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    Summary
    EudraCT Number:2017-001207-68
    Sponsor's Protocol Code Number:KKSH140
    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:2018-01-03
    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 number2017-001207-68
    A.3Full title of the trial
    A multicenter single-arm pilot study of ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors
    Multizentrische, einarmige Pilotstudie zu Ramucirumab in Kombination mit Dacarbazin bei Patienten mit progredienten, gut differenzierten metastasierten pankreatischen neuroendokrinen Tumoren
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the efficacy of ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic neuroendocrine tumors of the pancreas
    Studie zur Untersuchung der Wirksamkeit von Ramucirumab in Kombination mit Dacarbazin bei Patienten mit neuroendokrinen, fortgeschrittenen Tumoren der Bauchspeicheldrüse, welche eventuell schon Absiedlungen (Metastasen) gebildet haben.
    A.3.2Name or abbreviated title of the trial where available
    RamuNet
    RamuNet
    A.4.1Sponsor's protocol code numberKKSH140
    A.5.4Other Identifiers
    Name:German Clinical Trial RegisterNumber:DRKS00014689
    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 SponsorMartin-Luther-Universität Halle-Wittenberg
    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 supportLilly Deutschland GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinikum Halle
    B.5.2Functional name of contact pointPrincipal Investigator
    B.5.3 Address:
    B.5.3.1Street AddressErnst-Grube-Strasse 40
    B.5.3.2Town/ cityHalle (Saale)
    B.5.3.3Post code06120
    B.5.3.4CountryGermany
    B.5.4Telephone number+493455572661
    B.5.5Fax number+493455572253
    B.5.6E-mailpatrick.michl@kks-halle.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 Cyramza 10 mg/ml
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) No
    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
    Progressive well-differentiated metastatic pancreatic neuroendocrine tumors
    Progrediente, gut differenzierte metastasierte pankreatische neuroendokrine Tumore
    E.1.1.1Medical condition in easily understood language
    Progressive well-differentiated metastatic neuroendocrine tumors of the pancreas
    Neuroendokriner Tumor der Bauchspeicheldrüse, welcher fortgeschritten ist und eventuell schon Absiedlungen (Metastasen) gebildet hat
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10067518
    E.1.2Term Pancreatic neuroendocrine tumor
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10068916
    E.1.2Term Pancreatic neuroendocrine tumor metastatic
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this study is to investigate whether ramucirumab in combination with dacarbacine has an effect on the disease-control in patients with progressive pancreatic neuroendocrine tumors
    Ziel der Studie ist es, den Effekt von Ramucirumab in Kombinati-on mit Dacarbazin auf die Disease-Control-Rate bei Patienten mit progredienten, pankreatischen neuroendokrinen Tumoren zu untersuchen.
    E.2.2Secondary objectives of the trial
    Secondary aims are to investigate the tumor response, survival, progression-free survival, the toxicity profile of the combination therapy, the biochemical response and Quality of Life. Additionally a translational research aims to investigate predictive biomarkers.
    Sekundäre Ziele sind die Untersuchung des Gesamt- sowie progressionsfreien Überlebens, des Toxizitätsprofiles der Kombinationstherapie, das Ansprechen der Therapie bzgl. biochemischer Parameter und der Lebensqualität. In einem Begleitforschungsprojekt sollen zusätzlich prediktive Biomarker untersucht werden.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Histologically confirmed unresectable metastatic G1-G3 differentiated pancreatic neuroendocrine tumor (non-functional and functional NET) with a proliferation rate assessed by Ki-67 up to 55% - excluding neuroendocrine carcinomas
    - Age: 18-80 years
    - Measurable disease (RECIST 1.1)
    - Progressive disease under treatment with either non-DTIC-based chemotherapy, SSA analogues, everolimus or sunitinib.
    - No prior therapy with DTIC is allowed. Prior therapy with temozolomide is allowed with a temozolomide-free interval of at least 6 months prior to trial inclusion. Prior TACE and SIRT allowed with a minimum of 3 months before study entry, prior PRRT with a minimum of 12 months before study entry
    - ECOG 0-1
    - Life expectancy > 12 weeks
    - Adequate renal, hepatic, bone marrow and coagulation function
    - Sexually active patiens: postmenopausal, surgically sterile, or use of effective contraception (Pearl Index <1). Female patients of childbearing potential: negative serum pregnancy test within 7 days prior to first dose of protocol therapy.
    - Written informed consent
    - Histologisch bestätigter nicht-resektabler, gut differenzierter metastasierender G1-G3 pankreatischer neuroendokriner Tumor (funktionell aktiv und nicht-aktiv) mit einer Proliferationsrate er-mittelt mit Ki-67 bis zu 55%, mit Ausnahme neuroendokriner Karzinome (NEC).
    - Alter: 18-80 Jahre
    - Messbare Läsion (RECIST 1.1)
    - Progrediente Erkrankung unter Behandlung mit Nicht-DTIC-haltiger Chemotherapie. Keine vorherige Therapie mit DTIC. Vorangegangene Therapien mit Temozolomid sind erlaubt sofern diese mindestens 6 Monate vor Studienbeginn beendet wurden. Vorangegangene TACE und SIRT mit Minimum 3 Monate vor Studienbeginn sowie vorherige PRRT mit Minimum 12 Monate vor Studienbeginn zulässig.
    - ECOG 0-1
    - Lebenserwartung > 12 Wochen
    - Adäquate Nieren-, Leber-, und Knochenmarksfunktion
    - Adäquate Gerinnung
    - Sexuell aktive Patienten: postmenopausal, chirurgische Sterilisation oder effektive Kontrazeption (Pearl Index <1). Weibliche Patienten, die potenziell schwanger werden könnten: negativer Schwangerschaftstest innerhalb von 7 Tagen vor der ersten Gabe der Studienmedikation
    - Schriftliche, informierte Einwilligung
    E.4Principal exclusion criteria
    - Pregnancy or lactation.
    - Secondary malignancy in patient’s history with the exception of: disease-free period > 5 years before randomization or non-melanoma skin cancer or curatively treated cervical carcinoma in situ or other noninvasive in situ neoplasm.
    - Allergy against dacarbazine or ramucirumab
    - Current enrolment or participation within the last 4 weeks in a clinical drug trial
    - Any arterial thromboembolic events within 6 months prior to first dose of protocol therapy.
    Insufficient liver function
    - Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management
    - Chronic antiplatelet therapy, once-daily aspirin use (maximum dose 325 mg/day) permitted
    - Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.
    - History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to first dose of protocol therapy
    - Uncontrolled severe physical or mental disorders
    - Pathological condition present that carries a high risk of bleeding
    - History of gastrointestinal perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
    - Major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. Elective or planned major surgery to be performed during the course of the clinical trial.
    - Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.
    - officially and/or legally accomodated persons
    - Schwangerschaft (positiver Urin- oder Bluttest) oder Stillzeit..
    - Andere maligne Erkrankung innerhalb der letzten 5 Jahre vor Studieneinschluss. Ausnahmen: Kurativ behandelte Basalzellkarzinome der Haut und Carcinoma in situ der Zervix so-wie sonstige nichtinvasive in-situ Neoplasien.
    - Allergien gegen Dacarbazin und/oder Ramucirumab
    - Gleichzeitige oder innerhalb von 4 Wochen liegende Teilnahme an einer anderen klinischen Prüfung mit Arzneimitteln.
    - Jegliche arterielle thromboembolytische Ereignisse innerhalb 6 Monate vor der ersten Gabe der Studientherapie.
    - Unzureichende Leberfunktion
    - Unkontrollierte oder schwer zu kontrollierende Hypertonie
    - Dauerhafte thrombozyten-aggregationshemmenden Therapie inklusive ASS (ASS 1x täglich (max. 325 mg/Tag) erlaubt)
    - Grad 3-4 GI Blutung innerhalb der letzten 3 Monate vor der ersten Verabreichung der Studientherapie.
    - Stattgehabte tiefe Beinvenenthrombose (DVT), Lungenembolie (PE) oder jegliche andere signifikante Thromboembolie (Kathederthrombose und Thrombophlebitis gelten nicht als “signifikant”) während der letzten 3 Monate vor der ersten Verabreichung der Studientherapie.
    - Unkontrollierte physische oder mentale Störung wie neurologische oder psychische Störungen
    - Krankheitsbild mit hoher Blutungsneigung (z.B. Tumor mit großen Blutgefäßen oder bekannte Varizen)
    - Gastrointestinale Perforation oder Fistel (innerhalb der letzten 6 Monate vor der ersten Verabreichung der Studientherapie) oder Risikofaktoren für eine Perforation
    - Großer chirurgischer Eingriff innerhalb der letzten 28 Tage vor der ersten Verabreichung der Studientherapie oder kleinere Operation/subkutaner Portkatheder innerhalb der letzten 7 Tage vor Gabe der ersten Studientherapie. Vorgesehener großer chirurgischer Eingriff im Verlauf der klinischen Studie.
    - Schwere Wundheilungsstörung, Ulkus oder Knochenfraktur innerhalb der letzten 28 Tage vor der ersten Verabreichung der Studientherapie
    - behördlich und gerichtlich untergebrachte Personen
    E.5 End points
    E.5.1Primary end point(s)
    Disease control rate (DCR) after 6 months from study entry, determined according to RECIST 1.1 or death
    Disease-control rate (DCR) nach 6 Monaten ermittelt anhand der Kriterien nach RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months from study entry
    6 Monate nach Studienbeginn
    E.5.2Secondary end point(s)
    - Objective tumor response (ORR)
    - progression-free survival (PFS)
    - overall survival (OS)
    - toxicity
    - biochemical response (tumor marker chromogranin A; in cases of functional NET: gastrin, insulin)
    - Quality of Life (EORTC QLQ-C30 questionnaire)
    Translational research:
    - Predictive biomarkers (circulating VEGF, ANGPT1/2 and IL8 levels, immunohistochemical VEGFR2 expression).
    - Objektives Tumoransprechen
    - Progressionsfreies Überleben
    - Gesamtüberleben
    - Toxizität der Kombinationstherapie
    - Biochemisches Ansprechen (Tumormarker Chromogranin A, Gastrin, Insulin etc.)
    - Lebensqualität (EORTC QLQ-C30 Fragebogen)
    Begleitforschung:
    - Prediktive Biomarker (zirkulierende VEGF, ANGPT1/2 und IL8-Levels, immunohistochemische VEGFR2-Expression)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 6 months from study entry (ORR, QoL)
    - time point of tumor progression (PFS)
    - death of the patient (OS)
    - Until 30 days after last administration of study therapy (toxicity)
    - Baseline, day 1 of each cycle, end of treatment (biochemical response, predictive biomarkers)
    - 6 Monate nach Studienbeginn (ORR, QoL)
    - Zeitpunkt der Tumorprogression (PFS)
    - Tod des Patienten (OS)
    - bis 30 Tage nach letzter Gabe der Studienmedikation (Toxizität)
    - Baseline, Tag 1 eines jeden Zyklus, Ende der Behandlung (biochemisches Ansprechen, prediktive Biomarker)
    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 concerned10
    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 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
    Letzte Studienvisite des letzten Patienten
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    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: 15
    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 state45
    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 study treatment has been terminated due to disease progression or toxicity, post trial treatment will not differ from the expected normal treatment of that condition and will depends on ivestigator´s and patient's choice. Three-monthly telephone interviews will be conducted with patients not undergoing further therapy at the participating centers to record overall survival status and further therapeutic interventions such as additional chemotherapies or local-ablative measures.
    Nach Ende der Studientherapie aufgrund von Progression oder inakzeptablen Toxizitäten wird sich die weitere Behandlung nicht vom üblichen Vorgehen im Rahmen dieses Krankheitsbildes unterscheiden und vom behandelnden Arzt und dem Patienten individuell festgelegt. Wenn die die Weiterbehandlung nicht am Studienzentrum erfolgt, werden aller 3 Monate Telefoninterviews bzgl. Überleben und weiteren therapeutischen Interventionen, wie bspw. Chemotherapien oder lokal-ablativen Maßnahmen durchgeführt.
    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 Decision2018-04-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-20
    P. End of Trial
    P.End of Trial StatusOngoing
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