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    Summary
    EudraCT Number:2018-002643-28
    Sponsor's Protocol Code Number:CA209-8JD
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-02-25
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-002643-28
    A.3Full title of the trial
    Safety and tolerability of neoadjuvant nivolumab for locally advanced resectable oral cancer, combined with [18F]BMS-986192 / [18F]-FDG PET imaging and immunomonitoring for response prediction.
    Veiligheid en verdraagzaamheid van neoadjuvant nivolumab bij lokaal gevorderd resectabel mondholtecarcinoom, gecombineerd met [18F] BMS-986192 / [18F] -FDG PET-beeldvorming en immunomonitoring voor response predictie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The safety of nivolumab treatment in patients with oral cancer, and imaging using radioactive labelled anti-PD-L1 and radioactive glucose (sugar).
    De veiligheid van behandeling met nivolumab bij kanker in de mondholte, en beeldvorming met gebruik van radioactief gelabeld anti-PD-L1 en radioactief glucose (suiker).
    A.3.2Name or abbreviated title of the trial where available
    NeoNivo
    NeoNivo
    A.4.1Sponsor's protocol code numberCA209-8JD
    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 SponsorAmsterdam UMC, location VUmc
    B.1.3.4CountryNetherlands
    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
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmsterdam UMC, locatie VUmc
    B.5.2Functional name of contact pointDr. C.W. Menke-van Houven van Oordt
    B.5.3 Address:
    B.5.3.1Street Addressde Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number310204444321
    B.5.6E-mailc.menke@vumc.nl
    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-Meyers Squibb
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNivolumab
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number480
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    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 namePD-L1 adnectin PET tracer
    D.3.2Product code [18F]BMS-986192
    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 INNPD-L1 adnectin PET tracer
    D.3.9.2Current sponsor codeBMS-986192
    D.3.9.3Other descriptive nameBMS-986192
    D.3.9.4EV Substance CodeSUB182601
    D.3.10 Strength
    D.3.10.1Concentration unit MBq megabecquerel(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number225
    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 Yes
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Stage III/IV resectable oral squamous cell carcinoma
    Stadium III/IV resectabel plaveiselcelcarcinoom van de mondholte
    E.1.1.1Medical condition in easily understood language
    Oral cancer.
    Mondholtekanker.
    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 LLT
    E.1.2Classification code 10030961
    E.1.2Term Oral cancer stage unspecified
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To investigate heterogeneity in tumor uptake of [18F]BMS-986192 between patients and within tumor lesions of the same patient (primary tumor and TDLN/lymph node metastases) before treatment, in relation to changes in [18F]-FDG uptake before and on treatment

    2. To investigate the feasibility and safety of neoadjuvant nivolumab immunotherapy prior to surgery for locally advanced oral cancer.

    1. Onderzoeken van de heterogeniteit van opname van [18F]BMS-986192 in de tumor tussen patienten en tussen tumor laesies van dezelfde patient (primaire tumor, tumor drainerende lymfklieren en lymfkliermetastasen) vóór behandeling, in relatie tot veranderingen in [18F]-FDG opname vóór en tijdens behandeling.

    2. Onderzoeken van de haalbaarheid en veiligheid van neoadjuvante nivolumab immunotherapie vóór operatieve behandeling van lokaal gevorderd mondholtecarcinoom.
    E.2.2Secondary objectives of the trial
    1. To investigate effects of nivolumab treatment on PD-L1 expression and availability for tracer binding in the patient and the relation to (changes in) [18F]-FDG uptake.

    2. To investigate the relationship between [18F]BMS-986192 tumor uptake and tumor cell- and tumor infiltrating lymphocyte (TIL) PD-1 and PD-L1 expression as well as other immune parameters.

    3. To investigate changes in [18F]-FDG uptake during treatment.

    4. To investigate the genomic profile of the tumor (neoantigens, mutational load, copy number changes and splice variants), in relation to [18F]BMS-986192 uptake, immune activation parameters and clinical response.

    5. To investigate blood based analyses of the immuneprofile and plasma vesicle miRNAs on treatment and after treatment, in relation to immune activation parameters and clinical outcome.

    1. Onderzoeken van het effect van nivolumab op de PD-L1 expressie en beschikbaarheid voor tracer binding in de patient en de relatie tot (veranderingen in) [18F]-FDG opname.

    2. Onderzoeken van de relatie tussen de opname van [18F]BMS-986192 in de tumor en de expressie van PD-1 PD-L1 op tumorcellen en tumor infiltrerende lymfocyten, alsook andere immuunparameters.

    3. Onderzoeken van veranderingen in [18F]-FDG opname tijdens behandeling.

    4. Onderzoeken van het genetische profiel van de tumor (neoantigenen, mutational load, copy number veranderingen en splice varianten), in relatie tot de opname van [18F]BMS-986192, immuun activatie parameters en klinische response.

    5. Onderzoeken van het immuunprofiel en plasma vesicle mRNAs in het bloed tijdens en na behandeling, in relatie tot immuun activatie parameters en klinische response.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    1. Have a histologically confirmed diagnosis of locally advanced oral cancer (stage III/IV) which is planned for treatment with curative intent including surgical resection.
    2. Be willing and able to provide written informed consent/assent for the trial.
    3. 18 years of age or older on day of signing informed consent.
    4. Must agree to provide tissue from fresh tumor biopsy pretreatment and from the surgical resection material to determine the actual PD-L1 status and perform immunomonitoring/DNA/RNA profiling.
    5. Willing to allow up to two additional biopsies when baseline [18F]BMS-986192 PET /[18F]-FDG PET scans show heterogeneous and/or discrepant uptake.
    6. Have a performance status of 0-1 on the ECOG Performance Scale.
    7. Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 2 weeks before any study imaging procedures are performed.

    Table 1 Adequate Organ Function Laboratory Values
    System Laboratory Value
    Hematological
    White blood cell count (WBC) ≥2,000 /mcL
    Absolute neutrophil count (ANC) ≥1,500 /mcL
    Platelets ≥100,000 / mcL
    Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
    Renal
    Serum creatinine OR ≤1.5 X upper limit of normal (ULN)
    measured or calculated creatinine clearance ≥30 mL/min for subject with creatinine levels > 1.5 X institutional ULN
    (GFR can also be used in place of creatinine or CrCl)
    Hepatic
    Serum total bilirubin Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can
    have total bilirubin < 3.0 mg/dL)
    AST (SGOT) and ALT (SGPT) ≤ 3 X ULN

    8. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception during the study and for 23 weeks after the last dose of nivolumab. Women who are not of childbearing potential (i.e. who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception.
    9. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception during the study and for 31 weeks after the last dose of nivolumab.
    Om in aanmerking te komen voor deelname aan de studie, dienen patienten aan de volgende voorwaarden te voldoen:
    1. Histopathologisch bevestigde diagnose van lokaal gevorderd mondholtecarcinoom (stadium III/IV), welke gepland is voor in opzet curatieve operatieve behandeling.
    2. Bereidheid tot en in staat zijn tot het geven van geinformeerde toestemming.
    3. 18 jaar of ouder zijn op de dag van het tekenen van de toestemminsverklaring.
    4. Akkoord gaan met het ondergaan van biopsies van de tumor vóór de behandeling, en biopsies van het resectiemateriaal voor de bepaling van de actuele PD-L1 status en voor het verrichten van immuno/DNA/RNA profilering.
    5. Bereid zijn tot het ondergaan van maximaal 2 extra biopsies wanneer de baseline [18F]BMS-986192 PET of [18F]-FDG PET heterogeniteit of discrepantie in opname tonen.
    6. Een prestatie status van 0-1 op de ECOG prestatie schaal.
    7. Adequate orgaanfunctie zoals bepaald middels laboratoriumonderzoek van het bloed (Tabel 1). Al het screenend labonderzoek dient binnen 2 weken voor studiegebonden beeldvorming te zijn verricht.

    Tabel 1 Laboratoriumwaarden voor adequate orgaanfunctie
    Systeem Waarde
    Hematologisch
    Aantal witte bloedcellen ≥2,000 /mcL
    Aantal neutrofiele granulocyten ≥1,500 /mcL
    Trombocyten ≥100,000 / mcL
    Hemoglobine ≥9 g/dL or ≥5.6 mmol/L
    Nieren
    Serum kreatinine OF ≤1.5 x bovenlimiet
    gemeten of berekende kreatineklaring ≥30 mL/min voor patienten met kreatininewaarde van >1.5x bovenlimiet
    (GFR kan ook gebruikt worden in plaats van
    kreatinine of kreatinineklaring)
    Lever
    Totaal biluribine ≤ 1.5x bovenlimiet (bij Gilbert Syndrome < 3.0 mg/dL)
    AST (SGOT) and ALT (SGPT) ≤ 3x bovenlimiet

    8. Vruchtbare vrouwen dienen adequate contraceptieve maatregelen te treffen gedurende de studie en de 23 weken volgend op de laatste dosis nivolumab. Niet-vruchtbare vrouwen (postmenopauzaal, chirurgisch gesteriliseerd), alsook azoosperme mannen hoeven geen contraceptieve maatregelen te treffen.
    9. Mannen die seksueel actief zijn met vruchtbare vrouwen dienen (een) contraceptieve maatregel(en) te treffen met een percentage van falen van niet minder dan 1% per jaar. Mannen die behandeld worden met nivolumab die seksueel actief zijn met vruchtbare vrouwen zullen geinstrueerd worden deze contraceptieve maatregel(en) te handhaven tot 31 weken na de laastse dosis van nivolumab.
    E.4Principal exclusion criteria
    A subject who meets any of the following criteria will be excluded from participation in this study:
    1. Is currently participating in or has participated in a study of an investigational agent within 4 weeks of the first dose of treatment or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
    2. Has had another known invasive malignancy within the previous 5 years and/or has had surgery, chemotherapy, targeted small molecule therapy or radiation therapy within 5 years for a known malignancy prior to study day 0.
    3. Has a known current additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
    4. If subject received major surgery for any other reason, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
    5. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of day 0. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
    6. Has an active autoimmune disease requiring systemic steroid treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids.
    7. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
    8. Has an active infection requiring systemic therapy.
    9. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
    10. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    11. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks after the last dose of trial treatment.
    12. Has received prior therapy 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.
    13. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV 1/2 antibodies).
    14. Has known active Hepatitis B or C.
    Proefpersonen die aan één van volgende criteria voldoen zijn uitgesloten van deelname aan de studie:
    1. Patiënt neemt deel of heeft binnen 4 weken van geplande behandeling deelgenomen aan een andere studie met geneesmiddel of is nog niet hersteld van de gevolgen van een toegediend geneesmiddel langer dan 4 weken geleden.
    2. Patiënt heeft een andere invasieve maligniteit gehad in de voorgaande 5 jaren en/of heeft een operatie, chemotherapie, targeted small molecule therapie of irradiatie ondergaan voor een maligniteit in de 5 jaar voorafgaand aan studie dag 0.
    3. Patiënt heeft een andere invasieve maligniteit die progressief is of behandeling behoeft. Uitgezonderd zijn basaalcelcarcinoom van de huid, plaveiselcelcarcinoom van de huid, en in situ baarmoederhalscarcinoom waarvoor potentieel curatieve behandeling is ondergaan.
    4. Wanneer patiënt met een andere reden een grote operatie heeft ondergaan, dient patiënt adequaat hersteld te zijn van de toxiciteit en/of complicaties hiervan vóór de start van studie behandeling.
    5. Patient heeft een aandoening waarvoor systemische behandeling met corticosteroiden (equivalent van dagelijks >10mg prednison) of andere immuunsuppressiva binnen 14 dagen voor studiedag 0. Inhalatie- en topische steroiden, en bijnierschorssuppletie (equivalent <10mg prednison dagelijks) zijn toegestaan in afwezigheid van actieve autoimmuun aandoening.
    6. Patient heeft een actieve autoimmuun aandoening en is hiervoor behandeld met steroiden in de afgelopen 3 maanden, of patient heeft een gedocumenteerde geschiedenis van een ernstige autoimmuun aandoening of een syndroom waarvoor behandeling met steroiden nodig is.
    7. Patient heeft bewezen interstitiele longziekte of actieve, niet-infectieuze pneumonitis.
    8. Patient heeft een actieve infectie waarvoor systemische behandeling nodig is.
    9. Patiënt heeft een (geschiedenis van) enige aandoening, therapie of afwijkende bloedwaarde die mogelijk zal interfereren met de resultaten van de studie of met de deelname van de patiënt gedurende de gehele duur van de studie, of waardoor het niet in het belang van de patiënt wordt geacht om te participeren in de studie, naar oordeel van de onderzoeker.
    10. Patiënt heeft een psychiatrische aandoening of er is sprake van middelen misbruik welke mogelijk interfereren met het voldoen aan de verplichtingen die met de studie gepaard gaan.
    11. Patiënt is zwanger of geeft borstvoeding, of verwacht zwanger te worden dan wel te verwekken binnen de verwachte duur van de studie, startende bij de screening en durende tot en met 23 weken na de laatste dosis nivolumab.
    12. Patiënt is eerder behandeld met anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, of ander medicament specifiek gericht op T-cel costimulatie of immuun checkpoint pathway.
    13. Patiënt heeft een geschiedenis van infectie met Humaan Immunodeficientie Virus (HIV 1/2 antilichamen).
    14. Patiënt heeft actieve hepatitis B of C.
    E.5 End points
    E.5.1Primary end point(s)
    1. PET Imaging
    [18F]BMS-986192 and [18F]-FDG SUVmax, SUVmean, SUVpeak will be measured in all tumor lesions and (enlarged) lymph nodes using manually drawn volumes of interest (VOI) before and on treatment. For [18F]BMS-986192 manually drawn VOIs will also be calculated for liver, kidneys, lungs, spleen and left ventricle of the heart.

    2. (Serious) adverse events
    We will pay special interest to all adverse events during the study in order to obtain information on safety and tolerability of neoadjuvant nivolumab in patients with locally advanced oral cancer who are planned to treatment with curative intent including surgery.
    1. PET beeldvorming
    [18F]BMS-986192 en[18F]-FDG SUVmax, SUVmean en SUVpeak zullen gemeten worden in alle tumor laesies en lymfklieren door middel van handmatig ingetekende volumes van interesse (VOI) voor en na behandeling. For [18F]BMS-986192 zullen tevens VOIs ingetekend worden voor de lever, nieren, longen, milt en het linker ventrikel van het hart.

    2. (Ernstige) bijwerkingen
    Er zal extra aandacht uitgaan naar alle bijwerkingen gedurende de studie, om informatie over verdraagzaamheid en veiligheid van neoadjuvant nivolumab te verkrijgen bij patienten met lokaal gevorderd mondholtecarcinoom welke in opzet curatief chirurgisch behandeld zullen worden.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. PET imaging
    T0 = baseline
    T2 = two weeks after nivolumab treatment

    2. (Serious) adverse events
    Throughout entire study
    1. PET beeldvorming:
    T0 = baseline
    T2 = twee weken na nivolumab behandeling

    2. (Ernstige) bijwerkingen:
    Gedurende gehele studie.
    E.5.2Secondary end point(s)
    1. Heterogeneity analysis
    Interpatient, intrapatient and intratumor SUV heterogeneity.

    2. Correlation between PET scans, and between imaging and response
    The correlation between SUV for [18F]BMS-986192 and [18F]-FDG baseline and on treatment and early response evaluation with [18F]-FDG.

    3. Correlation between PET data and Blood/Tissue markers
    The correlation between continuous values as SUV and the categorical variables tissue PD-1 and PD-L1 IHC will be assessed for each tumor lesion. Correlation with immunomonitoring analysis in tumor tissue/lymph nodes and blood, plasma vesicle miRNAs from blood, as well as DNA/RNA profiling in tumor tissue at baseline and at surgery will be assessed.
    1. Heterogeniteitanalyse
    Interpatient, intrapatient, en intratumor SUV heterogeniteit.

    2. Correlatie tussen PET scans, en tussen beeldvorming en respons.
    De correlatie tussen de Standardized Uptake Volume (SUV) van [18F]BMS-986192 en [18F]-FDG op baseline en tijdens behandeling, en vroege response evaluatie middels [18]-FDG.

    3. Correlatie tussen PET beeldvorming een bloed/weefsel markers
    De correlatie tussen continue variabelen (zoals SUV) en de categoriale variabelen PD-1 en PD-L1 immunohistochemie zullen worden beoordeeld voor elke tumor laesie. De correlatie tussen immuunparameters in lymfklier/tumor en bloed, plasma vesicle mRNAs uit bloed, alsook DNA/RNA profilering in tumorweefsel zullen op baseline en na chirurgie worden beoordeeld.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Heterogeneity analysis
    T0 = baseline
    T2 = two weeks after nivolumab treatment
    T3 = after surgery

    2. Correlation between PET scans, and between imaging and response
    T0 = baseline
    T2 = two weeks after nivolumab treatment

    3. Correlation between PET data and Blood/Tissue markers
    T0 = baseline
    T2 = two weeks after nivolumab treatment
    T3 = after surgery
    1. Heterogeniteitanalyse
    T0 = baseline
    T2 = twee weken na nivolumab behandeling
    T3 = na chirurgie

    2. Correlatie tussen PET scans, en tussen beeldvorming en respons.
    T0 = baseline
    T2 = twee weken na nivolumab behandeling

    3. Correlatie tussen PET beeldvorming een bloed/weefsel markers
    T0 = baseline
    T2 = twee weken na nivolumab behandeling
    T3 = na chirurgie
    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    1. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard to subjects, specifically, during treatment with nivolumab, during surgery and during standard adjuvant treatment (if indicated). In case of (prolonged) grade 4 or grade 5 toxicity, the investigators can temporarily halt the study for further analyses.
    2. Quality or quantity of data recording is inaccurate or incomplete.
    3. Poor adherence to the protocol and regulatory requirements.
    1. De incidentie of ernst van bijwerkingen in deze of andere studies welke een mogelijk gezondheidsrisico voor proefpersonen aangeeft met name gedurende behandeling met nivolumab, chirurgie en adjuvante behandeling (indien geïndiceerd). In geval van graad 4-5 toxiciteit kunnen onderzoekers de studie tijdelijk stoppen voor verdere analyse.
    2. Kwaliteit of kwantiteit van de dataregistratie is inaccuraat of incompleet.
    3. Slechte naleving van het protocol en reglementaire vereisten.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state15
    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 Decision2019-02-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-14
    P. End of Trial
    P.End of Trial StatusOngoing
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