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    Summary
    EudraCT Number:2019-004916-76
    Sponsor's Protocol Code Number:TWINS-GU002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-10-21
    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 number2019-004916-76
    A.3Full title of the trial
    A phase II study of nivolumab combined with metformin in pre-treated metastatic renal cell carcinoma (mRCC) patients.
    Studio di fase II di nivolumab in combinazione con metformina in pazienti con carcinoma del rene metastatico pretrattato.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Combination study between nivolumab and metformin in advanced kidney cancer.
    Studio di combinazione tra nivolumab e metformina nel tumore del rene avanzato.
    A.3.2Name or abbreviated title of the trial where available
    NivoMet
    NivoMet
    A.4.1Sponsor's protocol code numberTWINS-GU002
    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 SponsorFONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDirezione scientifica Fondazione Policlinico A.Gemelli IRCCS
    B.5.2Functional name of contact pointDirezione Scientifica Fondazione Po
    B.5.3 Address:
    B.5.3.1Street AddressLargo Agostino Gemelli 8
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00168
    B.5.3.4CountryItaly
    B.5.4Telephone number0630155701
    B.5.5Fax number0630155701
    B.5.6E-maildirezione.scientifica@policlinicogemelli.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
    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 [Nivolumab]
    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.3.9.2Current sponsor code946414-94-4
    D.3.9.3Other descriptive nameNIVOLUMAB
    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 Yes
    D.3.11.13.1Other medicinal product typeanticorpo monoclonale
    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.2.5The 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 nameMetformina
    D.3.2Product code [Metformina]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETFORMINA
    D.3.9.1CAS number 657-24-9
    D.3.9.2Current sponsor code657-24-9
    D.3.9.3Other descriptive nameMETFORMINA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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
    Patients with advanced renal cell carcinoma pre-treated with VEGFR inhibitors.
    Pazienti con carcinoma renale avanzato pre-trattati con farmaci inibitori del VEGFR.
    E.1.1.1Medical condition in easily understood language
    Patients with advanced renal cell carcinoma pre-treated with VEGFR inhibitors.
    Pazienti con carcinoma renale avanzato pre-trattati con farmaci inibitori del VEGFR.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10073251
    E.1.2Term Clear cell renal cell carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate if the addiction of metformin increases the activiti of nivolumab in metastatic kidney cancer.
    Valutare se la metformina aumenta l'attività di nivolumab nel carcinoma renale metastatico.
    E.2.2Secondary objectives of the trial
    To investigate the safety, activity and quality of life of patients who received the combination of metformin and nivolumab for metastatic kidney cancer.
    Valutare la sicurezza, l'attività e la qualità della vita dei pazienti che hanno ricevuto la combinazione di metformina e nivolumab per carcinoma renale metastatico.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to provide written informed consent
    2. Male aged 18 years and above
    3. Histological confirmation of RCC with a clear cell component
    4. Advanced or metastatic RCC
    5. Measurable disease as defined by RECIST1.1criteria
    6. Must have received at least one prior systemic treatment regimen in the advanced or metastatic setting, and must have evidence of progression on or after the last treatment regimen received
    7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
    8. Adequate bone marrow and chemistry values defined as:
    a. Hemoglobin = 9.0 g/dL independent of transfusion
    b. Platelet count =100.000/µL
    c. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance = 40 mL/min
    d. Liver function:
    i. Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert’s disease)
    ii. AST or ALT < 2.5 x ULN
    9. Life expectancy of at least 6 months
    10. Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 13 weeks after last study drug administration.
    1. Pazienti in grado di fornire il consenso informato scritto
    2. Età di 18 anni e oltre
    3. Carcinoma a cellule renali con componente a cellule chiare istologicamente o citologicamente confermato
    4. Malattia avanzata o metastatica
    5. Malattia misurabile documentata da TC total body (e/o RMN addome e TC torace) secondo i criteri RECIST 1.1
    6. Progressione radiografica del carcinoma renale secondo i criteri RECIST ad almeno una precedente linea di terapia
    7. Stato di prestazione del gruppo di oncologia cooperativa orientale (ECOG) ¿ 2
    8. Valori adeguati del midollo osseo e della chimica definiti come:
    a. Emoglobina = 9.0 g/dL indipendente da trasfusione
    b. Conta piastrinica =100.000/µL
    c. Creatinina sierica <1,5 x ULN o clearance della creatinina calcolata = 40 ml/min
    d. Funzione epatica:
    ¿ Bilirubina sierica <1,5 x ULN (ad eccezione dei pazienti con malattia di Gilbert documentata)
    ¿ AST o ALT <2,5 x ULN
    9. Aspettativa di vita di almeno 6 mesi
    10. I pazienti che hanno partner in età fertile devono essere disposti a utilizzare un metodo di controllo delle nascite con un'adeguata protezione barriera durante lo studio e per 13 settimane dopo l’ultima somministrazione del farmaco in studio.
    E.4Principal exclusion criteria
    1. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection
    2. Any active known or suspected autoimmune disease
    3. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease
    4. Uncontrolled adrenal insufficiency
    5. Evidence of active pneumonitis during screening, except for pulmonary fibrosis induced by prior thoracic irradiation
    6. Dialitic patients
    7. Diabetes mellitus
    8. Any history of biguanide-based therapy within 1 year prior to enrollment
    9. Current severe, uncontrolled systemic disease
    10. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline
    11. Other malignancy with a previous diagnosis within 5 years (with the exclusions of NMIBC, CIN).
    12. Prior treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
    1. Epatite virale B o C attiva o cronica, o infezione da HIV
    2. Malattie autoimmuni
    3. Patologie che richiedano un trattamento corticostereoideo sistemico (> 10 mg/die di prednisone o equivalente) o altri farmaci immunosoppressivi entro 14 giorni prima della randomizzazione. Steroidi inalatori e terapia steroidea sostitutiva surrenalica > 10 mg di prednisone equivalente giornaliero sono consentiti in assenza di malattia autoimmune attiva.
    4. Insufficienza surrenalica non controllata
    5. Riscontro di polmonite attiva durante lo screening, ad eccezione di fribrosi polmonare indotta da precedente RT a livello toracico
    6. Pazienti in dialisi
    7. Diabete Mellito in terapia farmacologica
    8. Qualsiasi storia di terapia a base di biguanidi entro un anno prima dall’arruolamento
    9. Patologie concomitanti severe, non sotto controllo farmacologico e/o clinico
    10. Cardiopatia clinicamente significativa come evidenziato da infarto miocardico, o eventi trombotici arteriosi negli ultimi 6 mesi, angina grave o instabile, o cardiopatia di classe II-IV di New York Heart Association (NYHA) o misurazione della frazione di eiezione cardiaca <50%.
    11. Altri tumori maligni con una precedente diagnosi entro 5 anni (con le esclusioni di NMIBC, CIN).
    12. Precedente trattamento con anti-PD-1 o PD-L1 o anti-CTLA4
    E.5 End points
    E.5.1Primary end point(s)
    To evaluate the Progression-Free Survival (PFS) rate at 9 months of the combination of nivolumab plus metformin in mRCC patients previously treated with at least one anti-angiogenic therapy.
    Valutare il tasso di sopravvivenza libera da progressione (PFS) a 9 mesi dalla combinazione di nivolumab più metformina in pazienti con mRCC precedentemente trattati con almeno una terapia anti-angiogenica.
    E.5.1.1Timepoint(s) of evaluation of this end point
    9 months
    9 mesi
    E.5.2Secondary end point(s)
    Objective response rate; Median progression free surival; Overall survival; Safety of the combination; Quality of life
    Tasso di risposte obiettive; Tempo mediano alla progressione; Sopravvivenza complessiva; Sicurezza della combinazione; Qualità della vita
    E.5.2.1Timepoint(s) of evaluation of this end point
    9 months; 9 months; 9 months; 9 months; 9 months
    9 mesi; 9 mesi; 9 mesi; 9 mesi; 9 mesi
    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 No
    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 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 No
    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 concerned6
    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 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
    LVLS
    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 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: 9
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state21
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 21
    F.4.2.2In the whole clinical trial 21
    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)
    Patients will be treated according to clinical practice.
    I pazienti verranno trattati secondo la pratica clinica.
    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 Decision2020-07-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-09-13
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