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    Summary
    EudraCT Number:2017-003496-54
    Sponsor's Protocol Code Number:FOOTPATH
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-16
    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 - BfArM
    A.2EudraCT number2017-003496-54
    A.3Full title of the trial
    A multicenter randomized phase II study to determine the optimal first-line chemotherapy regimen in patients with metastatic pancreatic cancer (FOOTPATH)
    Eine randomisierte Multicenterstudie der Phase II zur Ermittlung des optimalen Chemotherapie-Regimes in der Erstlinientherapie von Patienten mit einem metastasierten Pankreaskarzinom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter randomized phase II study to determine the optimal first-line chemotherapy regimen in patients with metastatic pancreatic cancer (FOOTPATH)
    Eine randomisierte Multicenterstudie der Phase II zur Ermittlung des optimalen Chemotherapie-Regimes in der Erstlinientherapie von Patienten mit einem metastasierten Pankreaskarzinom
    A.3.2Name or abbreviated title of the trial where available
    FOOTPATH
    A.4.1Sponsor's protocol code numberFOOTPATH
    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 Hospital, LMU Munich (Germany)
    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 supportShire International
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Ludwig-Maximilian-Universität München, Klinikum Großhadern
    B.5.2Functional name of contact pointStudy Secretary
    B.5.3 Address:
    B.5.3.1Street AddressMarchioninistr. 15
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number004989440072208
    B.5.5Fax number004989440075256
    B.5.6E-mailmatthias.wolff@med.uni-muenchen.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 Onivyde
    D.2.1.1.2Name of the Marketing Authorisation holderBaxalta Innovations GmbH
    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 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.3.9.1CAS number 97682-44-5
    D.3.9.2Current sponsor codeNal-IRI
    D.3.9.3Other descriptive namePEG-IRINOTECAN
    D.3.9.4EV Substance CodeSUB30526
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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 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.IMP: 2
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 name5-Fluorouracil
    D.3.4Pharmaceutical form 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 INNFluorouracil
    D.3.9.1CAS number 51-21-8
    D.3.9.2Current sponsor code5-FU
    D.3.9.3Other descriptive nameFLUOROURACIL
    D.3.9.4EV Substance CodeSUB07721MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2400
    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 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 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.IMP: 3
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameFolinic Acid
    D.3.4Pharmaceutical form 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.3.9.1CAS number 1492-18-8
    D.3.9.3Other descriptive nameFOLINIC ACID
    D.3.9.4EV Substance CodeSUB13910MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 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 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.IMP: 4
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameOxaliplatin
    D.3.4Pharmaceutical form 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 INNOXALIPLATIN
    D.3.9.1CAS number 61825-94-3
    D.3.9.4EV Substance CodeSUB09490MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number85
    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 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 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.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameGemcitabine
    D.3.4Pharmaceutical form 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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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 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 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.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country 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.3.1Product nameNab-Paclitaxel
    D.3.4Pharmaceutical form 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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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 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 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
    Histologically (not cytologically) confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma (PDAC) [Stage IV according to UICC TNM edition 8 of 201622: each T, each N, M1]
    Histologisch (nicht zytologisch) bestätigte Diagnose eines metastasierten duktalen Adenokarzinoms des Pankreas (PDAC) [Stadium IV der UICC TNM Edition 8 von 2016 : jedes T, jedes N, M1]
    E.1.1.1Medical condition in easily understood language
    Metastatic pancreatic adenocarcinoma
    Metastasiertes Adenokarzinom des Pankreas
    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 10033605
    E.1.2Term Pancreatic cancer 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
    To determine the optimal first-line regimen in metastatic pancreatic cancer
    Ermittlung des optimalen Erstlinien-Regimes zur Behandlung des metastasierten Pankreaskarzinoms
    E.2.2Secondary objectives of the trial
    • To define the safety profile of the three regimens used (gemcitabine/nab-paclitaxel, NAPOLI-regimen, seq-NAPOLI/mFOLFOX6)
    • To assess the efficacy of the three regimens used (gemcitabine/nab-paclitaxel, NAPOLI-regimen, seq-NAPOLI/mFOLFOX6)
    • To assess the patient reported outcome in quality of life
    • To assess the rate of second-line treatment

    Additional exploratory objectives:
    • To validate the role of depth of radiologic response and tumour shrinkage as a predictor of patient outcome
    • To determine molecular predictors of response to first-line chemotherapy
    • To establish the role of liquid biopsies in the management of metastatic pancreatic cancer

    • Ermittlung des Sicherheitsprofils der drei eingesetzten Regime (Gem/nab- Paclitaxel, NAPOLI-Regime, seq-NAPOLI/mFOLFOX6)
    • Bewertung der Wirksamkeit der drei eingesetzten Regime (Gem/nab- Paclitaxel, NAPOLI-Regime, seq-NAPOLI/mFOLFOX6)
    • Bewertung der vom Patienten berichteten Auswirkungen auf die Lebensqualität
    • Beurteilung des Anteils der Patienten mit Zweitlinientherapie

    Zusätzliche explorative Studienziele:
    • Validierung der Bedeutung der Tiefe des radiologischen Ansprechens und der frühen Tumorreduktion als Prädiktor für das Behandlungsergebnis des Patienten
    • Ermittlung von molekularen Prädiktoren für ein Ansprechen auf die Erstlinientherapie
    • Etablierung der Bedeutung von Flüssigbiopsien für das Management des metastasiertem Pankreaskarzinom

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adult patients ≥ 18 years of age and ≤ 75 years
    • Histologically (not cytologically) confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma (PDAC) [Stage IV according to UICC TNM edition 8 of 201622: each T, each N, M1]
    • No option for surgical resection or radiation in curative intent
    • At least one unidimensionally measurable tumor lesion (according to RECIST 1.1)
    • ECOG performance status 0 - 1
    • Life expectancy at least 3 months
    • Adequate hepatic, renal and bone marrow function, defined as:
    - Absolute neutrophil count (ANC) ≥ 2.0 x 109/L
    - Haemoglobin ≥ 9 g/dL
    - Thrombocytes ≥ 100 x 109/L
    - Total bilirubin ≤ 1.5 x ULN. Patients with a biliary stent may be included provided that bilirubin level after stent insertion decreased to ≤ 1.5 x ULN and there is no cholangitis.
    - AST/GOT and/or ALT/GPT ≤ 2.5 x ULN or in case of liver
    metastasis ≤ 5 x ULN)
    - Serum creatinine within normal limits or creatinine clearance ≥ 60 mL/min/1.73 m2 as calculated by CKD-EPI formula for patients with serum creatinine levels above or below the institutional normal value.
    • Females of childbearing potential (FCBP) must have a negative highly sensitive serum pregnancy test within 7 days of the first administration of study treatment and must agree to undergo a further pregnancy tests at monthly intervals and at the end of treatment visit

    and

    FCBP must agree to use and be able to take highly effective contraceptive birth control methods (Pearl Index < 1) during the course of the study and for at least 1 month after last administration of study treatment. Complete sexual abstinence is acceptable as a highly effective contraceptive method only if the subject is refraining
    from heterosexual intercourse during the entire study treatment and at least one month after the discontinuation of study treatment and the reliability of sexual abstinence is in line with the preferred and usual lifestyle of the subject.
    A female subject following menarche is considered to be of childbearing potential unless she is naturally amenorrhoeic for ≥ 1 year without an alternative medical reason, or unless she is permanently sterile.
    • Males must agree to use condoms during the course of the trial and for at least 6 months after last administration of study drugs or practice complete abstinence from heterosexual intercourse.
    • Signed and dated informed consent before the start of any specific protocol procedures
    • Patient’s legal capacity to consent to study participation
    • Erwachsene Patienten/Patientinnen im Alter von ≥ 18 Jahren und ≤ 75 Jahren
    • Histologisch (nicht zytologisch) bestätigte Diagnose eines metastasierten duktalen Adenokarzinoms des Pankreas (PDAC) [Stadium IV der UICC
    TNM Edition 8 von 201610: jedes T, jedes N, M1]
    • Keine Möglichkeit für eine chirurgische Resektion oder eine Bestrahlung in kurativer Behandlungsintention
    • Mindestens eine unidimensional nach RECIST 1.1 messbare Tumorläsion
    • ECOG Performance Status 0 - 1
    • Lebenserwartung von wenigstens 3 Monaten
    • Adäquate Leber-, Nieren- und Knochenmarksfunktion, wie folgt definiert:
    - Absolute Zahl der Neutrophilen ≥ 2.0 x 109/L
    - Hämoglobin ≥ 9 g/dL
    - Thrombozyten ≥ 100 x 109/L
    - Gesamtbilirubin ≤ 1.5 x obere Grenze des Normalwertes. Patienten mit einem biliären Stent dürfen eingeschlossen werden, vorausgesetzt, dass der Bilirubinspiegel nach dem Einsetzen des Stents auf einen Wert ≤ 1.5 x obere Grenze des Normalwertes sinkt und dass keine Cholangitis besteht.
    - AST/GOT und/oder ALT/GPT ≤ 2.5 x obere Grenze des Normalwertes oder im Falle von Lebermetastasen ≤ 5 x obere Grenze des Normalwertes)
    - Kreatinin im Serum innerhalb des Normalbereiches oder eine Kreatinin-Clearance ≥ 60 mL/Min/1,73 m2 bei Berechnung mit der CKD-EPI Formel bei Patienten mit einem Serum Kreatinin-Spiegel oberhalb oder unterhalb des Normalwertes der Einrichtung.
    • Gebärfähige Frauen müssen einen negativen hochsensitiven Schwangerschaftstest innerhalb von 7 Tagen vor erster Gabe der Studienmedikation aufweisen und müssen einwilligen, sich weiteren Schwangerschaftstests in monatlichen Abständen sowie einem Schwangerschaftstest bei der Studienvisite nach Beendigung der Studientherapie zu unterziehen.

    und

    Gebärfähige Frauen müssen einwilligen und in der Lage sein, hochwirksame Methoden zur Schwangerschaftsverhütung (Pearl Index < 1) während des gesamten Verlaufs der Studie und wenigstens 1 Monat nach letzter Gabe der Studienmedikation anzuwenden. Vollständige sexuelle Enthaltsamkeit ist als hochwirksame Methode zur Schwangerschaftsverhütung akzeptabel, wenn sich die Patientin während der gesamten Dauer der Studienmedikation und wenigstens einen Monat nach Beendigung der Studienmedikation jeglichen heterosexuellen Geschlechtsverkehr enthält und die Zuverlässigkeit von sexueller Enthaltsamkeit in Übereinstimmung mit dem bevorzugten und üblichen Lebensstil der Patientin steht. Eine weibliche Person wird nach der Menarche als gebärfähig erachtet, solange sie nicht natürlicherweise seit mehr als einem Jahr keine Monatsblutungen hat ohne dass es einen alternativen medizinischen Grund hierfür gibt oder sofern sie nicht dauerhaft unfruchtbar ist.
    • Männer müssen zustimmen, während des gesamten Verlaufs der Studie und wenigstens 6 Monate nach letzter Gabe der Studienmedikamente beim Geschlechtsverkehr Kondome zu verwenden oder vollständige Enthaltsamkeit von heterosexuellem Geschlechtsverkehr zu praktizieren.
    • Unterschriebene und datierte Einwilligungserklärung vor dem Beginn irgendeiner studienprotokollspezifischen Maßnahme
    • Einwilligungsfähigkeit des Patienten in die Studienteilnahme
    E.4Principal exclusion criteria
    • Locally advanced PDAC without metastasis
    • Symptomatic/clinically significant ascites (expected indication for repeated paracentesis)
    • Known metastatic disease to the brain. Brain imaging is required in symptomatic patients to rule out brain metastases, but is not required in asymptomatic patients.
    • Previous palliative chemotherapy or other palliative systemic tumor therapy for metastatic disease of PDAC
    • Previous gemcitabine or 5-FU based treatment with exception of gemcitabine/fluoropyrimidine based treatment applied in the neoadjuvant or adjuvant setting (before/after potential curative R0 or R1 resection) and if the neoadjuvant/adjuvant chemotherapy was terminated at least 6 months before randomization
    • Previous radiotherapy of PDAC with exception of radiotherapy in the context of a neoadjuvant or adjuvant treatment setting that was terminated at least 6 months before randomization
    • Any major surgery within the last 4 weeks before randomization
    • Clinically significant decrease in performance status within 2 weeks of intended first administration of study medication (by medical history)
    • Severe tumor-related cachexia and/or known weight loss > 15% within one month before study enrollment
    • Pre-existing polyneuropathy ≥ grade 2 according to CTCAE version 5.0
    • Chronic intestinal diseases and gastrointestinal disorders with diarrhoea as a major symptom (e.g. Crohn’s disease, malabsorption), and chronic diarrhoea of any aetiology CTCAE version 5.0 grade  2
    • Any other severe concomitant disease or disorder, which could influence patient’s ability to participate in the study and his/her safety during the study or interfere with interpretation of study results e.g. active infection, uncontrolled hypertension, clinically significant cardiovascular disease e.g. cerebrovascular accident (≤ 6 months before study start), myocardial infarction (≤ 6 months before study start), unstable angina, heart failure ≥ NYHA functional classification system grade 2, severe cardiac arrhythmia requiring medication, metabolic dysfunction, severe renal disorder.
    • Any other malignancies than PDAC within the last 5 years before study start, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer
    • Hypersensitivity to the study drugs or to any of the excipients or to compounds with similar chemical or biologic composition
    • Use of strong CYP3A4 inhibitors (CYP3A4 inhibitors have to be discontinued at least one week prior to start of study treatment). Use of strong UGT1A1 inhibitors or strong CYP3A4 inducers unless there are no therapeutic alternatives.
    • Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
    • Known DPD deficiency (specific screening not required)
    • Treatment with nucleoside analogues including sorivudine or brivudine within 28 days before study enrollment or requirement for concomitant antiviral treatment with sorivudine or brivudine or analogues
    • Continuing abuse of alcohol, drugs, or medical drugs
    • Pregnant or breast-feeding females or FCBPs unable to either perform highly effective contraceptive measures or practice complete abstinence from heterosexual intercourse
    • Current or recent treatment with an investigational drug or participation in an interventional clinical trial within 4 weeks prior to randomization or within a period of 5 half-lives of the substances administered in an interventional clinical trial or during an experimental drug treatment prior to randomization, depending on which period is longer. In addition, simultaneous participation in another interventional clinical trial while receiving study treatment.
    .
    • Lokal fortgeschrittenes PDAC ohne Metastasierung
    • Symptomatischer/klinisch signifikanter Aszites (Indikation für wiederholte Parazentese zu erwarten)
    • Bekannte Metastasierung in das Gehirn. Eine bildgebende Untersuchung des Gehirns ist bei symptomatischen Patienten erforderlich, um Hirnmetastasen auszuschließen, aber bei asymptomatischen Patienten nicht notwendig.
    • Vorherige palliative Chemotherapie oder eine andere palliative systemische Tumortherapie zur Behandlung der metastasierten Erkrankung des PDAC.
    • Vorherige Gemcitabin- oder 5-FU basierte Therapie mit Ausnahme einer Gemcitabin/ Fluoropyrimidin-basierten Therapie, die in einem neoadjuvanten oder adjuvanten Setting (vor/nach potentiell kurativer R0 oder R1-Resektion) verabreicht wurde und falls die neoadjuvante/adjuvante Chemotherapie mindestens 6 Monate vor der Randomisierung beendet wurde.
    • Vorherige Strahlentherapie des PDAC mit Ausnahme einer Strahlentherapie im Rahmen eines neoadjuvanten oder adjuvanten Behandlungs-Setting, das mindestens 6 Monate vor der Randomisierung beendet wurde.
    • Jede größere Operation innerhalb von 4 Wochen vor der Randomisierung.
    • Klinisch signifikante Verschlechterung des Performance Status innerhalb von 2 Wochen vor der beabsichtigten ersten Gabe der Studienmedikation (entsprechend Anamnese).
    • Schwere tumorbedingte Kachexie und/oder Gewichtsverlust von >15% innerhalb eines Monat vor dem Studieneinschluss
    • Vorbestehende Polyneuropathie ≥ Grad 2 nach CTCAE Version 5.0
    • Chronische Darmerkrankungen und gastrointestinale Störungen mit Diarrhoe als Hauptsymptom (z.B. M. Crohn, Malabsorption) und chronische Diarrhoe jeglicher Ätiologie CTCAE Version 5.0 Grad  2
    • Jede schwere Begleiterkrankung oder Gesundheitsstörung, welche die Fähigkeit des Patienten, an der Studie teilzunehmen oder ihre/seine Sicherheit während der Studie störend beeinflussen könnte oder die Interpretation von Studienergebnissen stören könnte, wie z.B. eine aktive Infektion, unkontrollierter Bluthochdruck, eine klinisch signifikante kardiovaskuläre Erkrankung wie ein zerebrovaskulärer Insult (≤ 6 Monate vor Randomisierung), Myokardinfarkt (≤ 6 Monate vor Randomisierung), instabile Angina, Herzinsuffizienz ≥ NYHA Funktionsklasse 2, schwere Herzrhythmusstörungen, die medikamentös behandelt werden müssen, metabolische Dysfunktion, schwere Nierenerkrankung
    • Andere maligne Tumorerkrankung als das PDAC innerhalb der letzten 5 Jahre vor Randomisierung, mit Ausnahme eines adäquat behandelten Carcinoma in situ der Zervix, eines Basalioms oder Plattenepithelkarzinoms der Haut.
    • Überempfindlichkeit auf die Studienmedikamente oder auf sonstige Bestandteile der Zubereitung oder auf Substanzen mit ähnlicher chemischer oder biologischer Zusammensetzung
    • Verwendung von starken CYP3A4 Inhibitoren (CYP3A4 Inhibitoren müssen wenigstens eine Woche vor dem Beginn der Studientherapie abgesetzt werden). Verwendung von starken UGT1A1 Inhibitoren oder starken CYP3A4 Inducern, es sei denn, dass keine therapeutischen Alternativen bestehen.
    • Bekannter Glukuronidierungsdefekt (M. Gilbert-Meulengracht); spezifisches Screening nicht erforderlich
    • Bekannter DPD Mangel (spezifisches Screening nicht erforderlich)
    • Behandlung mit Sorivudin oder Brivudin innerhalb von 28 Tagen vor Studienbeginn oder die Erfordernis einer gleichzeitigen antivirale Behandlung mit Sorivudin oder Brivudin oder Analoga.
    • Fortgesetzter Alkohol-, Drogen- oder Medikamentenmissbrauch
    • Schwangere oder stillende Frauen oder gebärfähige Frauen, die nicht in der Lage sind, entweder hochwirksame empfängnisverhütende Maßnahmen anzuwenden oder sich vollständig jeden heterosexuellen Geschlechtsverkehrs zu enthalten.
    • Gleichzeitige oder kürzliche Behandlung mit einer experimentellen Substanz oder Teilnahme an einer interventionellen klinischen Studie innerhalb von 4 Wochen vor Randomisation oder innerhalb eines Zeitintervalls von 5 Halbwertzeiten der in einer interventionellen klinischen Studie oder der während einer experimentellen Behandlung verabreichten Substanzen vor Randomisation je nachdem, welcher Zeitabschnitt länger ist. Außerdem gleichzeitige Teilnahme an einer anderen interventionellen klinischen Studie während der Studienbehandlung.
    E.5 End points
    E.5.1Primary end point(s)
    • Progression-free survival (PFS)
    • Progressionsfreies Überleben (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Restaging according to RECIST 1.1 will be performed every eight weeks
    Die Tumorevaluierung wird gemäß RECIST 1.1 alle acht Wochen durchgeführt
    E.5.2Secondary end point(s)
    • Overall survival (OS)
    • Objective response rate (ORR) and disease control rate (DCR)
    • Duration of study treatment
    • Type, incidence, causal relationship and severity of adverse events according to NCI CTCAE version 5.0
    • Choice, duration and efficacy of second-line chemotherapy
    • Quality of life as assessed by EORTC-QLQ-C30
    • Gesamtüberleben (OS)
    • Objektive Ansprechrate (ORR) und Krankheitskontrollrate (DCR)
    • Dauer der Studienbehandlung
    • Art, Inzidenz, kausaler Zusammenhang und Schwere von unerwünschten Ereignissen entsprechend NCI CTCAE Version 5.0
    • Wahl, Dauer und Wirksamkeit der Zweitlinientherapie
    • Lebensqualität entsprechend der Beurteilung im EORTC-QLQ-C30 Fragebogen
    E.5.2.1Timepoint(s) of evaluation of this end point
    • OS will be evaluated in a continously manner, after study treatment every 3 month until death or end of study
    • Restaging according to RECIST 1.1 will be performed every eight weeks
    • Evaluated when end of treatment is reached
    • Safety and tolerability will be evaluated in a continously manner
    • evaluated after study treatment every 3 month until death or end of study
    • evaluated after every 28-day treatment cycle until end of treatment is reached
    • OS wird kontinuierlich untersucht und im Nachbeobachtungszeitraum alle 3 Monate bis zum Tod oder Studienende erhoben
    • Die Tumorevaluierung wird gemäß RECIST 1.1 alle acht Wochen durchgeführt
    • Erhebung wenn Therapieende erreicht wurde
    • Sicherheit und Tolerabilität werden kontinuierlich während der Studientherapie untersucht
    • Wird nach Therapieende erhoben, im Nachbeobachtungszeitraum alle 3 Monate bis zum Tod oder Studienende
    • Wird zur Baseline und nach jedem 28-tägigen Therapiezyklus erhoben bis das Therapieende erreicht wurde
    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 Yes
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial3
    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 concerned40
    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 im Follow-Up
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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 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.1.3Elderly (>=65 years) Yes
    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 state270
    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)
    The investigator is responsible for further treatment
    Die Entscheidung über die weitere Behandlung liegt beim Prüfarzt
    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 Decision2018-11-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-16
    P. End of Trial
    P.End of Trial StatusOngoing
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