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    Summary
    EudraCT Number:2014-004095-31
    Sponsor's Protocol Code Number:ModuLung
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-05
    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 number2014-004095-31
    A.3Full title of the trial
    A prospective phase II, randomized multi-center trial of a combined modularized treatment with metronomic low-dose treosulfan, pioglitazone and clarithromycin versus nivolumab in patients with squamous cell lung cancer and non- squamous cell lung cancer, respectively after platin failure (ModuLung)
    Eine prospektive, zweiarmige, randomisierte multizentrische Phase II Studie einer kombinierten modularisierten Therapie mit metronomen nieder-dosiertem Treosulfan, Pioglitazon und Clarithromycin versus Nivolumab bei Patienten mit Nicht-kleinzelligem Bronchialkarzinom nach Platinversagen (ModuLung)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A prospective phase II, randomized multi-center trial of a combined modularized treatment with metronomic low-dose treosulfan, pioglitazone and clarithromycin versus nivolumab in patients with squamous cell lung cancer and non- squamous cell lung cancer, respectively after platin failure (ModuLung)
    Eine prospektive, zweiarmige, randomisierte multizentrische Phase II Studie einer kombinierten modularisierten Therapie mit metronomen nieder-dosiertem Treosulfan, Pioglitazon und Clarithromycin versus Nivolumab bei Patienten mit Nicht-kleinzelligem Bronchialkarzinom nach Platinversagen (ModuLung)
    A.3.2Name or abbreviated title of the trial where available
    ModuLung
    A.4.1Sponsor's protocol code numberModuLung
    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 SponsorFreistaat Bayer respresented by University of Regensburg represented by Kaufmännischer Direktor
    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 supportmedac Gesellschaft für klinische Spezialpräparate
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportTakeda GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinikum Regensburg
    B.5.2Functional name of contact pointProf. A. Reichle
    B.5.3 Address:
    B.5.3.1Street AddressFranz-Josef-Strauß-Allee 11
    B.5.3.2Town/ cityRegensburg
    B.5.3.3Post code93053
    B.5.3.4CountryGermany
    B.5.4Telephone number00499419445541
    B.5.5Fax number00499419445543
    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 Actos
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda Pharma A/S
    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 namePioglitazone
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpioglitazone hydrochloride
    D.3.9.3Other descriptive namePIOGLITAZONE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB03834MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    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.2.1.1.1Trade name Ovastat
    D.2.1.1.2Name of the Marketing Authorisation holdermedac Gesellschaft für klinische Spezialpräparate mbH
    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 nameTreosulfan
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTREOSULFAN
    D.3.9.1CAS number 299-75-2
    D.3.9.3Other descriptive nameTreosulfan
    D.3.9.4EV Substance CodeSUB11235MIG
    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 nameChlarythromycin
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameCLARITHROMYCIN
    D.3.9.4EV Substance CodeSUB06641MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 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 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.2.1.1.1Trade name Nivolumab BMS
    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.3.4Pharmaceutical form Concentrate and solvent for 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.3.9.3Other 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) 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) Yes
    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 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 Actos
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda Pharma A/S
    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 namePioglitazone
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpioglitazone hydrochloride
    D.3.9.3Other descriptive namePIOGLITAZONE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB03834MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 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 Actos
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda Pharma A/S
    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 namePioglitazone
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpioglitazone hydrochloride
    D.3.9.3Other descriptive namePIOGLITAZONE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB03834MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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
    locally advanced or metastatic NSCLC, who have progressed during or following a platinum-containing regimen.
    lokal fortgeschrittenes oder metastasiertes nicht-kleinzelliges Lungenkarzinom, welches bereits progredient unter oder nach einer platinhaltigen Therapie war
    E.1.1.1Medical condition in easily understood language
    locally advanced or metastatic NSCLC, who have progressed during or following a platinum-containing regimen.
    lokal fortgeschrittenes oder metastasiertes nicht-kleinzelliges Lungenkarzinom, welches bereits progredient unter oder nach einer platinhaltigen Therapie war
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer 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 PT
    E.1.2Classification code 10029521
    E.1.2Term Non-small cell lung cancer stage IIIB
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029515
    E.1.2Term Non-small cell lung cancer recurrent
    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
    To assess the efficacy of a biomodulatory therapy with treosulfan, pioglitazone and clarithromycin compared to nivolumab in NSCLC (squamous and non-squamous cell lung cancer) as measured by progression-free survival (PFS)
    Die Bestimmung der Effektivität einer kombinierten biomodulatorischen Therapie bestehend aus Treosulfan, Pioglitazon und Clarithromycin, im Vergleich zu einer Therapie mit Nivolumab, gemessen am progressionsfreies Überleben (PFS)
    E.2.2Secondary objectives of the trial
    •evaluate the efficacy of the combined biomodulatory treatment with treosulfan, pioglitazone and clarithromycin compared to nivolumab measured by
    •overall survival
    •duration of response per RECIST v1.1
    •evaluate the safety and tolerability of the treatment with treosulfan, pioglitazone and clarithomycin compared to nivolumab
    •evaluate universal response parameters (cellular secretome analytics in serum) for modulation of hallmarks of cancer
    •To evaluate and compare patient reported outcomes of lung cancer symptoms, patient functioning, and health-related quality of life between treatment arms, using EORTC, QLQ-C30 and LC13
    •evaluate the relationship between tumor tissue PPARγ expression and efficacy
    •assess change in predictive and prognostic exploratory biomarkers in archival and/or fresh serum samples
    •Tumor tissue taken at diagnosis or relapse: Routine moleculargenetic biomarkers and tissue microarray for PPARgamma expression
    -Bestimmung der Effektivität einer kombinierten biomodulatorischen Therapie, bestehend aus Treosulfan, Pioglitazon und Clarithromycin, im Vergleich zu einer Therapie mit Nivolumab gemessen am
    oGesamtüberleben
    oDauer des Anprechens definiert durch RECIST v1.1
    -Bewertung der Sicherheit und Verträglichkeit der kombinierten biomodulatorischen Behandlung im Vergleich zur Behandlung mit Nivolumab
    -Bewertung von universellen Parametern (zelluläre Sekretomanalyse im Serum) zur Beurteilung der Modulation von ‚Hallmarks of Cancer‘,
    -Bewertung mit EORTC, QLQ-C30) und LC13.
    -Beurteilung der PPARgamma-Expression im Tumorgewebe und der Therapie-Effektivität
    -Bewertung von Änderungen prädiktiver oder prognostischer explorativer Biomarker in archiviertem und/oder frischem Tumormaterial und Blut
    -Tumorgewebe von der Erstdiagnose oder vom Rezidiv: Routinebestimmung von molekulargenetischen Biomarkern (EGFR, K-Ras, ALK) und Gewebemicroarry zur Bestimmung der PPARgamma-Expression.





    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Signed Informed Consent Form
    • Ability to comply with protocol
    • Age ≥ 18 years
    • Measurable disease, as defined by RECIST v1.1
    • ECOG performance status of 0 or 1
    • Life expectancy ≥ 12 weeks
    • Histologically or cytologically documented locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the Union Internationale Contre le Cancer/American Joint Committee on Cancer [UICC/AJCC] staging system); pathological characterization must be sufficient to define patients as having either squamous or non-squamous histology.
    o Patients who do not have tissue specimens meeting eligibility requirements may undergo a biopsy during the screening period.
    o Acceptable samples include core needle biopsies for deep tumor tissue (minimum 3 cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
    • Disease progression during or following treatment with a prior platinum-containing regimen for locally advanced, unresectable/inoperable or metastatic NSCLC or disease recurrence within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen
    • a maximum of two prior cytotoxic chemotherapy regimens
    • Patients with an EGFR mutation treated with EGFR TKI in first-line must have progressed during or after treatment or be intolerant to erlotinib, gefitinib, or another EGFR TKI.
    • Patients with an ALK fusion oncogene must have progressed during or after treatment with, or be intolerant to, crizotinib or another ALK inhibitor.
    • The last dose of prior systemic anti-cancer therapy must have been administered ≥ 21 days prior to randomization (≥ 14 days for vinorelbine or other vinca alkaloids or gemcitabine .
    • The last dose of treatment with any investigational agent or participation in a clinical trial with therapeutic intent must have ended ≥ 28 days prior to randomization.
    • Prior radiation therapy is allowed provided the patient has recovered from any toxic effects thereof and ≥ 7 days have elapsed between the last fraction and randomization.
    • Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first study treatment: ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks of test), WBC counts > 2,500/μL and < 15,000/μL, Lymphocyte count ≥ 500/μL, Platelet count ≥ 100,000/μL (without transfusion within 2 weeks of test), Hemoglobin ≥ 9.0 g/dL. Patients may be transfused or receive erythropoietic treatment to meet this criterion.
    • Adequate liver function: AST or ALT ≤ 2.5 × ULN, with normal alkaline phosphatase or AST and ALT ≤ 1.5 × ULN in conjunction with alkaline phosphatase > 2.5 × ULN; Serum bilirubin ≤ 1.0 × ULN. Patients with known Gilbert’s disease who have serum bilirubin level ≤ 3 × ULN are eligible.
    • INR and aPTT ≤ 1.5 × ULN (only for patients not receiving therapeutic anticoagulation). Patients receiving therapeutic anticoagulation must be on a stable dose for at least 1 week prior to randomization.
    • Female patients of childbearing potential and male patients with partners of childbearing potential, must agree to use a highly effective form of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) and to continue its use for 6 months after the last dose of the experimental treatment.
    • Patients must have recovered from all acute toxicities from previous therapy, excluding alopecia.
    Vorliegen einer unterschriebenen Einverständniserklärung
     Fähigkeit, die Vorgaben des Protokolls zu erfüllen
     Alter ≥ 18 Jahre
     Messbare Erkrankung, definiert nach RECIST V.1.
     ECOG performance status von 0 oder 1
     Lebenserwartung ≥ 12 Wochen
     Histologisch gesichertes lokal fortgeschrittenes oder metastasiertes (z.B. Stadium IIIB – für Radiochemotherapie ungeeignet, Stadium IV oder Rezidiv) NSCLC (nach dem UICC/AJCC System).
     Progression unter oder nach einer vorangegangenen platinhaltigen Therapie für das lokal fortgeschrittene, nicht-respektable/-operable oder metastasierte NSCLC, oder Rezidiv innerhalb von 6 Monaten nach einer platinbasierten adjuvanten/ neoadjuvanten Therapie
     Nicht mehr als 2 vorausgehende zytotoxische Chemotherapieregime
     Patienten mit Progress unter oder nach Behandlung mit EGFR TKI in der Erstlinie, oder Patienten die eine Behandlung mit Erlotinib, Geftinib oder anderen EGFR TKIs nicht vertragen, dürfen eingeschlossen werden.
     Patienten mit Progress unter oder nach einer Behandlung mit Crizotinib oder einem anderen ALK-Inhibitor
     Die letzte Behandlung mit einer vorausgehenden Tumortherapie muss mindestens 21 Tage vor Randomisierung beendet sein (≥ 14 Tage für Vinorelbin oder andere Vincaalkaloide oder Gemcitabin. Die letzte Behandlung mit einem experimentellen Wirkstoff muss mindestens 21 Tage vor Randomisierung beendet sein
     Eine vorangegangen Bestrahlung ist erlaubt, sofern alle Toxizitäten abgeklungen sind und die letzte Sitzung mehr als 7 Tage vor der Randomisierung liegt.
     Adäquate hämatologische und Organfunktion, definiert als:
    o Neutrophile (absolut) ≥ 1500 Zellen/μl (ohne GCS-F innerhalb der letzten 2 Wochen)
    o Leukozyten > 2,500/μL and < 15,000/μL
    o Lymphozyten ≥ 500/μL
    o Thrombozyten ≥ 100,000/μL (ohne Transfusion innerhalb der letzten 2 Wochen)
    o Hämoglobin ≥ 9.0 g/dL (Transfusionen oder erythropoetische Behandlung sind erlaubt)
     Adequate Leberfunktion definiert durch:
    o AST or ALT ≤ 2.5 × ULN alkalische Phosphatase > 2.5 × ULN
    o Serum Bilirubin ≤ 1.0 × ULN. Patienten mit bekanntem Morbus Meulengracht müssen einen Serum Bilirubin Level ≤ 3 × ULN haben.
     INR und aPTT ≤ 1.5 × ULN, ohne Antikoagulation. Patienten unter Antikoagulation müssen seit mindestens 1 Woche vor Randomisierung unter einer stabilen Dosierung sein.
     Weibliche Patienten im gebärfähigen Alter und männliche Patienten mit Partnerinnen im gebärfähigen Alter müssen einer hoch-effektiven Form der Kontrazeption (z.B. operative Sterilisation, verlässliche Barriere-Methode, Antibabypille oder Hormonimplantat) zustimmen und diese für mindestens 6 Monate nach Beendigung der kombinierten biomodulatorischen Studientherapie fortführen
     Alle Toxizitäten aus vorangegangenen Therapien müssen abgeklungen sein
    E.4Principal exclusion criteria
    Cancer-Specific Exclusion criteria

    • Known active or untreated central nervous system (CNS) metastases
    • Patients with a history of treated asymptomatic CNS metastases are eligible, if they meet all of the following criteria: No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm). Radiographic demonstration of improvement after CNS directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and CNS screening imaging.Screening CNS radiographic imaging ≥ 4 weeks since completion of radiotherapy and ≥ 2 weeks since discontinuation of corticosteroids
    • History of intracranial hemorrhage
    • Completed stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1, Day 1
    • Spinal cord compression not definitively treated with surgery and/or radiation, or previously treated spinal cord compression that has been clinically stable for less than 2 weeks prior to randomization
    • Leptomeningeal disease
    • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage
    • Uncontrolled tumor-related pain: Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to enrolment.
    • Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
    • Malignancies other than NSCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).

    General Exclusion criteria

    • History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis
    • Serum albumin < 2.5 g/dL
    • Patients with active hepatitis B or hepatitis C. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
    • Significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
    • Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina.
    • Patients with a known left ventricular ejection fraction (LVEF) < 40%. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical.
    • Active or latent tuberculosis
    • Severe infections within 4 weeks prior to randomization, including hospitalization for complications of infection, bacteraemia, or severe pneumonia
    • Received oral or IV antibiotics within 2 weeks prior to randomization
    • Major surgery within 4 weeks prior to randomization foreseen major surgery during the course of the study.
    • Prior treatment with nivolumab
    • Grade ≥ 2 peripheral neuropathy
    • Patients undergoing dialysis or creatinine clearance <30 mL per minute
    • Medically uncontrolled hypertension (RR continuously > 140/90 mm Hg)
    • Simultaneous treatment with another investigational agent or simultaneous anticancer treatment outside this trial


    Exclusion criteria related to the study drugs

    • Heart failure > NYHA 1, QT prolongation, ventricular arrhythmias, torsade de pointes
    • Creatinine > 1.5 mg/dL
    • Patients with chronic hypopotassemia
    • Patients with HIV infection requiring virostatic therapy
    • Any previous or concurrent malignancy or any cancer unless curatively treated > 3 years prior to study entry except cervical carcinoma in situ or adequate basal cell carcinoma
    • Patients with bladder cancer or bladder cancer in their medical history, patients with risk factors for bladder cancer (such as exposure to aromatic amines or heavy tobacco smokers), or macrohematuria of unknown origin
    • Known (at time of entry) gastrointestinal disorder, including malabsorption or active gastric ulcer, present to the extent that it might interfere with oral intake and absorption of study medication
    • Autoimmune disease, symptomatic interstitial lung disease, systemic immunosuppression, prior therapy with T-cell costimulation or checkpoint-targeted agent
    Krebs-spezifische Ausschlusskriterien
     Bekannte aktive oder unbehandelte Metastasen des zentralen Nervensystems (ZNS). Patienten mit bekannten, behandelten, asymptomatischen ZNS-Metastasen nur, wenn bei folgenden Voraussetzungen: Keine Metastasen im Hirnstamm, Mittelhirn, Pons, Medulla, Cerebellum oder innerhalb von 10 mm im optischen Apparat. Radiologische gesicherter Erfolg der abgeschlossenen ZNS-gerichteten Therapie und kein Nachweis eines Progresses zwischen Beendigung der ZNS-Therapie und dem Screening für die Studie. Eine bildgebende ZNS Untersuchung muss ≥ 4 Wochen nach Beendigung einer Radiotherapie oder ≥ 2 Wochen nach Beendigung einer Kortikoidgabe gemacht worden sein
     Bekannte intrakranielle Blutungen
     Fortlaufende Behandlung mit Dexamethason für eine ZNS-Erkrankung
     Stereotaktische Bestrahlung /Bestrahlung des gesamten Gehirns innerhalb von 28 Tagen vor Tag 1 von Zyklus 1
     Rückenmarkkompression, welche nicht durch einen operativen Eingriff und/oder Bestrahlung behandelt wurde, oder welche therapiert wurde und ≥ 2 Wochen vor Randomisation klinisch nicht stabil gewesen ist.
     Leptomeningeale Erkrankung
     Unkontrollierter Pleuraerguss, Perikarderguss oder Aszites, welcher wiederholt Drainagen erfordert
     Unkontrollierter tumorassoziierter Schmerz: Patienten unter Schmerztherapie müssen stabil eingestellt sein. Symptomatische Läsionen, die palliativ bestrahlt werden können, sollten vor Studienstart behandelt werden. Für asympt. metastastische Läsionen, deren weiteres Wachstum wahrscheinlich funktionelle Defizite oder nicht tolerierbare Schmerzen verursachen könnte, sollte eine lokoregionale Therapie vor Einschluss in die Studie in Erwägung gezogen werden.
     Hyperkalzämie (ca.> 1.5 mmol/L ionisiertes Kalzium oder Ca > 12 mg/dL oder korrigiertes Serum-Kalzium > ULN oder symptomatische Hyperkalzämie, welche eine kontinuierliche Biphosphonat-Therapie oder Gabe von Denosumab erfordert). Patienten ohne bislang bekannte symptomatische Hyperkalzämie, die eine prophylaktische Biphosphonattherapie oder Denosumab erhalten, um Skelettschädigungen zu vermeiden, können eingeschlossen werden.
     Andere Malignome (außer NSCLC) in den letzten 5 Jahren vor Randomisierung, ausgenommen solche mit vernachlässigbarem Risiko von Metastasierung oder Tod, welche kurative behandelt wurden
    Allgemeine Ausschlusskriterien
    - Bekannte idiopathische pulmonale Fibrose (einschl. Pneumonitis), Vorgeschichte einer medikamentös-induzierten Pneumonitis
    - Serum Albumin < 2.5 g/dL
    - Patienten mit einer aktiven Hepatitis B oder C. Patienten mit zurückliegenderoder ausgeheilter HBV können eingeschlossen werden. Patienten mit einem positiven Antikörpertiter für HCV können nur bei Nachweis eines negativem PCR-Test für HCV-RNA eingeschlossen werden.
    - Klinisch signifikante, unkontrollierte Begleiterkrankung, die die Befolgung des Studienprotokolls oder die Interpretation der Ergebnisse beeinträchtigen kann (inkl. signifikante Lebererkrankung, signifikante kardiovaskuläre Erkrankung (z.B. Myokardinfarkt in den letzten 3 Monaten vor Randomisierung, instabile Arrhythmien, instabile Angina)
    - Linksventrikuläre Ejektionsfraktion (LVEF) < 40%. Patienten mit bekannter koronarer arterieller Herzerkrankung oder kongestiver Herzinsuffizienz, die nicht auf die o.g. Kriterien zutreffen oder LEVF < 50% müssen stabil medikamentös eingestellt sein.
    - Tuberkulose
    - Schwerwiegende Infektionen innerhalb von 4 Wochen vor Randomisierung
    - Orale oder i.v. Antiobiotikagabe innerhalb von 2 Wochen vor Randomisierung
    - Größere operative Eingriffe innerhalb von 4 Wochen vor Randomisierung oder geplante größere operative Eingriffe im Studienverlauf, die nicht der Diagnosestellung dienen
    - Vorhergehende Behandlung mit Nivolumab
    - Periphere Neuropathie ≥ Grad 2 definiert nach NCI CTC AE v4.0 criteria
    - Patienten unter Dialyse oder mit einer Kreatinin Clearance <30 mL/ min, berechnet nach der MDRD-Formel
    - Patienten mit unkontrollierter Hypertonie (RR kontinuierlich >140/90 mm Hg)
    - Gleichzeitige Behandlung mit anderen experimentellen Substanzen oder gleichzeitige Krebstherapie außerhalb der Studie
    Ausschlusskriterien aufgrund der Studienmedikamente
     Herzinsuffizienz > NYHA 1, QT Verlängerung, ventrikuläre Arrythmie
     Heart failure, QT prolongation, ventricular arhythmias, Torsade de pointes
     Kreatinin > 1.5 mg/dL
     Chronische Hypokalämie
     HIV Infektion, die eine virostatische Therapie notwendig macht
     Vorangegangenes oder aktuelles Blasenkarzinom, erhöhtes Risiko für ein Blasenkarzinom (z.B. starke Raucher/Exposition von aromatischen Aminen) oder Markohämaturie unbekannten Ursprungs
     Bekannte gastrointestinale Störungen inkl.Unverträglichkeiten/ aktiver Magengeschwüre, welche mit der oralen Aufnahme oder Absorption der Studienmedikation interferieren könnten
    •Autoimmunerkrankungen, sympt. interst. Lungenerkrankungen, systemische Immunsupression, vorherige T-Zell-Costimmulation / Behandlung mit Checkpoint-target Substanzen
    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
    the analysis is event driven and will be done when 69 events have occured.
    Die PFS-Analyse ist ereignisbezogen und wird durchgeführt, wenn 69 Ereignisse eingetreten sind.
    E.5.2Secondary end point(s)
    • To evaluate the efficacy of the combined modularized treatment with treosulfan, pioglitazone and clarithromycin compared to nivolumab
    o overall survival (OS)
    o duration of response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)

    • To evaluate the safety and tolerability of the treatment with treosulfan, pioglitazone and clarithomycin compared to nivolumab.

    • To evaluate universal response parameters (cellular secretome analytics in serum) for modulation of hallmarks of cancer (inflammation, angiogenesis and immune response). To evaluate and compare patient reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL) between treatment arms, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and its Lung Cancer Module (LC13)

    • To evaluate the relationship between tumor tissue PPARγ expression and efficacy

    • To assess change in predictive and prognostic exploratory biomarkers on fresh serum samples
    - Bestimmung der Effektivität einer kombinierten biomodulatorischen Therapie, bestehend aus Treosulfan, Pioglitazon und Clarithromycin, im Vergleich zu einer Therapie mit Nivolumab , gemessen am
    o Gesamtüberleben (OS)
    o Dauer des Anprechens (DOR) definiert durch die „Response Evaluation Criteria in Solid Tumors“ (RECIST v1.1)
    - Bewertung der Sicherheit und Verträglichkeit der kombinierten biomodulatorischen Behandlung im Vergleich zur Behandlung mit Nivolumab
    - Bewertung von universellen Parametern (zelluläre Sekretomanalyse im Serum) zur Beurteilung der Modulation von ‚Hallmarks of Cancer‘, nämlich Entzündungen, Angiogenese und Immunantwort.
    - Bewertung mit Lebensqualitätsfragebögen ((EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) und Lung Cancer Module (LC13)), die von Patienten aus beiden Behandlungsarmen ausgefüllt werden.
    - Beurteilung der PPARgamma-Expression im Tumorgewebe und der Therapie-Effektivität
    - Bewertung von Änderungen prädiktiver oder prognostischer explorativer Biomarker in archiviertem und/oder frischem Tumormaterial und Blut (Serum)
    - Tumorgewebe von der Erstdiagnose oder vom Rezidiv: Routinebestimmung von molekulargenetischen Biomarkern (EGFR, K-Ras, ALK) und Gewebemicroarry zur Bestimmung der PPARgamma-Expression.
    - Serum: Sekretomanalyse zur Beobachtung der Funktion tumoraszoziierter Zellkompartimente. Serumproben werden zu Beginn eines jeden Zyklus abgenommen.
    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 Yes
    E.6.11Pharmacogenomic Yes
    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 Yes
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned11
    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
    Last Follow-Up view of the last patient
    Der letzte Kontakt im letzten FollowUp des letzten Patienten
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    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.1.3Elderly (>=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 state86
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Keine
    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 Decision2015-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-03-21
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