will be discontinued. The patients will be treated according to best clinical practice.
    Nach Behandlungsende werden die Patienten gemäß gültigen Leitlinien am jeweiligen Prüfzentrum weiterbehandelt.
    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 Decision2017-08-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-18
    P. End of Trial
    P.End of Trial StatusOngoing
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