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    Summary
    EudraCT Number:2016-003032-20
    Sponsor's Protocol Code Number:GOIRC-06-2016
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-01-13
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-003032-20
    A.3Full title of the trial
    Nivolumab plus Stereotactic Body Radiotherapy (SBRT) in II and III line of Patients With Metastatic Renal Cell Carcinoma (mRCC).
    Nivolumab plus Stereotactic Body Radiotherapy (SBRT) in II and III line of Patients With Metastatic Renal Cell Carcinoma (mRCC).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nivolumab plus radiotherapy in II and III line of Patients With Metastatic Renal Cell Carcinoma
    Nivolumab in combinazione con radioterapia come trattamento di seconda e terza linea dei pazienti affetti da carcinoma renale metastatico
    A.3.2Name or abbreviated title of the trial where available
    NIVES
    NIVES
    A.4.1Sponsor's protocol code numberGOIRC-06-2016
    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 SponsorGRUPPO ONCOLOGICO ITALIANO DI RICERCA CLINICA (GOIRC)
    B.1.3.4CountryItaly
    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 S.r.l.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharmaceutical Development and Services srl
    B.5.2Functional name of contact pointServizio Informazione sulla Sperime
    B.5.3 Address:
    B.5.3.1Street Addressvia dei Pratoni, 16
    B.5.3.2Town/ cityScandicci (FI)
    B.5.3.3Post code50018
    B.5.3.4CountryItaly
    B.5.4Telephone number0557224179
    B.5.5Fax number0557227014
    B.5.6E-mailedimartino@pharmades.it
    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 - 10 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 10 ML- 1 FLACONCINO
    D.2.1.1.2Name of the Marketing Authorisation holderBRISTOL-MYERS SQUIBB PHARMA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameOpdivo
    D.3.4Pharmaceutical form 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 codeGOIRC-06-2016
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic Renal Cell Carcinoma
    carcinoma renale metastatico
    E.1.1.1Medical condition in easily understood language
    Metastatic Renal Tumor
    tumore maligno del rene metastatico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10050076
    E.1.2Term Metastatic renal carcinoma
    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
    Evaluate the activity of nivolumab in combination with SBRT
    Valutare l¿attivit¿ di nivolumab in combinazione alla radioterapia stereotassica
    E.2.2Secondary objectives of the trial
    -evaluate the effectiveness and safety of the combination nivolumab + SBRT
    -to identify molecular basis of synergistic effect of stereotactic radiotherapy and
    Nivolumab, to identify potential resistance mechanisms, to characterize biological variables and somatic mutations that may help in optimizing the combination.
    - valutare l'efficacia e la sicurezza della combinazione nivolumab + SBRT
    - identificare le basi molecolari che modulano l¿effetto sinergico di Nivolumab e radioterapia stereotassica, potenziali meccanismi di resistenza, identificare variabili biologiche e mutazioni somatiche che possano migliorarne la combinazione.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Age = 18 years on day of signing informed consent
    - Performance status of 0, 1 on the ECOG Performance Scale
    -Histologically confirmed metastatic RCC not suitable for curative-intent local therapy
    - Disease progressed after = 2 prior anti-angiogenic therapies
    - Life expectancy > 12 weeks
    - 2 or more measurable non-brain sites of disease based on RECIST 1.1, whose at least one potentially suitable for treatment with SBRT. In the case of a non measurable bone lesion suitable for treatment with SBRT, even only one measurable non-brain site of disease is allowed
    - Patients are eligible if CNS metastases are treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 14 days prior to enrollment. In addition, patients must either be off corticosteroids or on a stable dose or decreasing dose of = 10 mg daily prednisone (or equivalent)
    - Adequate organ function
    · Età = 18 anni
    · Performance status (scala ECOG) di 0, 1
    · Conferma istologica di carcinoma renale metastatico non candidato a terapia locale con
    intento curativo
    · Malattia progredita dopo 1 o 2 terapie antiangiogentiche precedenti
    · Aspettativa di vita> 12 settimane
    · 2 o più lesioni metastatiche misurabili non-cerebrali (valutate secondo i criteri RECIST 1.1),
    di cui almeno una potenzialmente suscettibile di radioterapia stereotassica. Nel caso di una
    lesione ossea non misurabile idonea al trattamento stereotassico, è consentito anche un solo
    sito misurabile di malattia non-cerebrale
    · Sono eleggibili pazienti con metastasi del SNC trattate e pazienti neurologicamente
    asintomatici (ad eccezione di segni o sintomi residuati dopo un trattamento sul SNC) da
    almeno 14 giorni prima dell’arruolamento. Inoltre, i pazienti non dovrebbero utilizzare
    corticosteroidi o al massimo una dose = 10 mg di prednisone al giorno (o equivalente)
    · Adeguata funzione d'organo
    E.4Principal exclusion criteria
    • Prior therapy with an agent directed at PD-1, PD-L1, or PD-L2
    • Currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the first dose of treatment
    • Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger
    • Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
    • Active brain (CNS) metastases and/or carcinomatous meningitis
    • Prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
    • Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to a previously administered agent. Subjects with = Grade 2 neuropathy are an exception to this criterion and may qualify for the study
    • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    • Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment
    • Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection
    • 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
    • Evidence of interstitial lung disease, active non-infectious pneumonitis, or a history of grade 3 or greater pneumonitis
    • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    • Live vaccine within 30 days prior to the first dose of trial treatment
    Precedente terapia con un agente anti-PD-1, PD-L1, o PD-L2
    · Partecipazione ad uno studio con un farmaco o dispositivo sperimentale entro 2 settimane
    dalla prima dose di nivolumab
    · Anamnesi positiva per nota o sospetta malattia autoimmune o sindrome che ha richiesto
    corticosteroidi sistemici (> 10 mg al giorno di prednisone o equivalenti) o farmaci
    immunosoppressori ad eccezione di patologie dalle quali non ci si aspetterebbe una
    esacerbazione in assenza di una causa scatenante
    · Qualsiasi condizione che richieda un trattamento sistemico con corticosteroidi (> 10 mg
    equivalenti di prednisone al giorno) o altri farmaci immunosoppressori nei 14 giorni
    precedenti alla prima dose del farmaco in studio. Steroidi per inalazione e supplementi
    steroidei per deficit surrenalici alla dose > 10 mg di prednisone al giorno sono consentite in
    assenza di una malattia autoimmune attiva
    · Metastasi cerebrali attive e / o carcinomatosi meningea
    · Somministrazione di anticorpo monoclonale nelle 4 settimane precedenti al primo giorno di
    trattamento in studio o mancato recupero (vale a dire, = Grado 1 o al basale) da eventi
    avversi a causa di agenti somministrati più di 4 settimane prima
    · Precedente chemioterapia, terapia a bersaglio molecolare, o radioterapia nelle 2 settimane
    precedenti al primo giorno di trattamento in studio o mancato recupero (vale a dire, = Grado
    1 o al basale) da eventi avversi a causa di un agente precedentemente somministrato. I
    soggetti con neuropatia = grado 2 sono un'eccezione a questo criterio e possono pertanto
    essere eleggibili
    · Storia nota di test positivi per il virus dell'immunodeficienza umana (HIV) o confermata
    sindrome da immunodeficienza acquisita (AIDS)
    · Diagnosi confermata di immunodeficienza o utilizzo di terapia steroidea sistemica o di
    qualsiasi altra forma di terapia immunosoppressiva nei 14 giorni precedenti la prima dose
    del trattamento con nivolumab
    · Test positivo per epatite B o epatite C che indica un'infezione acuta o cronica
    · Altra patologia tumorale in progressione che richieda un trattamento attivo. Le eccezioni
    includono il carcinoma basocellulare della pelle, il carcinoma a cellule squamose della pelle,
    o carcinoma in situ del collo dell'utero che ha subito una terapia potenzialmente curativa
    · Evidenza di malattia polmonare interstiziale, polmonite non infettiva attiva, o una storia di
    polmonite di grado 3 o superiore
    · I soggetti che sono obbligatoriamente sottoposti ad un trattamento per malattie psichiatriche
    o organiche (per esempio malattie infettive)
    · Somministrazione di vaccino vivo nei 30 giorni precedenti alla prima dose del trattamento
    sperimentale
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response Rate (ORR) , as determined
    by investigator assessment per RECIST 1.1
    Tassi di risposte obiettive in base alla
    valutazione radiologica degli investigatori
    (utilizzo dei criteri RECIST 1.1)
    E.5.1.1Timepoint(s) of evaluation of this end point
    From the date the patient entered in the study until the end of the study
    Dalla data di entrata nello studio fino alla fine dello studio
    E.5.2Secondary end point(s)
    Safety assessments will include the incidence, nature, and severity of Adverse Events (AEs) and laboratory abnormalities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03; - to identify molecular basis of synergistic effect of stereotactic radiotherapy and
    immunotherapy in renal carcinomas
    - to identify potential resistance mechanisms
    - to characterize biological variables that may help in optimizing the timing and
    modalities of combination.
    - Identification of somatic mutations associated with acquired resistance to checkpoint
    inhibitors; Progression Free Survival (PFS); Overall Survival (OS); Objective Response Rate (ORR) of irradiated and non-irradiated metastases and duration of response, as determined by investigator assessment per RECIST 1.1.
    Valutazione della sicurezza che include l¿incidenza, la natura e la severit¿ degli eventi avversi ed i gradi di anormalit¿ degli esami di laboratorio definiti dal National Cancer Institute (NCI) CTCAE v. 4.03; -identificare basi molecolari dell¿effetto sinergico di radioterapia stereotassica ed
    immunoterapia nei carcinoma renali
    -identificare potenziali meccanismi di resistenza
    - caratterizzare variabili biologiche che possono aiutare nell¿ottimizzare il timing e le
    modalit¿ della combinazione
    - identificare mutazioni somatiche associate alla resistenza dei checkpoint della crescita
    cellulare; Sopravvivenza libera da progressione (PFS); Sopravvivenza globale (OS); Tassi di risposte obiettive delle metastasi irradiate e non-irradiate e la durata della risposta in base alla valutazione radiologica degli investigatori (utilizzo dei criteri RECIST 1.1)
    E.5.2.1Timepoint(s) of evaluation of this end point
    from the date the patient entered in the study until the end of the study; From the date the patient entered in the study until the end of the study; time between the date of registration and the first
    date of documented progression, based on invesigator assessment (as per RECIST 1.1
    criteria), or death due to any cause, whichever occurs first.; time between registration and the date of death from any cause; time between registration and the end of the study
    Dalla data di entrata in studio fino alla fine dello studio; Dalla data di entrata nello studio fino alla fine dello studio; tempo intercorso tra la data di registrazione e la prima data di documentata progressione in base alla
    valutazione radiologica degli investigatori (utilizzo dei criteri RECIST 1.1), o morte per qualsiasi causa a secondo di quello che si verifica prima.; tempo intercorso dalla registrazione alla data di morte per qualsiasi causa; tempo intercorso tra registrazione e fine dello studio
    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 trial1
    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 concerned18
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA18
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    36 months since the last first dose of nivolumab to a patient.
    36 mesi dall¿ultima prima somministrazione di nivolumab a un paziente
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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: 68
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 23
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state68
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 68
    F.4.2.2In the whole clinical trial 68
    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)
    /
    /
    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 Decision2017-03-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-22
    P. End of Trial
    P.End of Trial StatusCompleted
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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