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    Summary
    EudraCT Number:2016-004614-10
    Sponsor's Protocol Code Number:CA209-429
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-01-16
    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 - PEI
    A.2EudraCT number2016-004614-10
    A.3Full title of the trial
    An open label phase II study to evaluate safety and efficacy of combined treatment with ipilimumab and nivolumab in patients with four and more symptomatic brain metastases of melanoma
    Eine offene Phase II-Studie zur Evaluierung der Sicherheit und Wirksamkeit einer Kombinationstherapie mit Ipilimumab und Nivolumab bei Patienten mit vier und mehr symptomatischen Hirnmetastasen eines Melanoms
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test safety and efficacy of treatment with ipilimumab and nivolumab in patients suffering from melanoma having 4 and more brain metastases
    Eine Studie zur Prüfung der Sicherheit und Wirksamkeit einer Behandlung mit Ipilimumab und Nivolumab bei Patienten mit Melanom und 4 und mehr Hirnmetastasen
    A.3.2Name or abbreviated title of the trial where available
    BRAIN-IP
    A.4.1Sponsor's protocol code numberCA209-429
    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 Tübingen
    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 supportBristol-Myers Squibb GmbH & Co. KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Tübingen
    B.5.2Functional name of contact pointDepartment of Dermatology, Dermatoo
    B.5.3 Address:
    B.5.3.1Street AddressLiebermeisterstr. 25
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number004970712987110
    B.5.5Fax number00497071295187
    B.5.6E-mailclaus.garbe@med.uni-tuebingen.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 Yervoy
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameIpilimumab
    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 INNIPILIMUMAB
    D.3.9.1CAS number 477202-00-9
    D.3.9.2Current sponsor codeBMS-734016
    D.3.9.3Other descriptive nameIPILIMUMAB
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number40
    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.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.2.1.1.1Trade name Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameNivolumab
    D.3.2Product code BMS-936558
    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 INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Patients with stage IV melanoma and four or more symptomatic brain metastases, who are not eligible for surgery or radiosurgery
    Patienten mit einem Melanom im Stadium IV mit vier oder mehr symptomatischen Hirnmetastasen, die nicht für eine Operation oder Radiochirurgie geeignet sind.
    E.1.1.1Medical condition in easily understood language
    Patients with stage IV melanoma and four or more symptomatic brain metastases, who are not eligible for surgery or radiosurgery
    Patienten mit einem Melanom im Stadium IV mit vier oder mehr symptomatischen Hirnmetastasen, die nicht für eine Operation oder Radiochirurgie geeignet sind.
    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 10025655
    E.1.2Term Malignant melanoma of skin
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10025671
    E.1.2Term Malignant melanoma stage IV
    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 10006128
    E.1.2Term Brain metastases
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10025650
    E.1.2Term Malignant melanoma
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10027480
    E.1.2Term Metastatic malignant melanoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to assess the intracranial disease control rate (IC-DCR) at six months of treatment, defined as the proportion of patients with confirmed complete intracranial responses (CR), partial intracranial responses (PR) or stable in-tracranial disease (SD) assessed by investigators and secondary by an independent neuroradiology reference review in patients with melanoma-derived brain metastases treated with ipilimumab and nivolumab combination therapy.
    Das primäre Studienziel ist die Untersuchung der intrakraniellen Krankheitskontrollrate nach 6 Monaten Studientherapie, definiert als Anteil der Patienten mit bestätigter intrakranieller CR, PR und SD. Die Auswertung erfolgt sowohl durch den Investigator als auch durch einen unabhängigen Neuroradiologen.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to assess:
    • Overall and progression-free survival
    • Percentage of patients in whom stereotactic irradiation or surgery of all brain metastases becomes applicable after par-tial tumor remission
    • Tolerability according to NCI-CTCAE-Criteria (version 4.0)
    • Best Overall Response Rate (BORR) according to RECIST v1.1 at six months of treatment
    • Cognitive function assessed by standardized diagnostic pro-cedures
    • Quality of life
    Sekundäre Studienziele sind:
    • Gesamtüberleben und progressionsfreies Überleben
    • Prozent der Patienten, bei denen eine stereotaktische Bestrahlung oder Operation aller Metastasen möglich wird nach partieller Tumorremission
    • Verträglichkeit / Toxizität entsprechend NCI-CTCAE-Kriterien (Version 4.0)
    • Best Overall Response Rate (BORR) entsprechend RECIST v1.1 nach 6 Monaten Studientherapie
    • Kognitive Funktionen untersucht mittels standardisierter Diagnoseverfahren
    • Lebensqualität
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The subject population will be characterized by mutation of BRAF, NRAS, KIT and other genes. The relationship between mutation status as responsive or resistant to treatment will be evaluated. Cerebrospinal fluid (CSF) and blood samples will be collected to analyze for correlations of cognitive functions and treatment response.
    Die Patienten werden entsprechend der Mutationen in BRAF, NRAS (optional), KIT (optional) und anderen Genen charakterisiert. Die Beziehung zwischen dem Mutationsstatus und dem Ansprechen oder der Resistenz auf die Therapie werden untersucht. Rückenmarksflüssigkeit und Blutproben werden auf Korrelationen zwischen kognitiven Funktionen und dem Ansprechen auf die Behandlung untersucht.
    E.3Principal inclusion criteria
    1. Signed Informed Consent (ICF) prior to any screening procedures being performed
    2. Ability to comply with protocol requirements
    3. Metastatic histologically confirmed melanoma (per AJCC staging system) that is unresectable
    4. Presence of four or more active brain metastasis confirmed/evaluated by MRI
    Patients with symptomatic brain metastases will be defined as subjects with brain metastases and any of the following: focal neurological deficits, seizures, headache or any other neurological and/or psychiatric alteration with temporal relation to the diagnosis of CNS disease
    5. Measurable disease by MRI per iRANO and RECIST 1.1 criteria
    6. The time between the baseline MRI and the date of registration should not exceed 28 days. Steroid treatment is permissible before brain MRI evaluation but the dose should have been stable for at least 7 days and should be carefully documented
    7. Patient must agree to the cerebro-spinal fluid (CSF) collections which are planned according to the study protocol.
    8. Patients naïve for systemic treatment are eligible
    9. Patients pre-treated with systemic immunotherapy, targeted therapy or chemotherapy are eligible, with the exception of previous treatment with the combination of CTLA-4 and PD-1 antibodies (see exclusion criterion 2)
    10. Patients must have recovered completely from any treatment-related acute toxicity associated with prior therapy
    11. At least two weeks must have passed since the last systemic anti-cancer treatment
    12. Patients with prior local therapy of brain metastases are eligible
    13. Patients may have received irradiation therapies:
    a. A) None
    b. B) Whole brain irradiation only
    c. C) Stereotactic irradiation of single or few metastases. Such lesions cannot be selected as target lesions and must therefore be excluded for the evaluation of the IC-DCR
    d. D) Combined B+C)
    14. Screening laboratory values must meet the following criteria (using CTCAE v4.0)
    and should be obtained within 14 days prior to registration:
    • WBC ≥ 2,000/μL
    • Neutrophils ≥ 1,500/μL
    • Platelets ≥ 100 x103/μL
    • Hemoglobin > 9.0 g/dL
    • Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
    o Female CrCl = (140 - age in years) x weight in kg x 0.85 / (72 x serum creatinine in mg/dL)
    o Male CrCl = (140 - age in years) x weight in kg x 1.00 / (72 x serum creatinine in mg/dL)
    • AST/ALT ≤ 3 x ULN
    • Total bilirubin ≤ 1.5 x ULN (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
    • INR ≤ 1.5
    15. ECOG Performance Status 0, 1 or 2
    16. Expected life expectancy of ≥three months
    17. Males and females ≥ 18 years old
    18. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug
    19. Women must not be breastfeeding
    20. Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception, as indicated in the informed consent form (ICF), throughout the study and for 23 weeks after the last dose of investigational drug (induction or maintenance phase).
    21. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception, as indicated in the informed consent form, throughout the study and for a period of 31 weeks after the last dose of investigational drug (induction or maintenance phase). In addition, male patients must be willing to refrain from sperm donation during this time.
    22. Azoospermic males are exempt from contraceptive requirements. WOCBP who are permanently not heterosexually active are also exempt from contraceptive requirements, but must still undergo pregnancy testing as previously described.
    Patients must agree to use at least two methods of contraception, with at least one highly effective method as listed in the ICF
    1. Der Patient hat die Einverständniserklärung vor Beginn der Screening-Untersuchungen unterschrieben und kann die Protokollanforderungen erfüllen.
    2. Fähigkeit, mit den Anforderungen der Studie konform zu gehen.
    3. Metastasiertes, histologisch bestätigtes inoperables oder metastasiertes Melanom (nach AJCC Staging).
    4. Vorhandensein von ≥ vier aktiven Hirnmetastasen, bestätigt mittels MRI.
    Patienten mit symptomatischen Hirnmetastasen werden definiert als Patienten mit Hirnmetastasen und fokalen neurologischen Defiziten oder Krämpfen oder Kopfschmerzen oder anderen neurologischen und/oder psychiatrischen Änderungen, welche in einem zeitlichen Zusammenhang mit der Diagnose der Hirnmetasten stehen.
    5. Messbare Erkrankung mittels MRI nach iRANO und RECIST 1.1 Kriterien
    6. Die Zeit zwischen Baseline MRI und Zeitpunkt der Registrierung für die Studie soll 28 Tage nicht überschreiten. Eine Behandlung mit Steroiden ist vor MRI des Gehirns erlaubt, die Dosis sollte aber für 7 Tage stabil sein und dokumentiert werden.
    7. Patienten müssen den Liquor-Abnahmen, welche entsprechend des Protokolls vorgesehen sind, zustimmen.
    8. Keine systemische Vorbehandlung
    9. Systemische Immuntherapie, zielgerichtete Therapie oder Chemotherapie ist als Vorbehandlung erlaubt (siehe Ausschlusskriterium Nr. 2),mit der Ausnahme der Vorbehandlung mit einer Kombinationstherapie aus CTLA-4 und PD-1 Antikörpern.
    10. Patienten müssen sich vollständig von allen Nebenwirkungen der vorangegangenen Therapie erholt haben
    11. Vorangegangene systemische anti-kanzeröse Therapie muss mindestens zwei Wochen zurückliegen.
    12. Patienten mit vorheriger lokaler Therapie der Hirnmetastasen können eingeschlossen werden.
    13. Patienten können folgende vorherige Strahlentherapie erhalten haben:
    • A) Keine
    • B) Ganzhirnbestrahlung
    • C) Stereotaktische Bestrahlung einer oder mehrere Metastasen. Diese Läsionen können nicht als target-Läsionen ausgewählt werden und müssen daher von der Auswertung der intrakraniellen DCR ausgeschlossen werden.
    • D) B+C kombiniert
    14. Laborwerte bei Screening müssen innerhalb von 14 Tagen vor Registrierung erhoben werden und den folgenden Kriterien entsprechen (nach CTCAE v4.0):
    • Leukozyten ≥ 2000/μL
    • Neutrophile ≥ 1500/μL
    • Thrombozyten ≥ 100 x103/μL
    • Hämoglobin > 9.0 g/dL
    • Serumkreatinin ≤ 1.5 x ULN oder Kreatinin Clearance (CrCl) ≥ 40 mL/min nach der Cockcroft-Gault Formel:
    o CrCl für Frauen = (140 – Alter in Jahren) x Gewicht in kg x 0.85 / (72 x Serumkreatinin in mg/dL)
    o CrCl für Männer = (140 - Alter in Jahren) x Gewicht in kg x 1.00 / (72 x Serumkreatinin in mg/dL)
    • AST/ALT ≤ 3 x ULN
    • Gesamtbilirubin ≤ 1.5 x ULN (Ausnahme: Patienten mit Gilbert Syndrom dürfen einen Gesamtbilirubinwert von < 3.0 mg/dL haben)
    • INR ≤ 1.5
    15. ECOG Performance Status 0, 1 oder 2
    16. Voraussichtliche Lebenserwartung von > 3 Monaten
    17. Männer und Frauen ≥ 18 Jahre alt
    18. Frauen im gebärfähigen Alter müssen einen negative Serum-Schwangerschaftstest (minimale Sensitivität 25 IU/L oder äquivalente Einheiten von HCG) innerhalb von 24 Stunden vor erster Gabe der Studienmedikation haben.
    19. Frauen dürfen nicht stillen.
    20. Frauen im gebärfähigen Alter müssen den Anweisungen für die Schwangerschaftsverhütung, wie in der Patienteninformation aufgeführt, während der Studie und für 23 Wochen nach der letzten Gabe der Studienmedikation folgen.
    21. Männer, die mit einem weiblichen Partner im gebärfähigen Alter sexuell aktiv sind, müssen den Anweisungen zur Schwangerschaftsverhütung, wie in der Patienteninformation aufgeführt, für die Dauer der Studie und für einen Zeitraum von 31 Wochen nach der letzten Gabe der Studienmedikation folgen.
    Zusätzlich dürfen männliche Patienten während dieser Zeitdauer keinen Samen spenden.
    22. Männer mit Azoospermie sind ausgenommen von den Anforderungen zur Schwangerschaftsverhütung.
    Frauen im gebärfähigen Alter, die durchgängig nicht heterosexuell aktiv sind, sind ebenfalls von den Anforderungen zur Schwangerschaftsverhütung ausgenommen. Schwangerschaftstests müssen aber dennoch wie beschrieben, durchgeführt werden.
    Der Patient muss zustimmen, wenigstens zwei Methoden der Schwangerschaftsverhütung zu verwenden, eine hochwirksame Methode und eine hoch- oder weniger wirksame Methode, wie in der Patienteninformation beschrieben.
    E.4Principal exclusion criteria
    1. Diagnosed ocular melanoma
    2. Previous systemic therapy with the combination of CTLA-4 and PD-1 antibodies
    3. Use of any investigational or non-registered product within the 30 days before registration in the study
    4. Prior active malignancy within the previous 3 years except locally curable cancers that have been apparently cured, such as: basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix, or breast
    5. History of organ transplantation
    6. Active infection requiring systemic therapy
    7. Active, known or suspected autoimmune disease.
    Exceptions: Patients with controlled Type I diabetes mellitus (patients who keep their preprandial blood glucose within the target range of 4 to 7 mmol/L), hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, can be enrolled.
    8. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
    9. Any serious or uncontrolled medical disorders thatmay increase the risk associated with study participation or study drug administration, impair the ability of the patient to receive protocol therapy, or interfere with the interpretation of study results in the opinion of the investigator.
    10. Known substance abuse or psychiatric disorders that would preclude cooperation with tany requirements of the trial.
    11. Legal incapacity or limited legal capacity
    12. Administration of live, attenuated vaccine within 4 weeks prior to the start of study drug
    13. Positive test for hepatitis B virus surface antigen (HBs Ag) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
    14. Known history of a positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    15. Patients with known allergy or hypersensitivity to any of the study drugs or excipients
    Patients with results of imaging or radiological examinations indicating increased cerebral pressure which would prevent lumbar puncture
    1. Diagnostiziertes okuläres Melanom
    2. Patienten, deren Hirnmetastasen vorher mit systemischer Therapie in Kombination mit CTLA-4 und PD-1 Antikörpern behandelt wurden
    3. Verwendung von Versuchsmedikation oder nicht zugelassener Medikation innerhalb von 30 Tagen vor Registrierung in der Studie
    4. Aktive bösartige Tumorerkrankung innerhalb der vorherigen 3 Jahre, mit Ausnahme von lokalen heilbaren Krebserkrankungen, die offensichtlich geheilt sind, wie Basalzellkarzinome oder Plattenepithelkarzinome der Haut, oberflächliche Blasenkarzinome oder in situ Karzinome von Prostata, Gebärmutterhals oder Brust
    5. Organtransplantation in der Anamnese
    6. Aktive Infektion, die eine systemische Behandlung erforderlich macht
    7. Aktive, bekannte oder vermutete Autoimmunerkrankung. Ausnahmen:
    o Patienten mit kontrolliertem Typ I Diabetes mellitus innerhalb der Grenzwerte von 4-7mmol/L
    o Patienten mit Hypothyreose, die nur eine Hormonersatztherapie benötigen
    o Hauterkrankungen wie Vitiligo, Psoriasis, oder Alopezie, die keine systemische Behandlung erfordern
    o Konditionen, die ohne einen externen Auslöser nicht auftreten
    8. Interstitielle Lungenerkrankung, die symptomatisch ist oder die Erkennung oder Behandlung von vermuteten pulmonalen Nebenwirkungen beeinträchtigt
    9. Jede schwerwiegende oder unkontrollierte Erkrankung, die nach Einschätzung des Prüfers das mit der Studienteilnahme oder Verabreichung der Studienmedikation verbundene Risiko erhöht, die nach der Einschätzung des Arztes die protokollgemäße Therapie oder die Interpretation der Studienergebnisse beeinträchtigt
    10. Bekannter Drogenmissbrauch oder psychiatrischer Gesundheitszustand, der die Einhaltung studienspezifischer Anforderungen ausschließt
    11. Geschäftsunfähigkeit oder eingeschränkte Geschäftsfähigkeit
    12. Impfung mit einem Lebendimpfstoff innerhalb der vorangegangenen 4 Wochen vor Start der Studientherapie
    13. Positiver Test auf Hepatitis B-Virus Oberflächenantigen (Hbs Ag) oder Hepatitis C-Virus Ribonukleinsäure (HCV Antikörper), was auf eine akute oder chronische Infektion hinweist
    14. Vorgeschichte oder positiver Test auf eine HIV-Infektion oder ein bekanntes erworbene Immundefektsyndrom (AIDS)
    15. Bekannte Überempfindlichkeit gegen Substanzen oder Hilfsstoffe der Studienbehandlung
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for this study is Disease Control Rate at 6 months (week 24) according RECIST 1.1 and iRANO [30] as assessed by the treating physicians. The analysis of the primary endpoint will be done when all patients, who are still on-treatment, have had, at least, 2 evaluations after baseline.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint for this study is Disease Control Rate at 6 months (week 24) according RECIST 1.1 and iRANO [30] as assessed by the treating physicians. The analysis of the primary endpoint will be done when all patients, who are still on-treatment, have had, at least, 2 evaluations after baseline.
    E.5.2Secondary end point(s)
    The following secondary endpoints should be evaluated
    • Overall and progression-free survival
    • Percentage of patients in whom stereotactic irradiation or surgery of all metasta-ses becomes applicable after partial tumor remission
    • Tolerability according to NCI-CTCAE-Criteria (version 4.0)
    • Best Overall Response Rate (BORR) according to RECIST v1.1 and iRANO at six months of treatment
    • Cognitive function
    • Quality of life
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 6 months (week 24): For consistency, the secondary endpoints will use the same analysis population as the primary endpoint
    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 concerned15
    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
    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 months7
    E.8.9.1In the Member State concerned days
    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: 34
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 34
    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 state68
    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)
    No further treatment will be applied within the scope of the protocol as soon as it was decided to permanently discontinue study treatment, e.g. due to unacceptable toxicity. Thereafter, further patient treatment will then be performed according to the updated national and international guidelines at the discretion of the investigator.
    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 Decision2017-05-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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