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    Summary
    EudraCT Number:2015-005741-31
    Sponsor's Protocol Code Number:AIO-YMO/TRK-0415
    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:2016-07-18
    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 number2015-005741-31
    A.3Full title of the trial
    Fostering efficacy of anti – PD-1 – treatment: Nivolumab plus radiotherapy in advanced
    NSCLC
    Förderung der Wirksamkeit einer anti-PD-1-Behandlung (Immuntherapie Nivolumab) in Kombination mit Strahlentherapie zur Behandlung des fortgeschrittenen nicht-kleinzelligen Lungenkarzinoms (NSCLC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Fostering efficacy of anti – PD-1 – treatment: Nivolumab plus radiotherapy in advanced
    NSCLC
    A.3.2Name or abbreviated title of the trial where available
    FORCE
    FORCE
    A.4.1Sponsor's protocol code numberAIO-YMO/TRK-0415
    A.5.4Other Identifiers
    Name:BMS study numberNumber:CA209-430
    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 SponsorAIO-Studien-gGmbH
    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 organisationAIO-Studien-gGmbH
    B.5.2Functional name of contact pointDr. Aysun Karatas
    B.5.3 Address:
    B.5.3.1Street AddressKuno-Fischer-Straße 8
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code14057
    B.5.3.4CountryGermany
    B.5.4Telephone number004930814534431
    B.5.5Fax number004930322939226
    B.5.6E-mailinfo@aio-studien-ggmbh.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 (R)
    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.3.4Pharmaceutical 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.3.9.4EV 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 Yes
    D.3.11.13.1Other medicinal product typeNivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains.
    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
    metastatic non-squamous Non-Small Cell Lung Cancer (Lung adenocarcinoma metastatic and Large cell lung cancer metastatic)
    metastasiertes nicht-squamöses nicht-kleinzelliges Lungenkarzinom (metastasiertes nicht-kleinzelliges Adenokarzinom der Lunge und metastasiertes großzelliges Lungenkarzinom)
    E.1.1.1Medical condition in easily understood language
    metastatic non-squamous Non-Small Cell Lung Cancer (Lung adenocarcinoma metastatic and Large cell lung cancer metastatic)
    metastasiertes nicht-squamöses nicht-kleinzelliges Lungenkarzinom (metastasiertes nicht-kleinzelliges Adenokarzinom der Lunge und metastasiertes großzelliges Lungenkarzinom)
    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 10069730
    E.1.2Term Large 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064049
    E.1.2Term Lung adenocarcinoma 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
    The primary objective is to investigate clinical efficacy of a nivolumab-radiotherapy combination treatment..
    Das primäre Studienziel ist die Untersuchung der Wirksamkeit einer Kombination aus Nivolumab und palliativer Strahlentherapie in Patienten mit metastasiertem nicht-squamösem NSCLC.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    • information on safety and tolerability of nivolumab in combination with radiotherapy by measurement of incidence and severity of AEs and specific laboratory abnormalities in all treated subjects by subject subgroups
    • further efficacy data will in patients without necessity of radiotherapy
    • information on individual, patient reported and investigator-assessed quality of life
    • To explore immune related RECIST criteria as an evaluation method for clinical benefit of nivolumab and nivolumab/radiotherapy
    Exploratory objectives:
    • Tissue collection and blood sampling whilst course of disease to explore potential predictors of response to nivolumab
    • To address the role of radiotherapy in the context of immune modulation, several aspects of radiation planning and treatment are planned to be explored
    Sekundär:
    • Informationen über die Sicherheit und Verträglichkeit von Nivolumab in Kombination mit einer Strahlentherapie durch Messung der Häufigkeit und Schwere von AEs und Veränderungen spezifischer Laborwerte bei allen behandelten Patienten und in Subgruppen
    • weiterer Wirksamkeitsdaten bei Patienten ohne Notwendigkeit einer Strahlentherapie
    • Informationen über individuelle, von Patienten berichtete und vom Prüfarzt bewertete, Lebensqualität
    • Prüfung, ob die immuntherapie-bezogenen RECIST-Kriterien eine geeignete Evaluierungsmethode des klinischen Nutzens einer Nivolumab-Monotherapie bzw. einer Nivolumab-Strahlen-Kombinationstherapie sind
    Explorativ:
    • Sammlung von Gewebe- und Blutproben im Verlauf der Behandlung, um mögliche Prädiktoren für das Krankheitsansprechen nach Nivolumabgabe zu untersuchen
    • Bestimmung der Rolle der Strahlentherapie im Kontext der Immunmodulation wobei verschiedene Aspekte der Planung und Durchführung der Strahlentherapie erforscht werden sollen
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years at time of study entry.
    2. ECOG performance status 0-1.
    3. Patients with metastatic non-squamous non-small cell lung cancer after failure of platinum-based doublet chemotherapy and
    a) no necessity of radiotherapy (group B) or
    b) the necessity of radiotherapy of a metastatic bone lesion or soft tissue lesion (group A)
    4. Patients must have measurable disease by CT or MRI per RECIST 1.1 criteria.
    5. For each patient a formalin fixed, paraffin-embedded tumor tissue block (archival or recent) or a minimum of 15 unstained slides of tumor sample (2-3 µm sections; slices must be recent and collected on slides provided by the sponsor) must be available for biomarker (PD-L1) evaluation. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient.
    E.4Principal exclusion criteria
    1. Patients who require ongoing treatment with more than 10‑mg of prednisone (or steroid equivalent, excluding inhaled or topical steroids) daily.
    2. Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
    3. Patients with an active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids/immunosuppressive medications EXCEPT for syndromes which would not be expected to recur in the absence of an external trigger. (Subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement or skin disorders, (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.)
    4. Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy
    5. Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required or anticipated to be required during the study period.
    6. Brain metastases mandating active treatment in terms of WBI (whole brain irradiation or stereotactic brain irradiation).
    7. Subjects with brain metastases are eligible if metastases have been treated and treatment has been completed at least 12 weeks before inclusion in this study for group B and 2 weeks for group A. Moreover, there must be no magnetic resonance imaging (MRI) evidence of progression within 28 days prior to the first dose of nivolumab 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. Patients with stable/asymptomatic brain metastases that do not require local therapy with irradiation (whole brain irradiation or stereotactic brain irradiation) can be included. In ambiguous cases, consultation with the LKP or any authorized person ist advised
    8. Known activating EGFR mutation or a known ALK translocation.
    E.5 End points
    E.5.1Primary end point(s)
    • ORR according to RECIST 1.1 criteria
    • objektive Ansprechrate (ORR) nach RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    approx. 36 months after FPI, approx. 6 months after LPI
    ca. 36 Monate nach FPI, ca. 6 Monate nach LPI
    E.5.2Secondary end point(s)
    • PFS
    • PFS and ORR using assessment according to irRECIST
    • OS
    • 1 year OS rate
    • Descriptive subgroup analyses of efficacy in relation to PD-L1 expression levels (e.g. cut-off 1%, 5%, 10%)
    • Treatment Emergent Adverse Events according to CTC 4.03
    • Frequency of abnormal laboratory parameters
    • QoL [FACT-L]
    • Progressionsfreies Überleben (PFS) nach RECIST 1.1
    • PFS und ORR Bestimmung nach nach immuntherapie-bezogenden RECIST-Kriterien
    • Gesamtüberleben (OS)
    • 1-Jahres-Gesamtüberlebensrate
    • Deskriptive Subgruppenanalysen der Wirksamkeit in Bezug auf PD-L1-Expressions des Tumors (z.B. Schwellenwert 1%, 5%, 10%)
    • Behandlungsspezifische unerwünschte Ereignisse nach CTC 4.03
    • Häufigkeit anormaler Laborparameter
    • QoL [FACT-L]
    E.5.2.1Timepoint(s) of evaluation of this end point
    approx. 48 months after FPI
    ca. 48 Monate nach FPI
    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 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) 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 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 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
    End of study (EoS) is defined as the time point when the last patient in (LPI) has completed an 18 month treatment and follow-up observation phase period.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months48
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state130
    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)
    further treatment is at the discretion of the treating physican
    In the event that patients show continued clinical benefit from treatment with nivolumab at EOS date, the decision to continue treatment shall be based on the marketing authorization of nivolumab and the clinical judgment of the investigator/treating physician.
    die weitere Behandlung liegt im Ermessen des Arztes
    Für den Fall, dass der Patient zum Zeitpunkt der Beendigung der klinischen Prüfung von der Behandlung mit Nivolumab weiterhin profitiert, kann nach Ermessen des Prüfers die Therapie mit Nivolumab gemäß der Zulassung fortgeführt werden
    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 Decision2016-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-02
    P. End of Trial
    P.End of Trial StatusOngoing
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