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    Summary
    EudraCT Number:2020-000409-94
    Sponsor's Protocol Code Number:FIL_DALYA
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-08-30
    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 number2020-000409-94
    A.3Full title of the trial
    An Open Label, Phase 2 Study to Evaluate Activity and Safety of Daratumumab in combination with Bortezomib and Dexamethasone in patients with Relapsed or Refractory Plasmablastic lymphoma (DALYA trial).
    Studio in aperto di fase II di valutazione dell’efficacia e della sicurezza di un trattamento con Daratumumab in combinazione con Bortezomib e Desametasone in pazienti con Linfoma Plasmablastico recidivato o refrattario (studio DALYA).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study to Evaluate Activity and Safety of Daratumumab with Bortezomib and Dexamethasone in patients with Relapsed or Refractory Plasmablastic lymphoma.
    Studio di fase 2 per valutare attività e sicurezza di Daratumumab con bortezomib e desametasone in pazienti con linfoma plasmablastico recidivante o refrattario.
    A.3.2Name or abbreviated title of the trial where available
    Phase 2 Study to Evaluate Activity and Safety of Daratumumab with Bortezomib and Dexamethasone in pa
    Studio di fase 2 per valutare attività e sicurezza di Daratumumab con bortezomib e desametasone in p
    A.4.1Sponsor's protocol code numberFIL_DALYA
    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 ITALIANA LINFOMI ONLUS
    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 supportJanssen-Cilag SpA
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione Italiana Linfomi Onlus
    B.5.2Functional name of contact pointUfficio start up
    B.5.3 Address:
    B.5.3.1Street AddressSpalto Marengo 44 c/o Uffici PACTO
    B.5.3.2Town/ cityAlessandria
    B.5.3.3Post code15121
    B.5.3.4CountryItaly
    B.5.4Telephone number0131033153
    B.5.5Fax number0131263455
    B.5.6E-mailstartup@filinf.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 DARZALEX
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN-CILAG INTERNATIONAL N.V.
    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 nameDaratumumab
    D.3.2Product code [IMP 1]
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeIMP 1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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 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 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.2.1.1.1Trade name VELCADE - 1 FLACONCINO DA 3.5 MG
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN-CILAG INTERNATIONAL N.V.
    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 nameBortezomib
    D.3.2Product code [IMP 2]
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBORTEZOMIB
    D.3.9.1CAS number 179324-69-7
    D.3.9.2Current sponsor codeIMP 2
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2500
    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 Yes
    D.3.11.13.1Other medicinal product typeFarmaci antineoplastici
    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 Relapsed or Refractory Plasmablastic lymphoma (PBL).
    Pazienti con linfoma plasmablastico recidivato o refrattario (PBL).
    E.1.1.1Medical condition in easily understood language
    Patients with relapsed or refractory Plasmablasticlymphoma (PBL), who are not eligible for autologous or allogeneic transplantation or experienced relapse.
    Pazienti con linfoma Plasmablastico recidivato o refrattario (PBL), che non sono eleggibili per trapianto autologo o allogenico o ha subito una ricaduta.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10065039
    E.1.2Term Plasmablastic lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the activity of daratumumab as single agent and in combination with bortezomib/dexamethasone in patients with relapsed or refractory Plasmablastic lymphoma (PBL), who are not eligible for autologous or allogeneic transplantation or experienced relapse after a prior autologous stem cell transplantation.
    Valutare l’efficacia di un trattamento con daratumumab in monoterapia e in combinazione con bortezomib e desametasone in pazienti con Linfoma Plasmablastico (PBL) recidivato o refrattario (R/R), non eleggibili a trapianto autologo o allogenico o in recidiva dopo trapianto autologo di cellule staminali.
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy in terms of Progression-free survival (PFS);
    • To evaluate the efficacy in terms of Overall survival (OS);
    • To evaluate the efficacy in terms of Duration of response (DOR);
    • To evaluate the safety of daratumumab as single agent and in combination with bortezomib/dexamethasone.
    • To assess the role of daratumumab maintenance;
    • To evaluate the association between intensity of CD38 expression and response.
    • Valutare l’efficacia in termini di sopravvivenza libera da progressione (PFS);
    • Valutare l’efficacia in termini di sopravvivenza globale (OS);
    • Valutare l’efficacia in termini di durata della risposta (DOR);
    • Valutare la sicurezza del daratumumab somministrato in monoterapia e in combinazione con bortezomib/desametasone;
    • Valutare il ruolo del mantenimento con daratumumab;
    • Valutare la possibile associazione tra intensità di espressione di CD38 e risposta al trattamento.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Biological study included in the main study version 2.1 dated 30 March 2021.
    Objectives:
    • To evaluate the effect of daratumumab/bortezomib on a) CD4 and CD8 T cell homeostasis; b) regulatory cells (MDSC and Treg) homeostasis; c) inflammatory cytokines profile.
    • To evaluate the effect of daratumumab/bortezomib treatment on functional properties of HIV-specific, EBV-specific and CMV-specific T cells.
    • To analyze the microenvironment of the PBL.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Studio biologico incluso nello studio principale versione 2.1 del 30 Marzo 2021.
    Obiettivi:
    • Valutare l’effetto di daratumumab/bortezomib su: a) omeostasi delle cellule T CD4 e CD8; omeostasi delle cellule regolatorie (MDSC [cellule soppressorie di derivazione mieloide] e Treg); c) profilo delle citochine infiammatorie.
    • Valutare l’effetto del trattamento con daratumumab/bortezomib sulle proprietà funzionali delle cellule T HIV-, EBV- e CMV-specifiche.
    • Analizzare il microambiente del PBL.
    E.3Principal inclusion criteria
    a. Histologically confirmed plasmablastic lymphoma according to WHO 2017, CD38-positive by immunohistochemistry (=5% of positive cells)
    Local diagnosis of PBL and local CD38 assessment =5% will suffice for enrollment and start of treatment.
    b. Patients with plasmablastic lymphoma relapsed or refractory:
    - after at least one line of conventional-dose chemotherapy followed or not by autologous stem cell transplantation;
    - after at least one line of conventional-dose chemotherapy and not eligible for salvage autologous or allogeneic transplantation;
    c. ECOG Performance Status less than or equal to 3;
    d. Age greater than or equal to 18 years;
    e. Both HIV-negative and HIV-positive patients are eligible;
    f. HIV infection responsive to ongoing cART (combination antiretroviral therapy);
    g. At least one measurable disease lesion identifiable by imaging:
    - A nodal lesion must be at least 11 mm x 11 mm OR = 16 mm in the greatest transverse diameter (regardless of short axis measurement).
    - An extranodal lesion must be at least 10 mm x 10 mm.
    h. Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and 7 months (for women) o 4 months (for men) after last administration of bortezomib or 6 months after last daratumumab dose, regardless of sex. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control method (failure rate of less than 1%) e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile.
    WOCBP must have two negative pregnancy tests as verified by the study doctor prior to starting study therapy and must agree to undergo pregnancy testing during the course of the study, and after end of study therapy, if clinically indicated. This applies even if the subject practices complete abstinence from heterosexual contact.
    i. Subject understands and voluntarily signs and dates an informed consent form approved by an Independent Ethics Committee (IEC), prior to the initiation of any screening or study-specific procedures
    j. Subject must be able to adhere to the study visit schedule and other protocol requirements.
    a. Diagnosi istologicamente confermata di linfoma plasmablastico secondo la classificazione WHO 2017, CD38+ valutato in immunoistochimica (=5% di cellule positive). La diagnosi e la valutazione del CD38 eseguite localmente sono sufficienti per arruolare i pazienti e iniziare il trattamento.
    b. Pazienti con linfoma plasmablastico in recidiva o refrattario:
    - dopo almeno una linea di chemioterapia a dosi convenzionali seguita o meno da trapianto autologo di cellule staminali;
    - dopo almeno una linea di chemioterapia a dosi convenzionali e non eleggibili al salvataggio con trapianto autologo o allogenico;
    c. ECOG Performance Status minore o = 3;
    d. Età maggiore o = 18 anni;
    e. Sono eleggibili sia pazienti HIV negativi che HIV positivi;
    f. Infezione da HIV controllata da somministrazione in corso di cART (terapia antiretrovirale di combinazione);
    g. Presenza di almeno una lesione misurabile di malattia identificabile con esami strumentali:
    - Una lesione nodale di almeno 11 mm x 11 mm OPPURE = 16 mm nel diametro trasverso maggiore (indipendentemente dalla misura dell’altro diametro trasverso).
    - Una lesione extranodale di almeno 10 mm x 10 mm.
    h. Le donne potenzialmente fertili e gli uomini devono accettare di usare metodi contraccettivi efficaci, se sessualmente attivi, a partire dalla firma del consenso informato e fino a dopo 7 mesi (per le donne) o 4 mesi (per gli uomini) dall’ultima somministrazione di bortezomib, o fino a 3 mesi indipendentemente dal sesso dopo l’ultima dose di daratumumab. Una donna è considerata potenzialmente fertile da dopo il menarca fino alla menopausa, a meno che permanentemente sterile. I metodi di sterilizzazione permanente includono, ma non sono limitati a, isterectomia, salpingectomia bilaterale e ovariectomia bilaterale. Lo stato di menopausa è definito da un periodo di amenorrea di almeno 12 mesi consecutivi, in assenza di altra causa clinica. Un valore dei livelli di ormone follicolo stimolante (FSH) all’interno del range caratteristico della menopausa può essere utilizzato a conferma dello stato di menopausa nelle donne che non utilizzino contraccettivi ormonali o siano in terapia ormonale sostitutiva. Lo sperimentatore, o un suo collaboratore, deve informare la paziente su quali metodi siano altamente efficaci nel controllo delle nascite (vale a dire quelli che hanno meno dell’1% di fallimento), ad esempio dispositivi intrauterini (spirale o IUD), dispositivi intrauterini a rilascio ormonale (IUS), legatura bilaterale delle tube, vasectomia del partner o astinenza sessuale completa. Per i maschi è richiesto l’utilizzo del preservativo a meno che la donna non sia permanentemente sterile.
    Le donne potenzialmente fertili devono avere 2 test di gravidanza negativi verificati del medico dello studio prima di iniziare il trattamento e devono accettare di sottoporsi ad ulteriori test di gravidanza in corso di trattamento ai timepoint previsti dallo studio, e dopo la fine del trattamento, in caso di indicazione clinica. I test sono obbligatori anche in caso di astinenza da rapporti sessuali.
    i. I soggetti devo comprendere a fondo tutti gli aspetti dello studio e firmare e datare in maniera del tutto volontaria il foglio di consenso informato, approvato da un Comitato Etico indipendente, prima dell’inizio di qualsiasi tipo di valutazioni basali e procedure studio-specifiche.
    j. I soggetti devono essere in grado di ottemperare a tutte le procedure dello studio e di seguire diligentemente quanto previsto dal protocollo di studio.
    E.4Principal exclusion criteria
    a. Histologic diagnosis different from confirmed plasmablastic lymphoma according to WHO 2017 and/or CD38 expression < 5% of positive cells
    b. CNS involvement
    c. Patients with known hypersensitivity to the investigational drug or to product components or severe allergic or anaphylactic reactions to humanized products
    d. Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy including targeted small molecule agents within 14 days prior to the first dose of study drug
    e. Concomitant Kaposi sarcoma; however, patients with only skin involvement of KS can be included.
    f. Subject is:
    - Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]. Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [HBcAb] ± antibodies to hepatitis B surface antigen [HBsAb]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (HBsAb positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
    - Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
    g. Any history of another cancer during the last 5 years with the exception of non-melanoma skin tumors, in situ cervical carcinoma, or in situ breast cancer treated with curative intent with no history of metastatic disease.
    h. Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis or tuberculosis. Drugs for HIV treatment are allowed, as per local investigator prescription.
    i. Active ongoing infection from SARS-CoV-2. Patients who experienced a previous SARS-CoV-2 infection are eligible for the study.
    j. Screening laboratory values (due to causes different than lymphoma):
    - Absolute neutrophil count (ANC) <1.0 x 109/L (unless secondary to documented marrow involvement by lymphoma)
    - Platelet count <75 x 109/L
    - Hemoglobin < 7.5 g/dL
    - Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) > 3.5 times the upper limit of normal (ULN)
    - Alkaline phosphatase > 3.5 times ULN
    - Bilirubin > 2 times x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
    - Serum Creatinine Clearance < 20 ml/h
    k. Subject has clinically significant cardiac disease, including:
    - Myocardial infarction within 6 months before date of registration, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
    - Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] current version Grade 2 or higher) or clinically significant ECG abnormalities. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec
    l. Evidence of any other clinically significant uncontrolled condition(s)
    m. Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent
    n. Breastfeeding women or women with a positive pregnancy test at screening
    a. Diagnosi istologica diversa da linfoma plasmablastico secondo la WHO 2017 e/o espressione del CD38 < 5%.
    b. Coinvolgimento del sistema nervoso centrale (SNC).
    c. Pazienti con ipersensibilità nota al farmaco sperimentale o ai suoi componenti o che abbiano avuto allergie gravi o reazioni anafilattiche a prodotti umanizzati.
    d. Soggetti che abbiano ricevuto qualsiasi terapia antitumorale inclusi chemioterapia, radioterapia, terapie sperimentali, comprese quelle con agenti target, nei 14 giorni precedenti alla somministrazione della prima dose del trattamento in protocollo.
    e. Presenza concomitante di sarcoma di Kaposi; tuttavia pazienti che abbiano coinvolgimento cutaneo esclusivo da parte del sarcoma possono partecipare.
    f. Soggetti con:
    - sieropositivà per l’epatite B [HBsAg]. I soggetti con infezione risolta (vale a dire soggetti negativi all’HBsAg ma positivi agli anticorpi contro l’antigene core dell’epatite B [HBcAb] ± agli anticorpi contro l’antigene di superficie dell’epatite B [HBsAb]) devono essere sottoposti a valutazione in PCR (real-time polymerase chain rection) dei livelli di DNA del virus dell’epatite B (HBV DNA): quelli che risultano positivi non possono essere arruolati nello studio. ECCEZIONE: soggetti con reperti nel siero suggestivi di vaccinazione contro l’HBV (che hanno come unico marker sierico la presenza di HBsAb positività) E storia nota di precedente vaccinazione per l’HBV, non devono essere testati per l’HBV DNA in PCR;
    - sieropositività nota all’epatite C, fatta eccezione per i soggetti che presentano risposta virologica sostenuta [SVR], definita come aviremia per almeno 12 settimane dopo la fine della terapia antivirale, che possono essere arruolati.
    g. Anamnesi di altro tumore negli ultimi 5 anni fatta eccezione per tumori della pelle non melanomatosi, carcinoma in situ della cervice, o neoplasia mammaria in situ trattati con intento curativo e senza storia di metastasi.
    h. Malattie infettive croniche o acute in corso che necessitano di trattamento sistemico, quali, ad esempio, ma non limitati a, infezioni renali croniche, infezioni croniche del torace con bronchiettasie o tubercolosi. I farmaci per il trattamento dell’HIV sono ammessi secondo prescrizione dello sperimentatore locale.
    i. Infezione attiva in corso da SARS-CoV-2. I pazienti che hanno avuto un'infezione precedente da SARS-CoV-2 sono idonei per lo studio.
    j. Valori di laboratorio al basale (non dovuti al linfoma) quali i seguenti:
    - Conta assoluta dei neutrofili (ANC) <1,0 x 109/L (a meno che secondaria ad infiltrazione midollare da parte del linfoma);
    - Conta piastrinica <75 x 109/L;
    - Emoglobina < 7,5 g/dL;
    - Alanina aminotrasferasi (ALT) e/o Aspartato aminotrasferasi (AST) > 3,5 volte il valore massimo ammissibile (ULN);
    - Fosfatasi alcalina > 3,5 volte x ULN;
    - Bilirubina > 2 volte x ULN (a meno che l’aumento di bilirubina non sia dovuto a sindrome di Gilbert o abbia origine non epatica)
    - Clearance sierica della creatinina < 20 ml/h.
    k. Presenza di patologie cardiache clinicamente significative quali:
    - infarto miocardico nei 6 mesi precedenti alla registrazione nello studio, o patologie/condizioni instabili o non controllate correlate o che influenzano la funzionalità cardiaca (ad es. angina instabile, insufficienza cardiaca congestizia di classe III-IV della New York Heart Association);
    - Aritmia cardiaca (di grado = 2 secondo la versione corrente dei CTCAE) o anomalie clinicamente significative dell’ECG. ECG a 12 derivazioni allo Screening con un intervallo QT di base, corretto con formula di Fridericia, (QTcF) > 470 msec
    l. Presenza di qualsiasi altra condizione clinicamente significativa non controllata.
    m. Anamnesi di malattie neurologiche, psichiatriche, endocrinologiche, metaboliche, immunologiche o epatiche importanti, che possano precludere la partecipazione allo studio o di fornire un consenso informato.
    n. Donne in corso di allattamento al seno o donne con test di gravidanza positivo allo Screening.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Response Rate (ORR = Complete response, CR+ Partial response, PR) after induction cycle 1 (daratumumab alone), after induction cycles 3, 6 and 9 (end of induction, EOI); after maintenance cycles 12 and 15 (end of treatment, EOT). Response will be defined according to the Lugano 2014 criteria. The best response achieved per patient will be considered for analysis.
    Tasso di Risposta globale (ORR = somma risposte complete [CR] + risposte parziali [PR]) dopo 1 ciclo di induzione con daratumumab in monoterapia, dopo i cicli 3, 6 e 9 di induzione (ciclo 9 = fine dell’induzione, EOI); dopo i cicli 12 e 15 di mantenimento (ciclo 15 = fine del trattamento, EOT). La risposta verrà valutata secondo i criteri di Lugano 2014. Per l’analisi verrà considerata, per ogni paziente, la risposta migliore al trattamento ottenuta dall’inizio del trattamento all’ultima valutazione di malattia.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From the date of beginning of treatment to the last response evaluation.
    Dall’inizio del trattamento all’ultima valutazione di malattia.
    E.5.2Secondary end point(s)
    Progression-free survival (PFS), defined as the time from treatment start and progression/relapse or death from any cause (Lugano 2014); Overall survival (OS), defined as the time from treatment start and death from any cause (Lugano 2014).; Duration of response (DOR), defined for all patients who achieved a response (CR or PR) according to Response Criteria for NHL CT-based and/or PET-based (Lugano 2014), and is measured from the date when criteria for response are met (CR or PR) until the date of progression or relapse.; Role of daratumumab maintenance in terms of conversion rate of SD to PR or from SD/PR to CR.; Association between intensity of CD38 expression and response. The extent of CD38 expression evaluated by immunochemistry will be correlated with response measured according to the Lugano 2014 criteria at various timepoints.
    Sopravvivenza libera da progressione (PFS), definita come il tempo tra l’inizio del trattamento e la progressione/recidiva o la morte per qualsiasi causa (Lugano 2014); Sopravvivenza globale (OS), definita come il tempo tra l’inizio del trattamento e la morte per qualsiasi causa (Lugano 2014); Durata della risposta (DOR), definita per i pazienti che ottengono una risposta (CR o PR) valutata secondo i Criteri di Risposta per i linfomi non-Hodgkin alla TAC o alla PET (Lugano 2014), e misurata dalla data di ottenimento della risposta (CR o PR) alla data di progressione/recidiva.; Ruolo del mantenimento con daratumumab in termini di conversione da malattia stabile (SD) a PR o da SD/PR a CR.; Associazione tra l’intensità di espressione del CD38 e la risposta al trattamento secondo i criteri di Lugano 2014. La percentuale di espressione di CD38 valutata in immunoistochimica verrà correlata con la risposta valutata secondo i criteri di Lugano 2014 ad ogni timepoint.
    E.5.2.1Timepoint(s) of evaluation of this end point
    From treatment start to evidence of disease progression or death for any cause.; From treatment start to death.; From the date when criteria for response are met (CR or PR) until the date of progression or relapse.; From evidence of Stable Disease (SD) to evidence of Partial Response (PR) or from SD/PR to Complete Response (CR).; All treatment response assessment timepoints listed in the study.
    Dall'avvio del trattamento all'evidenza di progressione di malattia o decesso per qualsiasi causa.; Dall'avvio del trattamento al decesso.; Dalla data di ottenimento della risposta (CR o PR) alla data di progressione/recidiva.; Dall'evidenza di stabilità di malattia (SD) all'evidenza di Risposta Parziale (PR) o da SD/PR a Risposta Completa (CR).; Tutti i timepoints di rivalutazione della risposta al trattamento elencati in 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 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 concerned19
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 28
    F.4.2.2In the whole clinical trial 28
    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)
    After the participation in the study, the patients will be followed-up according to clinical practice timeline and procedures.
    Al termine della partecipazione allo studio, i pazienti saranno seguiti secondo le tempistiche e procedure dettate dalla normale 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 Decision2021-03-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-10
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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