Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   38003   clinical trials with a EudraCT protocol, of which   6235   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2016-003334-25
    Sponsor's Protocol Code Number:Uni-Koeln-2785
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-11-15
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2016-003334-25
    A.3Full title of the trial
    A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in relapsed lung cancer and to evaluate biomarkers predictive for response to immune checkpoint inhibition
    Eine Phase II-Studie mit Nivolumab in Kombination mit Ipilimumab zur Evaluierung der Sicherheit und Wirksamkeit im rezidivierten Lungenkrebs und zur Evaluierung von prädiktiven Biomarkern
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of advanced lung cancer
    Behandlung von fortgeschrittenem Lungenkrebs
    A.3.2Name or abbreviated title of the trial where available
    BIOLUMA
    A.4.1Sponsor's protocol code numberUni-Koeln-2785
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03083691
    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 of Cologne
    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 of Cologne
    B.5.2Functional name of contact pointDr. Antonio Pinto
    B.5.3 Address:
    B.5.3.1Street AddressKerpener Str. 62
    B.5.3.2Town/ cityCologne
    B.5.3.3Post code50937
    B.5.3.4CountryGermany
    B.5.4Telephone number+4922147898766
    B.5.5Fax number+492214783978
    B.5.6E-mailantonio.pinto@uk-koeln.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 OPDIVO
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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.3.4Pharmaceutical 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.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number40 to 100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 Yervoy
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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.3.4Pharmaceutical 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.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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.2.1.1.1Trade name OPDIVO
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing 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.3.4Pharmaceutical 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.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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.2.1.1.1Trade name OPDIVO
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing 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.3.4Pharmaceutical 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.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 Yervoy
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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.3.4Pharmaceutical 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.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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
    Patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) and patients with Small cell lung cancer (SCLC) after failure of platinum-based first-line therapy.
    Patienten mit lokal fortgeschrittenem oder metastasiertem Adenokarzinom der Lunge und Patienten mit einem kleinzelligem Lungenkarzinom in frühen oder fortgeschrittenen Stadium nach Versagen einer Platinhaltigen Erstlinientherapie.
    E.1.1.1Medical condition in easily understood language
    Adult patients with locally advanced or metastatic lung cancer.
    Erwachsene Patienten mit fortgeschrittenem oder metastasierten Lungenkrebs.
    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 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 21.1
    E.1.2Level PT
    E.1.2Classification code 10041068
    E.1.2Term Small cell lung cancer extensive stage
    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 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 21.1
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    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 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.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10041070
    E.1.2Term Small cell lung cancer recurrent
    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 10059514
    E.1.2Term Small cell lung cancer metastatic
    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
    Cohort 1:
    To assess ORR when ipilimumab is added to nivolumab after progression on nivolumab monotherapy in patients relapsed with non-squamous NSCLC (second line).
    Note: Cohort 1 is closed for enrollment. Subjects who started screening for cohort 1 prior to stop of recruitment initiated by Coordinating PI on April 25 2019 will continue to receive treatment. SCLC subjects eligible for BIOLUMA will be enrolled in cohort 2b after TMB-Prescreening from October 29 2018 on.
    Cohort 2a:
    To assess ORR of the combination therapy of ipilimumab and nivolumab in patients with relapsed SCLC and non-discriminated TMB (second line).
    Note: Cohort 2a is closed for enrollment. SCLC Subjects eligible for BIOLUMA will be enrolled in Cohort 2b after TMB-Prescreening from October 29 2018on.

    Cohort 2b:
    To assess ORR of the combination therapy of ipilimumab and nivolumab in patients with relapsed SCLC and high TMB (second line).

    Kohorte 1 (NSCLC): Erhebung der Ansprechrate der Kombinationstherapie aus Nivolumab und Ipilimumab nach Tumorprogress unter Nivolumab-Monotherapie bei Patienten mit rezidiviertem AD-NSCLC in der Zweitlinientherapie.

    Für Kohorte 1 wurde ab dem 25.04.2019 durch den Sponsor aus medizinischen Gründen ein Einschlussverbot erteilt.

    Kohorte 2a (SCLC): Erhebung der Ansprechrate der Kombinationstherapie aus Nivolumab und Ipilimumab bei Patienten mit rezidiviertem SCLC und nicht weiter diskriminierter Tumor-Mutationslast in der Zweitlinientherapie.

    In Kohorte 2a kann seit dem 29.10.2018 nicht mehr eingeschlossen werden.

    Kohorte 2b (SCLC): Erhebung der Ansprechrate der Kombinationstherapie aus Nivolumab und Ipilimumab bei Patienten mit rezidiviertem SCLC und hoher Tumor-Mutationslast in der Zweitlinientherapie.
    E.2.2Secondary objectives of the trial
    •To assess efficacy of nivolumab monotherapy/ nivolumab + ipilimumab combination therapy
    •To characterize safety and tolerability of nivolumab monotherapy/ nivolumab + ipilimumab combination therapy
    •To assess the predictive value of PD-L1- and PD-L2 positivity of tumor cells for response to nivolumab monotherapy/ nivolumab + ipilimumab combination therapy
    •To correlate overall TMB and neoepitope signatures with clinical outcome in the NSCLC cohort and in the SCLC cohort recruited before restriction to TMB high patients
    •To correlate neoepitope signatures with clinical outcome in the SCLC TMB high cohort
    •Erhebung der Wirksamkeit der Nivolumab-Monotherapie und der Kombinationstherapie mit Nivolumab und Ipilimumab
    •Charakterisierung der Sicherheit und Tolerabilität der Nivolumab-Monotherapie und der Kombinationstherapie mit Nivolumab und Ipilimumab
    •Beurteilung des prädiktiven Wertes der PD-L1- und PD-L2-Positivität der Tumorzellen für das Ansprechen auf die Nivolumab-Monotherapie und Kombinationstherapie mit Nivolumab und Ipilimumab
    •Korrelation von Mutationslast und Neoepitop-Signaturen mit dem klinischen Therapieansprechen in der NSCLC-Kohorte und in der SCLC-Kohorte, welche vor der Beschränkung auf Patienten mit hoher Tumor-Mutationslast eingeschlossen wurden
    •Korrelation von Neoepitop-Signaturen mit dem klinischen Therapieansprechen in der SCLC-Kohorte mit hoher Tumor-Mutationslast

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Note: Cohort 1 is closed for enrollment. Subjects who started screening for cohort 1 prior to stop of recruitment initiated by Coordinating PI on April 25 2019 will continue to receive treatment.

    • Cohort 1: Subjects with histologically or cytologically confirmed advanced non-squamous non-small cell lung cancer who present with stage IIIB/IV disease after failure of platinum-based first-line therapy (second line). Subjects who received adjuvant/neoadjuvant therapy or definitive chemoradiation and develop recurrence or progression, with evidence of stage IIIB-IV disease within 6 months after completion of therapy, are eligible.

    • Cohort 2a: Subjects with histologically or cytologically confirmed limited-stage or extensive-stage small cell lung cancer after failure of platinum-based first-line therapy with or without anti-PD-1/PD-L1 treatment.(TMB non-discrimated SCLC patients).
    Note: Cohort 2a is closed for enrollment.

    • Cohort 2b: Subjects with histologically or cytologically confirmed limited-stage or extensive-stage TMB high small cell lung cancer after failure of platinum-based first-line therapy with or without anti-PD-1/PD-L1 treatment.Inclusion after 2nd line Topotecan-Therapy is allowed. Only TMB high SCLC patients are included, as tested on tumor material during routine biopsies for first diagnosis (whole exome sequencing on FFPE tissue). For definition of TMB high, please refer to chapter 5.5.1.2

    The following inclusion criteria apply for Cohort 1, 2a and 2b:
    • Signed and dated IRB/IEC-approved written informed consent form must be obtained before the performance of any study-specific procedure
    • Male or female patients over 18 years of age
    • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
    • Subjects must be willing to undergo at baseline screening biopsy.
    • Subjects must be considered as suitable for conduction of 2 biopsies (baseline and in case of progression) by the responsible local investigator.
    • Measurable disease by CT or MRI per RECIST 1.1 criteria. Target lesions may be located in a previously irradiated field if there is documented disease progression in that site after completion of radiation therapy
    • Subjects with CNS metastases are eligible if CNS metastases are treated and subjects have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 28 days prior to first dose of study drug administration. In addition, subjects must either be off corticosteroids or on a stable dose or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
    • Cohort 2b: Subjects with CNS metastases are eligible. Radiation of CNS metastases at initiation of study drug treatment is allowed if the trial subject has target lesions outside of the brain.
    • Note for Cohort 2b: higher doses of corticosteroids for patients receiving radiation therapy of brain metastases are allowed
    Notiz: In Kohorte 1 kann seit dem 25.04.2019 nicht mehr eingeschlossen werden.

    •Kohorte 1 (NSCLC): Zweitlinientherapie für Patienten mit histologisch oder zytologisch gesichertem, fortgeschrittenem Adenokarzinom der Lunge im Stadium IIIB/IV mit Tumorprogress nach Platin-haltiger Erstlinientherapie. Patienten, die eine adjuvante oder neoadjuvante Therapie, oder eine definitive Radiochemotherapie erhalten haben und innerhalb von sechs Monaten nach Vollendung der Therapie ein Rezidiv oder einen Tumorprogress mit Stadium IIIB/IV erleiden, sind zur Teilnahme berechtigt.

    •Kohorte 2a (SCLC): Zweitlinientherapie für Patienten mit histologisch oder zytologisch gesichertem SCLC n frühem oder fortgeschrittenem Stadium mit Tumorprogress nach Platin-haltiger Erstlinientherapie mit oder ohne anti-PD-1/PD-L1 Behandlung (ohne Unterscheidung der Tumormutationslast des Patienten).
    Notiz: In die Kohorte 2a kann nicht mehr eingeschlossen werden.

    •Kohorte 2b: Zweitlinientherapie für Patienten mit histologisch oder zytologisch gesichertem SCLC und hoher Tumor-Mutationslast (TMB high) in frühem oder fortgeschrittenem Stadium mit Tumorprogress nach Platin-haltiger Erstlinientherapie. Einschluss nach Topotecan-Therapie in der Zweitlinie ist erlaubt. Nur TMB high SCLC Patienten werden eingeschlossen. Die Bestimmung der Tumor -Mutationslast erfolgt in einem Prescreenig per whole exome sequencing aus Tumorblöcke der Erstdiagnose.

    Die folgenden Einschlusskriterien gelten für die Kohorte 1, 2a und 2b:
    •Unterschriebene und datierte Patienteneinwilligung, welche vor jeglicher Studien-spezifischen Maßnahme eingeholt werden muss und welche zuvor von einer unabhängigen Ethikkommission genehmigt wurde
    •Männliche oder weibliche Patienten über 18 Jahre
    •Eastern Cooperative Oncology Group (ECOG) Performance Status von 0-1
    •Studienpatienten müssen bereit sein, mindestens beim Screening eine baseline Tumorbiopsie durchführen zu lassen.
    •Der jeweilige Prüfarzt muss den Studienpatienten für fähig erachten, zwei Tumorbiopsien durchführen zu lassen (Baseline und bei Tumorprogress)
    •Mindestens eine nach RECICT 1.1 auswertbare Tumorläsion im CT oder MRT. Zielläsionen können in einer zuvor bestrahlten Region liegen, wenn ebendort ein Tumorprogress nach Vollendung der Bestrahlung dokumentiert wurde
    •Patienten mit ZNS-Metastasen dürfen an der Studie teilnehmen, wenn diese behandelt wurden und die Patienten für mindestens 28 Tage vor Verabreichung der ersten Studienmedikation ihren neurologischen Ausgangsstatus wieder erreicht haben (davon ausgenommen sind verbleibende Symptome, die mit der Therapie in Zusammenhang stehen). Zusätzlich darf keine Therapie mit Corticosteroiden mehr notwendig sein, bis auf eine stabile oder abnehmende Dosis von täglich ≤ 10 mg Predisonäquivalent.
    Kohorte 2b: Teilnehmer mit ZNS Metastasen dürfen teilnehmen. Bestrahlung von ZNS Metastasen bei Beginn der Behandlung ist erlaubt, falls die Zielläsionen außerhalb des ZNS liegen.
    Für Teilnehmer der Kohorte 2b sind höhere Dosen an Corticosteroiden möglich.


    E.4Principal exclusion criteria
    • Subjects with squamous cell NSCLC
    • For Cohort 1 only: EGFR activating mutation or ALK translocation
    • More than one prior line of chemotherapy for treatment of advanced disease
    • Medical conditions associated with significantly increased risk for bleeding complications caused by biopsy procedures (e.g. known coagulopathies, therapeutic anticoagulation)
    • Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks after treatment has been completed and within 28 days prior to the first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
    • Presence or history of any other primary malignancy other than non-squamous NSCLC for Cohort 1 and SCLC for Cohort 2a/2b within 5 years prior to enrolment into the trial, except for adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma.
    • Subjects with active, known or suspected autoimmune disease. Subjects are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
    • Positive test for hepatitis B virus surface antigen (HBV sAg or HBV-DNA) or hepatitis C virus ribonucleic acid (HCV-RNA) indicating acute or chronic infection
    • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    • Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease
    • Note for Cohort 2b: higher doses of corticosteroids for patients receiving radiation therapy of brain metastases are allowed
    • Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
    • Prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
    Note for Cohort 2b: inclusion of patients who received 2nd line treatment is allowed if 2nd line did not include an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA-4 antibody as monotherapy or in combination with other than platinum-based chemotherapy.
    • Any other serious or uncontrolled medical disorder, active infections, physical exam findings, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject’s ability to comply with the study requirements, substantially increase risk to the subject, or negatively impact the interpretation of study results.
    • History of allergies or severe hypersensitivity reaction to study drug components or to any monoclonal antibody
    •Patienten mit Plattenpithelkarzinom der Lunge
    •Betrifft nur die Kohorte 1(NSCLC): aktivierende EGFR-Mutation oder ALK-Translokation
    •Vorliegen eines medizinischen Zustandes, der mit signifikant erhöhtem Risiko für Blutungskomplikationen im Rahmen der Tumorbiopsie einhergeht (z.B. bekannte Koagulopathie, therapeutische Antikoagulation)
    •Aktive Hirn- oder leptomeningeale Metastase. Patienten mit Hirnmetastasen kommen für den Studieneinschluss in Frage, wenn die Metastase behandelt wurde und im MRT vier Wochen nach Abschluss der Therapie, sowie innerhalb von 28 Tagen vor Beginn der Studienmedikation kein Progresses nachzuweisen ist. Außerdem darf für mindestens zwei Wochen vor Studientherapiegabe keine Notwendigkeit einer systemischen Therapie mit Corticosteroiden > 10 mg Prednisonäquivalent täglich bestehen
    •Aktuell vorliegende, oder innerhalb der letzten fünf Jahre vor Studieneinschluss zurückliegende, weitere Malignomerkrankung, mit Ausnahme von adäquat behandeltem Basalzellkarzinom oder Plattenepithelkarzinom der Haut, oder jedes anderen adäquat behandelten Carcinoma in situ
    •Patienten mit aktiver, bekannter, oder vermuteter Autoimmunerkrankung. Patienten mit Vitiligo, Diabetes mellitus Typ 1, Autoimmunhypothyreose welche lediglich einer Hormonersatztherapie bedarf, Psoriasis ohne Notwendigkeit einer systemischen Therapie, oder Patienten mit einer Autoimmunerkrankung, von der nicht zu erwarten ist, dass sie ohne externen Auslöser wieder auftritt, kommen für den Studieneinschluss in Frage
    •Aktive oder chronische Hepatitis B- oder Hepatitis C-Infektion mit Nachweis von Hepatitis B-Virusoberflächenantigen (HBV sAG) oder von Hepatitis C-RNA (HCV RNA)
    •Bekannte Infektion mit dem humanen Immundefizienzvirus (HIV) oder positiver HIV-Test, oder bekannte AIDS-Erkankung (acquired immunodeficiency syndrome)
    •Jedweder Zustand, der eine systemische Therapie mit entweder Corticosteroiden (> 10 mg Prednisonäquivalent täglich), oder anderer immunsuppressiver Medikation innerhalb von 14 Tagen vor Verabreichung der ersten Studienmedikation, erforderlich macht. Inhalative oder topische Steroide und Corticosteroiddosen als Nebennierenersatztherapie von < 10 mg Prednisonäquivalent pro Tag sind bei Abwesenheit einer aktiven Autoimmunerkrankung erlaubt .
    Für Teilnehmer der Kohorte 2b sind höhere Dosen an Corticosteroiden möglich.
    •Patienten mit interstitieller Lungenerkrankung, die symptomatisch ist, oder sich störend auf die Detektion oder das Management von Therapie-bezogenen pulmonalen Toxizitäten auswirken könnte
    •Vorhergehende systemische Therapie mit einem anti-PD-1-, anti-PD-L1-, anti-PD-L2- oder anti-CTLA-4-Antikörper, oder jedem anderen Antikörper oder Medikament welcher/welches spezifisch auf die T-Zell-Kostimulation oder einen Immuncheckpoint-Signalweg zielt.
    Notiz: SCLC-Patienten, die in der Zweitlinie nicht mit anti-PD-1/PD-L1/anti-PD-L2 oder anti-CTLA-4 Medikation behandelt wurden, können eingeschlossen werden.
    •Jedwede/jedeweder andere ernsthafte oder unkontrollierte medizinische Zustand, aktive Infektion, Auffälligkeit bei der körperlichen Untersuchung, Laborwertveränderung, Veränderung des Geisteszustandes oder psychiatrische Auffälligkeit, die nach Ansicht des Prüfarztes die Fähigkeit des Patienten sich an die für die Studie notwendigen Vereinbarunge zu halten beeinträchtig, erheblich das Patientenrisiko erhöht, oder sich negativ auf die Interpretaion der Studienergebnisse auswirkt
    •Bekannte Allergie oder schwere Hypersensitivitätsreaktion gegen einen Bestandteil der Studienmedikation, oder gegen jeglichen monoklonalen Antikörper
    E.5 End points
    E.5.1Primary end point(s)
    Cohort 1 (NSCLC): ORR according to investigator-assessed RECIST 1.1 criteria of the combination of nivolumab and ipilimumab after progression on nivolumab monotherapy in patients relapsed with non-squamous NSCLC.
    Cohort 2a and 2b (SCLC): ORR according to investigator-assessed RECIST 1.1 criteria of the combination of nivolumab and ipilimumab in patients with relapsed SCLC and TMB.
    Kohorte 1 (NSCLC): Die nach RECIST 1.1 durch den Prüfer erhobene Ansprechrate der Kombinationstherapie mit Nivolumab und Ipilimumab nach Tumorprogress unter Nivolumab-Monotherapie bei Patienten mit rezidiviertem AD-NSCLC.
    Kohorte 2a und 2b (SCLC): Die nach RECIST 1.1 durch den Prüfer erhobene Ansprechrate der Kombinationstherapie mit Nivolumab und Ipilimumab bei Patienten mit rezidiviertem SCLC und hoher Tumor-Mutationslast.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cohorte 1 (NSCLC); Part A: tumor assessment begins at Week 8 and is performed every 8 weeks (+/- 1 week). Part B: tumor assessments are continued every 8 weeks until Week 48 (C24D1), then every 12 weeks (+/- 1 week).
    Cohorte 2a und 2b (SCLC); Part A: tumor assessment is performed at Week 5 (C3D1) and Week 11 (C6D1). Part B: first tumor assessment is performed at C4D1 (+/- 1 week) and then every 8 weeks until Week 48 (C24D1), then every 12 weeks (+/- 1 week).
    Kohorte 1 (NSCLC); Part A: Tumorkontrolluntersuchungen beginnen in der Woche 8 und werden alle 8 Wochen (+/- 1 Woche) durchgeführt. Part B: alle 8 Wochen bis zur Woche 48 (C24D1), im weiteren Verlauf alle 12 Wochen (+/- 1 Woche).
    Kohorte 2a und 2b (SCLC); Part A: Tumorkontrolluntersuchungen finden in der Woche 5 (C3D1) und Woche 11 (C6D1) statt. Part B: erste Tumorkontrolluntersuchung an C4D1 (+/- 1 Woche) und dann alle 8 Wochen bis Woche 48 (C24D1), im weiteren Verlauf alle 12 Wochen (+/- 1 Woche).
    E.5.2Secondary end point(s)
    •OS, PFS, DCR and DOR of nivolumab monotherapy/ nivolumab + ipilimumab combination therapy
    •Incidence, severity and grading of AEs and SAEs during nivolumab monotherapy/ nivolumab + ipilimumab combination therapy

    All biomarker related secondary endpoints will be assessed for nivolumab monotherapy as well as for the nivolumab + ipilimumab combination therapy

    •Predictive value of the pretreatment ≥1%, ≥5%, ≥10%, ≥25% and ≥50% PD-L1/ PD-L2 positive tumor cell cut-offs for ORR, DCR, PFS, OS, TTR and DOR
    •Correlation of pretreatment tumor-associated immune cells PD-L1/ PD-L2/ PD-1 positivity with ORR, DCR, PFS, OS, TTR and DOR
    •Predictive value of the composite of the pretreatment immune cell infiltrate for ORR, DCR, PFS, OS, TTR and DOR
    •Predictive value of additional co-inhibitory molecules for ORR, DCR, PFS, OS, TTR and DOR
    •Predictive value of PD-L1 and PD-L2 RNA expression for ORR, DCR, PFS, OS, TTR and DOR
    •Predictive value of TMB and predicted neoepitopes for ORR, PFS and OS in the NSCLC cohort and in the SCLC cohort before recruitment of TMB high patients only for SCLC patients
    •Predicitve value of predicted neoepitopes for ORR, PFS and OS in the TMB high SCLC cohort

    •OS, PFS, DCR und DOR unter der Nivolumab-Monotherapie und unter der Kombinationstherapie mit Nivolumab und Ipilimumab
    •Inzidenz und Schweregrad von unerwünschten Ereignissen (UEs) und schwerwiegenden unerwünschten Ereignissen (SUEs) unter der Nivolumab-Monotherapie und unter der Kombinationstherapie mit Nivolumab und Ipilimumab

    Alle Biomarker-bezogenen sekundären Enpunkte werden sowohl für die Nivolumab-Monotherapie, als auch für die Kombinationstherapie mit Nivolumab und Ipilimumab erhoben:

    •Prädiktiver Wert der PD-1/PD-L2-Positivität der Tumorzellen vor der Studientherapie für ORR, DCR, PFS, OS, TTR und DOR (Grenzwerte ≥1%, ≥5%, ≥10%, ≥25% und ≥50%)
    •Korrelation der PD-L1/PD-L2/PD-1-Positivität der Tumor-assoziierten Immunzellen vor der Studientherapie mit ORR, DCR, PFS, OS, TTR und DOR
    •Prädiktiver Wert der Zusammensetzung des Immunzellinfiltrates vor der Studientherapie für ORR, DCR, PFS, OS, TTR und DOR
    •Prädiktiver Wert von zusätzlichen ko-inhibitorischen Molekülen für ORR, DCR, PFS, OS, TTR und DOR
    •Prädiktiver Wert der RNA-Expression von PD-L1 und PD-L2 für ORR, DCR, PFS, OS, TTR und DOR
    •Prädiktiver Wert der Tumormutationslast und der vorherberechneten Neoepitope für ORR, PFS und OS in der NSCLC-Kohorte und in der SCLC-Kohorte, welche vor der Beschränkung auf Patienten mit hoher Tumor-Mutationslast eingeschlossen wurden
    •Prädiktiver Wert von Neoepitop-Signaturen mit ORR, PFS und OS in der SCLC-Kohorte mit hoher/mittlerer/niedriger Tumor-Mutationslast

    E.5.2.1Timepoint(s) of evaluation of this end point
    Cohorte 1 (NSCLC); Part A: every 8 weeks (+/- 1 week). Part B: every 8 weeks until Week 48 (C24D1), then every 12 weeks (+/- 1 week).
    Cohorte 2 (SCLC); Part A: tumor assessment is performed at Week 5 (C3D1) and Week 11 (C6D1). Part B: first tumor assessment is performed at C4D1 (+/- 1 week) and then every 8 weeks until Week 48 (C24D1), then every 12 weeks (+/- 1 week).
    Kohorte 1 (NSCLC); Part A: alle 8 Wochen (+/- 1 Woche). Part B: alle 8 Wochen bis zur Woche 48 (C24D1), im weiteren Verlauf alle 12 Wochen (+/- 1 Woche).
    Kohorte 2 (SCLC); Part A: Woche 5 (C3D1) und Woche 11 (C6D1). Part B: erste Tumorkontrolluntersuchung an C4D1 (+/- 1 Woche) und dann alle 8 Wochen bis Woche 48 (C24D1), im weiteren Verlauf alle 12 Wochen (+/- 1 Woche).
    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.8.2.4Number 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 concerned14
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 53
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 53
    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 state106
    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
    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 Decision2017-01-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-26
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA