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    Summary
    EudraCT Number:2018-004185-34
    Sponsor's Protocol Code Number:54767414MMY2065
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-17
    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 number2018-004185-34
    A.3Full title of the trial
    A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination with Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib and Dexamethasone (Kd) in Participants with Multiple Myeloma who have been Previously Treated with Daratumumab Intravenous (Dara-IV) to Evaluate Daratumumab Retreatment
    Uno studio di fase II che mette a confronto daratumumab somministrato per via sottocutanea (Dara-SC) in associazione con carfilzomib e desametasone (DKd) rispetto a carfilzomib e desametasone (Kd) in soggetti con mieloma multiplo, precedentemente trattati con daratumumab somministrato per via endovenosa (Dara-EV), per valutare il ritrattamento con daratumumab.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 2 study to compare Daratumumab in combination with Carfilzomib and Dexamethasone compared with Carfilzomib and Dexamethasone in participants with multiple myeloma previously treated with Daratumumab.
    Uno studio di fase II per confrontare daratumumab in associazione con carfilzomib e desametasone rispetto a carfilzomib e desametasone in partecipanti con mieloma multiplo precedentemente trattati con daratumumab.
    A.3.2Name or abbreviated title of the trial where available
    LYNX
    LYNX
    A.4.1Sponsor's protocol code number54767414MMY2065
    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 SponsorJANSSEN CILAG INTERNATIONAL NV
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    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 organisationJanssen-Cilag International N.V.
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715242166
    B.5.5Fax number+31715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.com
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab
    D.3.2Product code [JNJ-54767414]
    D.3.4Pharmaceutical form 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 INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJNJ-54767414
    D.3.9.3Other descriptive nameD.3.6.2 - dose massima specificare: Dose giornaliera; D.3.6.2.1 - valore: 1800; D.3.6.2.2 - unita': mg milligram(s); D.3.6.2.3 - via di somministrazione: Subcutaneous use(CURRENT)
    D.3.9.4EV Substance CodeSUB175772
    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 No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/08/548
    D.3 Description of the IMP
    D.3.1Product nameCarfilzomib
    D.3.2Product code [L01XX45]
    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 INNCarfilzomib
    D.3.9.1CAS number 868540-17-4
    D.3.9.2Current sponsor codeCarfilzomib
    D.3.9.4EV Substance CodeSUB32911
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Multiple Myeloma
    Mieloma Multiplo
    E.1.1.1Medical condition in easily understood language
    Bone marrow cancer
    Tumore del midollo osseo
    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 LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of Dara-SC in combination with Kd with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab intravenous (Dara-IV) to evaluate daratumumab retreatment.
    L’obiettivo primario è confrontare l’efficacia (tasso di risposta parziale molto buona [VGPR] o migliore, come risposta migliore secondo la definizione dei criteri IMWG [International Myeloma Working Group]) di Dara-SC in associazione con Kd rispetto all’efficacia di Kd in soggetti con mieloma multiplo recidivante refrattario precedentemente esposti a daratumumab per via endovenosa (Dara-EV) per valutare il ritrattamento con daratumumab
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    • To further characterize the efficacy (progression-free survival [PFS], overall survival [OS], overall response rate [ORR], rate of complete response[CR]/stringent complete response [sCR]) of Dara-SC in combination with Kd
    • To evaluate the minimal residual disease (MRD) negativity rate and durability of MRD negativity status
    • To characterize the safety of Dara-SC in combination with Kd
    • To determine time to next treatment
    • To evaluate the pharmacokinetics (PK)of Dara-SC
    • To determine the immunogenicity of daratumumab recombinant human hyaluronidase PH20 (rHuPH20)
    Gli obiettivi secondari sono i seguenti:
    • Descrivere ulteriormente l’efficacia (sopravvivenza libera da progressione [PFS], sopravvivenza globale [OS], tasso di risposta globale [ORR], tasso di risposta completa [CR] o risposta completa rigorosa [sCR]) di Dara-SC in associazione con Kd
    • Valutare il tasso di negatività per la malattia minima residua (MRD) e la durata dello stato di negatività per la MRD
    • Valutare il profilo di sicurezza di Dara-SC in associazione con Kd
    • Stabilire il tempo che intercorre tra la fine del trattamento dello studio e l’inizio del trattamento successivo
    • Valutare la farmacocinetica (PK) di Dara-SC
    • Determinare l’immunogenicità di daratumumab e della ialuronidasi umana ricombinante PH20 (rHuPH20)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each potential participant must satisfy all of the following criteria to be enrolled in the study:
    1. At least 18 years of age.
    2. Documented multiple myeloma as defined by the criteria below:
    Multiple myeloma diagnosis according to the International Myeloma Working Group (IMWG) diagnostic criteria.
    Measurable disease at screening as defined by any of the following: Serum M-protein level >=1.0 g/dL in participants with immunoglobulin G (IgG) type, or serum M-protein level >=0.5 g/dL in participants with non- IgG type, or urine M-protein level >=200 mg/24 hours; or Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) >=10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
    3. Evidence of a response (partial response or better based on investigator’s determination of response by IMWG criteria) to daratumumab-containing IV therapy with response duration of at least 4 months.
    4.1 Participants must have progressed from or be refractory to their last line of treatment. Relapsed or refractory disease as defined below:
    Relapsed disease is defined as an initial response to previous treatment, followed by confirmed PD by IMWG criteria >60 days after cessation of treatment.
    Refractory disease is defined as <25% reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or 60 days after cessation of treatment.
    5. Received 1 or 2 prior line(s) of treatment of which one contained Dara-IV, and completed Dara-IV at least 3 months prior to randomization. A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy.
    6. ECOG Performance Status score of 0, 1, or 2.
    7. Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
    a) hemoglobin >=8 g/dL (>=5mmol/L) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);
    b) absolute neutrophil count (ANC) >=1.0 × 10^9/L (prior growth factor support is permitted but must be without support within the 7 days prior to the laboratory test);
    c) platelet count >=75 ×10^9/L for participants in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count of >=50×10^9/L. Transfusions are not permitted within 7 days of testing to achieve this minimum platelet count.
    d) aspartate aminotransferase (AST) <=2.5 × upper limit of normal (ULN);
    e) alanine aminotransferase (ALT) <=2.5 × ULN;
    f) total bilirubin <=1.5 × ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin <=1.5× ULN is required);
    g) estimated creatinine clearance (CrCl) >=20mL/min per 1.73m^2. CrCl to be calculated using estimated glomerular filtration rate Modification of Diet in Renal Disease (MDRD) formula.
    h) albumin-corrected serum calcium <=14 mg/dL (<=3.5 mmol/L) or free ionized calcium <=6.5 mg/dL (<=1.6mmol/L)

    For full inclusion criteria modified (n. 8.1 and 10.1), refer page no: 33 to 35 of the protocol.
    Per essere arruolati nello studio, i potenziali soggetti devono soddisfare tutti i criteri elencati di seguito:
    1. Essere di età non inferiore a 18 anni.
    2. Presentare un mieloma multiplo documentato, secondo quanto definito dai seguenti criteri: Diagnosi di mieloma multiplo in base ai criteri diagnostici IMWG (Tabella 10). Malattia misurabile allo screening come definita da uno qualsiasi dei seguenti criteri: Livello di proteina M nel siero >=1,0 g/dL in soggetti con immunoglobuline di tipo G (IgG), oppure livello di proteina M nel siero >=0,5 g/dL in soggetti con immunoglobuline di tipo non-IgG, oppure livello di proteina M nelle urine >=200 mg/24 ore; oppure Mieloma multiplo a catene leggere senza malattia misurabile nel siero o nelle urine: catene leggere libere di immunoglobuline nel siero (FLC) >=10 mg/dL e rapporto FLC di immunoglobuline kappa/lambda anomalo nel siero.
    3. Presentare un'evidenza di risposta (risposta parziale o migliore sulla base della determinazione della risposta da parte dello sperimentatore secondo i criteri IMWG) a terapia EV contenente daratumumab e una durata della risposta non inferiore a quattro mesi.
    4.1 I soggetti devono presentare una progressione o essere refrattari alla loro prima linea di trattamento. Presentare una malattia recidivante o refrattaria come di seguito definita: per malattia recidivante si intende una risposta iniziale a un trattamento precedente, seguita da progressione di malattia confermata secondo i criteri IMWG >60 giorni dopo il termine del trattamento. Per malattia refrattaria si intende una riduzione <25% della proteina M oppure una progressione di malattia confermata secondo i criteri IMWG durante un trattamento precedente o <=60 giorni dopo il termine del trattamento.
    5. Aver ricevuto 1 o 2 linee di trattamento precedenti, una delle quali contenente daratumumab per via endovenosa (Dara-EV), e aver completato Dara-EV almeno 3 mesi prima della randomizzazione. Una singola linea terapeutica può essere composta da uno o più agenti e può includere l'induzione, il trapianto di cellule staminali ematopoietiche e la terapia di mantenimento. La radioterapia, la terapia con bifosfonati o un singolo ciclo breve di corticosteroidi (non superiore all'equivalente di desametasone 40 mg/die per 4 giorni) non verranno considerati come linee di trattamento precedenti.
    6. Punteggio del performance status ECOG pari a 0, 1 o 2.
    7. I valori degli esami clinici di laboratorio pre-trattamento devono soddisfare i seguenti criteri durante la fase di screening:
    a) emoglobina >=8 g/dL (>=5 mmol/L) (senza precedente trasfusione di RBC entro 7 giorni prima dell'esame di laboratorio; è consentito l'uso di eritropoietina umana ricombinante);
    b) conta assoluta dei neutrofili (ANC) >=1,0 × 10^9/L (è consentito un supporto dei fattori di crescita precedente, ma non è consentito un supporto nei 7 giorni antecedenti l'esame di laboratorio);
    c) conta piastrinica >=75 × 10^9/L in soggetti nei quali <50% delle cellule nucleate del midollo osseo sono cellule plasmatiche; altrimenti conta piastrinica >=50 × 10^9/L. Le trasfusioni non sono consentite nei 7 giorni precedenti l'esame di laboratorio al fine di ottenere questo valore minimo di conta piastrinica;
    d) aspartato aminotransferasi (AST) <=2,5 volte il limite superiore alla norma (ULN);
    e) alanina aminotransferasi (ALT) <=2,5 × ULN;
    f) bilirubina totale <=1,5 × ULN; eccetto in soggetti con bilirubinemia congenita, come la sindrome di Gilbert (in tal caso è richiesta bilirubina diretta <=1,5 × ULN);
    g) clearance della creatinina stimata (CrCl) >=20 mL/min per 1,73 m^2. La CrCl deve essere calcolata attraverso la formula MDRD (“Modification of Diet in Renal Disease”) per la velocità di filtrazione glomerulare stimata;
    h) calcio sierico corretto per l'albumina <=14 mg/dL (<=3,5 mmol/L) oppure calcio libero ionizzato <=6,5 mg/dL (<=1,6 mmol/L)

    Per tutti i criteri di inclusione mod. (n. 8.1 e 10.1) vedere da pag. 33 a pag. 35 del protocollo.
    E.4Principal exclusion criteria
    Any potential participant who meets any of the following criteria will be excluded from participating in the study:
    1. Previous treatment with Dara-SC.
    2. Previous treatment with carfilzomib.
    3. Previous treatment with daratumumab within the last 3 months prior to randomization.
    4. Discontinuation of Dara-IV due to a daratumumab-related AE.
    5. History of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease. Further exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years.
    6. Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, mAbs, human proteins, or their excipients (refer to the IB), or known sensitivity to mammalian derived products. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
    7. Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
    8.1 Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization (except for investigational anti-myeloma
    treatments, which cannot be taken within 2 weeks or 5 PK half-lives of the treatment from the date of randomization, whichever is longer)
    9. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study intervention.
    10. Plans to father a child while enrolled in this study or within 3 months after the last dose of study intervention.
    11. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
    12.1. Received anti-myeloma treatment within 2 weeks or 5 PK half-lives of the treatment from the date of randomization, whichever is longer.
    The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days; see Appendix 10) up to 21 days before treatment. A list of anti-myeloma
    treatments with the corresponding PK half-lives is provided in the Site Investigational Product Procedures Manual.
    13. Received autologous stem cell transplant within 12 weeks before the date of randomization, or the participant has previously received allogeneic stem cell transplant (regardless of timing).
    14. Plans to undergo a stem cell transplant prior to progression of disease on this study.

    For full exclusion criteria, refer page no: 35 to 38 of the protocol.
    I potenziali soggetti in possesso di uno qualsiasi dei criteri seguenti saranno esclusi dalla partecipazione allo studio:
    1. Precedente trattamento con daratumubab per via sottocutanea (Dara-SC).
    2. Precedente trattamento con carfilzomib.
    3. Precedente trattamento con daratumumab somministrato nei 3 mesi antecedenti alla randomizzazione.
    4. Interruzione di Dara-EV dovuta ad evento avverso correlato a daratumumab.
    5. Storia di tumore maligno (diverso dal mieloma multiplo), fatta eccezione per il caso in cui il trattamento del tumore maligno sia stato concluso almeno 2 anni prima del del consenso e il paziente non presenti evidenza della malattia. Costituiscono un'ulteriore eccezione i carcinomi della pelle a cellule squamose e basali e il carcinoma in situ della cervice o del seno o altre lesioni non invasive che, secondo lo sperimentatore, di concerto con il monitor medico dello sponsor, sono considerate curate con rischio minimo di ricorrenza entro 3 anni.
    6. Allergie, ipersensibilità o intolleranza nota a daratumumab, alla ialuronidasi, agli mAb, alle proteine umane o ai relativi eccipienti (consultare il Dossier dello sperimentatore [IB]) oppure sensibilità nota a prodotti di derivazione mammifera. Storia nota di allergia a Captisol (un derivato della ciclodestrina impiegato per solubilizzare carfilzomib).
    7. Controindicazioni all'uso di qualsiasi componente impiegato nei regimi di terapia di backbone, conformemente alle informazioni di prescrizione locali.
    8.1 Aver ricevuto un trattamento sperimentale (inclusi i vaccini sperimentali) o aver utilizzato un dispositivo medico sperimentale invasivo nelle 4 settimane precedenti la randomizzazione (fatta eccezione per i trattamenti anti-mieloma sperimentali, che non possono essere assunti entro 2 settimane o 5 emivite farmacocinetiche del trattamento dalla data della randomizzazione, a seconda del periodo più lungo).
    9. Gravidanza o allattamento al seno in atto oppure intenzione di iniziare una gravidanza durante l'arruolamento nello studio o nei 3 mesi successivi all'assunzione dell'ultima dose di trattamento dello studio.
    10. Intenzione di concepire un figlio durante l'arruolamento nello studio o nei 3 mesi successivi all'ultima dose di trattamento dello studio.
    11. Presenza di qualsiasi condizione per cui, secondo il giudizio dello sperimentatore, la partecipazione non sarebbe nel miglior interesse del soggetto (ad es., ne comprometterebbe il benessere) o potrebbe impedire, limitare o confondere le valutazioni specificate dal protocollo.
    12.1 Aver ricevuto un trattamento anti-mieloma entro 2 settimane o 5 emivite farmacocinetiche del trattamento dalla data della randomizzazione, a seconda del periodo più lungo. Fa eccezione solo l'uso in caso di emergenza di un ciclo breve di corticosteroidi (equivalente di desametasone 40 mg/die per un massimo di 4 giorni) fino a 21 giorni prima dell'inizio del trattamento. Un elenco dei trattamenti anti-mieloma con le corrispondenti emivite farmacocinetiche viene fornito nel Manuale sulle procedure per il prodotto sperimentale del centro.
    13. Essere stato sottoposto a trapianto autologo di cellule staminali nelle 12 settimane precedenti la data di randomizzazione oppure aver ricevuto in precedenza un trapianto allogenico di cellule staminali (a prescindere da quando è avvenuto).
    14. Prevedere di sottoporsi a trapianto di cellule staminali prima della progressione della malattia in studio.

    Per tutti i criteri di esclusione, vedere da pag. 35 a pag. 38 del protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    The rate of very good partial response (VGPR) or better as defined by the IMWG criteria.
    Tasso di risposta parziale molto buona (VGPR) o migliore, secondo la definizione dei criteri IMWG.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Randomization to death, disease progression (DP), or lack of VGPR after 16 cycles of treatment (approximately 1 year and 3 months)
    Dalla randomizzazione alla morte, progressione di malattia (PD), o perdita di VGPR dopo 16 cicli di trattamento (approssimativamente 1 anno e 3 mesi)
    E.5.2Secondary end point(s)
    1. Overall response rate (ORR) [rate of partial response (PR), very good partial response (VGPR), complete response (CR), stringent complete response (sCR)]
    2. Rate of CR/sCR
    3. Progression free survival (PFS)
    4. Overall survival (OS)
    5. Minimal residual disease (MRD) negativity rate
    6. Time to next treatment
    7. Serum daratumumab concentrations
    8. Prevalence and incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
    1. tasso di risposta globale (ORR), tasso di risposta parziale (PR), risposta parziale molto buona (VGPR), tasso di risposta completa (CR), risposta completa rigorosa (sCR)
    2. Tasso di CR/sCR
    3. Sopravvivenza libera da progressione PFS
    4. Sopravvivenza globale (OS)
    5. Tasso di negatività per la malattia minima residua (MRD)
    6. Tempo che intercorre tra la fine del trattamento dello studio e l’inizio del trattamento successivo
    7. Concentrazioni sieriche di daratumumab
    8. Prevalenza e incidenza degli anticorpi anti-daratumumab e degli anticorpi anti-rHuPH20
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Randomization (R) to death, DP or lack of VGPR/PR/CR/sCR after 16 cycles (C) of treatm.(about 1 yr and 3 mths)
    2.R to death, DP or lack of CR/sCR after 16 C of treatment (about 1 yr and 3 months)
    3.From R to PFS after about 18.7 mths
    4.From R to end of study(defined as no later than 2 yrs after the last participant has received their initial dose of study intervention or when the sponsor decides to stop the study)
    5.Bone marrow aspirates will be collected at time of suspected CR/sCR and for participants achieve CR,have not progressed, and remain on the study,additional bone marrow aspirate will be obtained at 12,18 and 24 mth post C1Day1
    6.From R to next Myeloma treatm.(about 16 C)
    7.Arm A: C1, C3; Arm B: C1,C3,C7 and Post-treatm. Wk8
    8.Arm A: C1; Arm B: C1,C7 and Post-treatm. Wk8
    1.Randomizazione(R)a morte,PD o mancanza di VGPR/PR/CR/sCR dopo 16 cicli(C)di trattamento (circa 1 anno(A) e 3 mesi(M));2.R a morte,PD o mancanza di CR/sCR dopo 16 C di trattamento(circa 1A e 3M);3.Da R a PFS dopo circa 18,7 mesi;4.Da R a fine studio(non più tardi di 2 anni dopo che l'ultimo soggetto ha ricevuto dose iniziale del trattamento di studio o quando lo sponsor decide di interrompere lo studio);5.Aspirati di midollo osseo verranno raccolti al momento di sospetta CR/sCR e per chi ha ottenuto CR,non è andato in progressione, e che rimane in studio,un aspirato midollare supplementare sarà ottenuto ai mesi 12,18,24 da C1G1;6.Da R a successivo trattamento per mieloma(circa 16C);7.Braccio A:C1,C3;Braccio B:C1,C3,C7 e Wk8 post-trattamento(P-T);8.Braccio A:C1; Braccio B:C1,C7 e Wk8(P-T)
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity and Biomarker analyses
    Immunogenicità e analisi dei biomarcatori
    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 Yes
    E.8.1.7.1Other trial design description
    E.8.1.1. Randomizzato: SI - E.8.1.2. In aperto: SI
    E.8.1.1. Randomized: YES - E.8.1.2. Open-label: YES
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Brazil
    Canada
    Denmark
    France
    Germany
    Greece
    Italy
    Netherlands
    Poland
    Russian Federation
    Spain
    United States
    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
    The end of study is no later than 2 years after the last participant has received their initial dose of study intervention or when the sponsor decides to stop the study.
    La fine dello studio sarà non più tardi di 2 anni da quando l'ultimo soggetto ha ricevuto la sua prima dose di trattamento o quando lo sponsor decide di terminare lo studio.
    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 months3
    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: 23
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 207
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 155
    F.4.2.2In the whole clinical trial 230
    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)
    The sponsor will ensure that participants benefiting from study treatment will be able to continue receiving Dara-SC and carfilzomib after the end of the study until these agents are commercially available or available from another source. Subsequent therapy is left to the investigator's discretion. Subsequent therapy should be documented in the CRF.
    Lo Sponsor assicurerà che i partecipanti che trarranno beneficio dal trattamento con Daratumumab sottocute e Carfilzomib continueranno a ricevere il trattamento dopo la fine dello studio fino a che i due farmaci non saranno commercialmente disponibili o disponibili da un'altra fonte. La terapia successiva è a discrezione dello sperimentatore. La terapia successiva deve essere documentata nella CRF.
    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 Decision2019-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-06
    P. End of Trial
    P.End of Trial StatusOngoing
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