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    Summary
    EudraCT Number:2017-003700-44
    Sponsor's Protocol Code Number:BGB-A317-207
    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:2021-01-19
    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 number2017-003700-44
    A.3Full title of the trial
    A Phase 2, Open-Label Study of BGB-A317 in Patients with Relapsed or Refractory Mature T- and NK-cell Neoplasms
    Studio di fase 2, in aperto, su BGB-A317 in pazienti recidivati o refrattari con neoplasie a cellule T e NK mature
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multi-center, open-label, phase 2 clinical study to evaluate the safety and efficacy of the investigational drug BGB-A317 in patients with T-cell or NK-cell lymphoma
    Studio multicentrico, in aperto, di fase 2 per valutare la sicurezza e l'efficacia del medicinale sperimentale BGB-A317 in pazienti con linfoma a cellule T o NK
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberBGB-A317-207
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03493451
    A.5.4Other Identifiers
    Name:-Number:-
    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 SponsorBEIGENE USA, INC.
    B.1.3.4CountryUnited States
    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 supportBeiGene, Ltd.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBeiGene, Ltd.
    B.5.2Functional name of contact pointBeiGene Clinical Support
    B.5.3 Address:
    B.5.3.1Street AddressUSA
    B.5.3.2Town/ cityUSA
    B.5.3.3Post codeUSA
    B.5.3.4CountryUnited States
    B.5.4Telephone number000000
    B.5.5Fax number000000
    B.5.6E-mailclinicaltrials@beigene.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBGB-A317
    D.3.2Product code -
    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 INNTislelizumab
    D.3.9.1CAS number 1858168-59-8
    D.3.9.2Current sponsor codeBGB-A317
    D.3.9.4EV Substance CodeSUB189550
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.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
    Relapsed or Refractory Mature T- and NK-cell Neoplasms
    Neoplasie recidivanti e refrattarie a cellule T e NK mature
    E.1.1.1Medical condition in easily understood language
    Mature T-cell and nature killer (NK)-cell lymphomas are lymphoid malignancies that are derived from proliferation of mature post-thymic lymphocytes.
    I linfomi a cellule T e a cellule natural killer (NK) mature sono neoplasie maligne che derivano dalla proliferazione dei linfociti mature post-thymic.
    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 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10025321
    E.1.2Term Lymphomas non-Hodgkin's T-cell
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate efficacy of BGB-A317 in patients Relapsed or Refractory Mature T- and NK-cell Neoplasms as measured by overall response rate and determined by investigator.
    • For cohorts 1 and 2, overall response rate will be measured using the Lugano criteria (Cheson et al 2014) with Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) modification for immunomodulatory drugs (Cheson et al 2016).
    • For cohort 3, overall response rate will be measured using the International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) guidelines (Olsen et al 2011).
    Valutare l’efficacia di BGB-A317 in pazienti recidivanti o refrattari a neoplasie a cellule T e NK mature misurata dal tasso di risposta complessiva e determinata dallo sperimentatore.
    • Per le coorti 1 e 2, il tasso di risposta complessiva sarà misurato utilizzando i criteri di Lugano (Cheson et al 2014) con la modifica dei criteri relativi alla risposta del linfoma alla terapia immunomodulatoria (LYRIC) per i farmaci immunomodulatori (Cheson et al 2016).
    • Per la coorte 3, il tasso di risposta complessiva sarà misurato utilizzando le linee guida della Società internazionale per i linfomi cutanei/Organizzazione europea per la ricerca e la cura del cancro (ISCL/EORTC) (Olsen et al 2011).
    E.2.2Secondary objectives of the trial
    For cohorts 1 and 2, efficacy measures will be determined using the Lugano criteria (Cheson et al 2014) with LYRIC modification for immunomodulatory drugs (Cheson et al 2016). For cohort 3, efficacy measures will be determined using the ISCL/EORTC guidelines (Olsen et al 2011).
    •To evaluate efficacy, as determined by investigator and measured by the following:
    - Duration of response for all cohorts
    - Progression-free survival for all cohorts
    - Overall survival for cohorts 1 and 2
    - Rate of complete response or complete metabolic response for all cohorts
    - Time to response for all cohorts
    - Patient reported outcomes (EQ-5D-5L and EORTC QLQ C30) for all cohorts
    • To evaluate safety and tolerability of tislelizumab for all cohorts
    Per le coorti 1 e 2, le misure di efficacia saranno determinate utilizzando i criteri di Lugano (Cheson et al 2014) con modifica dei LYRIC per i farmaci immunomodulatori (Cheson et al 2016). Per la coorte 3, le misure di efficacia saranno determinate utilizzando le linee guida ISCL/EORTC (Olsen et al 2011).
    • Valutare l’efficacia, determinata dallo sperimentatore e misurata mediante i seguenti criteri:
    - Durata della risposta per tutte le coorti
    - Sopravvivenza libera da progressione per tutte le coorti
    - Sopravvivenza complessiva per le coorti 1 e 2
    - Tasso di risposta completa o risposta metabolica completa per tutte le coorti
    - Tempo alla risposta per tutte le coorti
    - Esiti riferiti dal paziente (questionario europeo sulla qualità della vita a 5 dimensioni su scala a 5 livelli [EQ-5D-5L] e questionario sulla qualità della vita a 30 voci di EORTC [QLQ C30]) per tutte le coorti
    • Valutare la sicurezza e la tollerabilità di tislelizumab per tutte le coorti
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed diagnosis of relapsed or refractory, mature Tcell and NK-cell neoplasms based on the WHO 2016 classification of tumors of hematopoietic and lymphoid tissue. Patients will be allocated to one of three cohorts based on their histologic diagnosis:
    • Cohort 1: Extranodal NK/T-cell lymphoma (nasal or non-nasal type)
    ¿ Patients with aggressive NK leukemia are excluded
    • Cohort 2: Other mature T-cell neoplasms, limited to the following histologies:
    ¿ Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)
    ¿ Angioimmunoblastic T-cell lymphoma (AITL)
    ¿ Anaplastic large cell lymphoma (ALCL)
    • Cohort 3: Stage IB-IVB cutaneous T-cell lymphomas, limited to the following histologies (Appendix 15):
    ¿ Mycosis fungoides (MF)
    ¿ Sèzary syndrome (SS)
    2. Male or female = 18 years of age at the time of informed consent (or acceptable age according to local regulations, whichever is older)
    3. Previously received 1 or more appropriate systemic therapies (e.g., non-anthracycline based regimens, such as L-asparaginase-based therapy) for cohort 1 or combination chemotherapy (e.g. CHOP, EPOCH,or similar therapy) for cohort 2. Radiation therapy alone would not be acceptable as previous therapy.
    • For patients with relapsed or refractory anaplastic large cell lymphoma, regardless of anaplastic lymphoma kinase (ALK) status, must have received prior therapy with brentuximab vedotin (applicable only to countries where brentuximab vedotin received marketing approval)
    4. Disease progression during or after completion of most recent therapy or refractory disease. Refractory disease is defined as failure to achieve CR or PR to most recent therapy, and most recent therapy was an appropriate systemic therapy for mature T-cell or NK-cell lymphoma
    5. For cohorts 1 and 2, patients must have lesions that are measurable by imaging, where measurable is defined as = 1 lesion that is > 1.5 cm for nodal lesions and > 1 cm for extranodal lesions. For cohort 3, patients are not required to have measurable disease by
    imaging.
    6. Availability of either unstained tissue (block or unstained slides) or stained slides, and pathology report for central confirmation of mature T-cell or NK-cell lymphoma. If stained slides or unstained tissue (block or unstained slides) are not available or are insufficient, a fresh tumor tissue sample is mandatory for central pathology. Central pathology confirmation is not required prior to enrollment.
    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see table 3 in protocol).
    8. Has life expectancy = 6 months.
    9. Patients must have forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test (PFT), carbon monoxide diffusion capacity (DLCO) > 60% predicted value, and FEV1 and FVC > 50% predicted value; all PFTs must be obtained within 4 weeks prior to the first dose of tislelizumab
    10. Adequate organ function defined as:
    • Absolute neutrophil count (ANC) > 1000/mm3(without growth factor support within 7 days of ANC measurement)
    • Platelet > 50000/mm3(without growth factor support or transfusion within 7 days of platelets measurement)
    • Hemoglobin > 80 g/L (prior transfusion is acceptable)
    • Creatinine clearance = 30 ml/min (as estimated by the CockcroftGault equation or as measured by nuclear medicine scan or 24-hour urine collection) (see Appendix 9 of protocol)
    • Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase = 3.0 × upper limit of
    normal (ULN)
    • Serum total bilirubin < 2.0 × ULN (unless documented Gilbert's syndrome)
    11. Female patients of childbearing potential must be willing to use a highly effective method of birth control/contraception for the duration of the study, and for at least 120 days after the last dose of tislelizumab, and have a negative serum pregnancy test within 7 days of the first dose of study drug. Please r
    1. Diagnosi confermata istologicamente di neoplasia recidiva e refrattaria a cellule T e NK mature secondo la classificazione OMS 2016 dei tumori del tessuto ematopoietico e linfoide. I pazienti saranno assegnati a una di tre coorti sulla base della loro diagnosi istologica:
    - Coorte 1: linfoma a cellule NK/T extranodali (di tipo nasale o non nasale)
    ¿ I pazienti con leucemia NK aggressiva sono esclusi
    - Coorte 2: altre neoplasie a cellule T mature, limitatamente alle seguenti istologie:
    ¿ Linfoma periferico a cellule T-non altrimenti specificato (PTCL-NOS)
    ¿ Linfoma angioimmunoblastico a cellule T (AITL)
    ¿ Linfoma anaplastico a grandi cellule (ALCL)
    • Coorte 3: Linfomi cutanei a cellule T allo stadio IB-IVB, limitati alle seguenti istologie (Appendice 15):
    ¿ Micosi fungoide (MF)
    ¿ Sindrome di Sèzary (SS)2. Maschio o femmina di età = 18 anni al momento del consenso informato (o età accettabile in base alla normativa locale, a seconda di chi sia più anziano)
    2. Maschio o femmina di età = 18 anni al momento del consenso informato (o età accettabile in base alla normativa locale, a seconda di chi sia più anziano)
    3. Dovranno aver già ricevuto una terapia sistemica di prima linea appropriata (come la terapia non antraciclinica a base di L-asparaginasi) per i pazienti della coorte 1 o la chemioterapia di combinazione, (come CHOP, EPOCH o simili) per i pazienti della coorte 2. La sola radioterapia non è accettabile come precedente terapia.
    • I pazienti con linfoma anaplastico a grandi cellule recidivante o refrattario, a prescindere dallo stato di ALK (anaplastic lymphoma kinase), devono aver ricevuto una precedente terapia con brentuximab vedotin (applicabile solo ai Paesi in cui brentuximab vedotin ha ricevuto l’approvazione all’immissione in commercio)
    4. Progressione della malattia durante o dal completamento della più recente terapia (entro I 12 mesi) o malattia refrattaria. La malattia refrattaria è definita come insuccesso nell’ottenimento di CR o PR durante la più recente terapia., posto che la più recente terapia fosse una terapia sistemica appropriata per il linfoma a cellule T o NK mature
    5. Per le coorti 1 e 2, i pazienti devono presentare lesioni misurabili mediante diagnostica per immagini, dove per misurabile si intende = 1 lesione che sia > 1,5 cm per lesioni nodali e > 1 cm per lesioni extranodali.
    Per la coorte 3, i pazienti non sono tenuti a manifestare una malattia misurabile mediante diagnostica per immagini.
    6. Disponibilità o di tessuto non colorato (blocco o sezioni non colorate) o sezioni colorate, e referto patologico per conferma centrale di linfoma a cellule T o NK mature. Se le sezioni colorate o tessuto non colorato (blocco o sezioni non colorate) non sono disponibili o sufficienti, un campione di tessuto tumorale fresco è obbligatorio per la patologia centrale e altre analisi con biomarcatori. La conferma della patologia centrale non è richiesta prima dell’arruolamento.
    7. Eastern Cooperative Oncology Group (ECOG) performance status di 0, 1 o 2 (fare riferimento alla tabella 3 nel protocollo).
    8. Ha un’aspettativa di vita = 6 mesi
    9. I pazienti devono avere un forced expiratory volume in un secondo (FEV1)/forced vital capacity (FVC) > 60% tramite test della funzionalità polmonare (PFT), capacità di diffusione del monossido di carbonio (DLCO) > 60% del valor eprevisto, e FEV1 e FEV tutti > 50% del valore previsto; tutti i PFTs devono essere ottenuti entro 4 settimane prima della prima dose di tislelizumab.
    10. Funzione d’organo adeguata definita come:
    - conta neutrofila assoluta (ANC) > 1000 / mm3 (senza il supporto del fattore di crescita entro 7 giorni dalla conta dell’ANC);
    - Piastrine > 50000 / mm3 (senza il supporto del fattore di crescita o trasfusione entro 7 giorni dalla conta piastrinica);
    - Emoglobina > 80 g /l (precedente trasfusione è accettabile);
    - Clearance della creatinina = 30 ml/ min (come stimato dell’equazione di Cockcroft-Gault o come misurato dallo sca
    E.4Principal exclusion criteria
    1. Known central nervous system involvement by leukemia or lymphoma
    2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 agent
    3. Meets one of the following scenarios for hematopoietic stem cell transplantation and/or chimeric antigen receptor T cell (CAR-T) therapy:
    • Is eligible for autologous or allogeneic stem cell transplantation, unless patient has refused transplantation
    • Has undergone prior allogeneic hematopoietic stem cell transplantation or organ transplantation
    • Has received autologous stem cell transplantation within 6 months prior to first dose of study drug
    • Has received CAR-T therapy within 12 months prior to the first dose of study drug
    4. Has received:
    • Systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks (or 5 half-lives, whichever is shorter) prior to study Day 1
    • Recent treatment with another monoclonal antibody within 4 weeks prior to study Day 1
    • Investigational treatment or device within 4 weeks (or 5 half-lives,whichever is shorter) prior to study Day 1
    • For cohort 3 patients, phototherapy within 2 weeks or any topical therapy within 1 week prior to study Day 1
    • Or has not recovered from AEs (ie, = Grade 1 or baseline level) due to prior therapy.
    5. Concurrent or prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 or lower prostate cancer
    6. Active autoimmune diseases or history of autoimmune diseases that may relapse (see Appendix 3) Note: Patients with the following diseases are not excluded and may proceed to further screening:
    a. Type I diabetes under control
    b. Hypothyroidism (provided it is managed with hormone replacementtherapy only)
    c. Controlled celiac disease
    d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis,alopecia), except when such diseases significantly interfere with response assessment of patients in cohort 3
    e. Any other disease that is not expected to recur in the absence ofexternal triggering factors
    7. Has known history of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, acute lung diseases or evidence of dyspnea at rest or pulse oximetry of < 92% while breathing room air
    8. Has any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 14 days before study drug administration. Note: Patients who are currently or have previously been
    on any of the following steroid regimens are not excluded:
    a. Adrenal replacement steroid (dose = 10 mg daily of prednisone or equivalent)
    b. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal systemic absorption, except when given for treatment of MF or SS
    c. Short course (= 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen
    9. Has a known active TB (Bacillus Tuberculosis) infection
    10. Known infection with HIV, human T-cell lymphotropic virus-1, -2, or serologic status reflecting active hepatitis B or C infection as follows:
    • Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible only if hepatitis B virus (HBV) DNA is undetectable by an assay with sensitivity = 20 IU/mL. If so patients may either undergo regularly scheduled monitoring of HBV-DNA or less frequent monitoring of HBV DNA while on prophylactic antiviral medication as defined by
    regional standard of care.
    Please refer to the protocol for the remaining exclusion criteria
    1. Noto coinvolgimento del sistema nervoso centrale da leucemia o linfoma
    2. Ha ricevuto precedentemente una terapia con anti-PD-1. Anti-PD-L1, anti-PD-L2 o agente anti-CTLA-4
    3. Soddisfa uno dei seguenti scenari per la terapia con trapianto di cellule staminali ematopoietiche e/o con recettore dell’antigene chimerico a cellule T (CAR-T):
    - E’ eleggibile per trapianto autologo o allogenico di cellule staminali, a meno che il paziente abbia rifiutato il trapianto
    - Ha ricevuto un trapianto autologo di cellule staminali entro 6 mesi prima della prima dose del farmaco sperimentale
    - Ha ricevuto una terapia con CAR-T entro 12 mesi prima della prima dose del farmaco sperimentale
    4. Ha ricevuto:
    - antecedente chemioterapia sistemica, mirata alle cellule piccole, o radioterapia, entro 2 settimane ( o 5 emivite, ove la durata sia superiore) dal Giorno1 dello studio
    - Recente trattamento con un altro anticorpo monoclonale nelle 4 settimane precedenti il Giorno 1 dello studio
    - Trattamento o dispositivo sperimentale nelle 4 settimane (o 5 emi-vite, quando sono più brevi) precedenti al Giorno 1 dello studio
    - Per i pazienti della coorte 3, la fototerapia entro 2 settimane o qualsiasi terapia topica entro 1 settimana prima del Giorno 1 dello studio
    - o non si è ripreso da precedenti eventi avversi (es., = Grado 1 o al baseline) causati da agenti somministrati precedentemente
    5. Concomitante o antecedente neoplasia negli ultimi 3 anni, tranne che trattamenti curativi per cancro della pelle a cellule basali o squamose, carcinoma superficiale della vescica, carcinoma in situ alla cervice o alla mammella, o cancro alla prostata localizzato con punteggio Gleason di 6 o più basso
    6. Malattie autoimmuni attive o pregresse che possano recidivare (si veda l’Appendice 3 del protocollo)
    Nota: i pazienti con le seguenti patologie non sono esclusi e possono procedere con ulteriori screening:
    a. Diabete di tipo I sotto controllo
    b. Ipotiroidismo (trattato solo con terapia di sostituzione ormonale)
    c. Celiachia controllata
    d. Malattie cutanee che non necessitano di trattamento sistemico (ad es. vitiligine, psoriasi, alopecia), eccetto quando interferiscono significativamente con la valutazione della risposta di pazienti nella coorte 3e. Ogni altra malattia che non ci si aspetta possa recidivare in assenza di fattori esterni scatenanti
    7. Ha una storia conosciuta di malattia polmonare interstiziale, polmonite non infettiva, fibrosi polmonare, malattie acute al polmone o evidenza di dispnea a riposo o pulsossimetria < 92% mentre respira aria dell’ambiente.
    8. Presenta qualsiasi condizione che ha richiesto trattamento sistemico con corticosteroidi (> 10 mg al giorno di prednisone o equivalente) o altri immunosoppressivi nell’arco di 14 giorni prima della somministrazione del medicinale sperimentale. Nota: i pazienti che sono o sono stati in terapia con i seguenti steroidi non sono esclusi:
    a. Terapia steroidea surrenalica sostitutiva (dosaggio = 10 mg al giorno di prednisone o equivalente)
    b. Terapia cortisonica topica, oculare, intra-oculare, intranasale o inalatoria con minimo assorbimento sistemico, tranne quando usata come trattamento di MF o SS
    c. Breve ciclo (= 7 giorni) di corticosteroidi prescritti a scopo profilattico (es, contrastare allergia al colorante) o per il trattamento di una condizione non-autoimmune (es., ipersensibilità di tipo ritardata causata da un allergene da contatto)
    9. Ha un’infezione attiva da TB (Bacillus Tubercolosus)
    10. Infezione nota da virus dell’HIV, virus umano T-linfotropico di tipo 1, 2, o stato sierologico che riflette la presenza di epatite B o epatite C in fase attiva nel modo seguente:
    - Presenza dell’antigene di superficie dell’epatite B (HBsAg) o di anticorpi contro l’antigene core dell’epatite B (HBcAb). I pazienti che presentano HBcAb, ma non HBsAg, sono idonei solo se il DNA del virus dell’epatite B (HBV) non è rilevabile mediante test con sensibilità = 20 UI/ml. In tal caso, i pa
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is overall response rate as determined by investigator. Overall response rate is defined as the proportion of patients achieving a best overall response of complete response or partial response. Efficacy will be assessed every 12 weeks for 96 weeks, then every 24 weeks for an additional 96 weeks, and then yearly until disease progression.
    • For cohorts 1 and 2, overall response rate will be measured using the Lugano criteria (Cheson et al 2014) with LYRIC modification for immunomodulatory drugs (Cheson et al 2016).
    • For cohort 3, overall response rate will be measured using the ISCL/EORTC guidelines (Olsen et al 2011).
    L’endpoint primario è il tasso di risposta complessiva determinato dallo sperimentatore. Il tasso di risposta complessiva è definito come la percentuale di pazienti che ottengono una miglior risposta complessiva di risposta completa o risposta parziale. L’efficacia sarà valutata ogni 12 settimane per 96 settimane, successivamente ogni 24 settimane per ulteriori 96 settimane e, in seguito, con cadenza annuale fino a progressione della malattia.
    • Per le coorti 1 e 2, il tasso di risposta complessiva sarà misurato utilizzando i criteri di Lugano (Cheson et al 2014) con modifica dei LYRIC per i farmaci immunomodulatori (Cheson et al 2016).
    • Per la coorte 3, il tasso di risposta complessiva sarà misurato utilizzando le linee guida ISCL/EORTC (Olsen et al 2011).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy will be assessed every 12 weeks for 96 weeks, then every 24 weeks for an additional 96 weeks, and then yearly until disease progression.
    L’efficacia sarà valutata ogni 12 settimane per 96 settimane, poi ogni ogni 24 settimane per ulteriori 96 settimane, e poi ogni anno fino a progressione della malattia.
    E.5.2Secondary end point(s)
    For cohorts 1 and 2, efficacy measures will be determined using the Lugano criteria (Cheson et al 2014) with LYRIC modification for immunomodulatory drugs (Cheson et al 2016). For cohort 3, efficacy measures will be determined using the ISCL/EORTC guidelines (Olsen et al 2011). All measures will be assessed by the investigator.
    • Duration of response defined as the time from the first determination of an objective response until progression or death, whichever occurs first, for all cohorts
    • Progression-free survival defined as the time from first study drug administration to the date of disease progression or death, whichever occurs first, for all cohorts
    • Overall survival, defined as the time from first study drug administration to the date of death due to any reason, for cohorts 1 and 2
    • Rate of complete response or complete metabolic response defined as the proportion of patients who achieve complete response or complete metabolic response as best overall response, for all cohorts
    • Time to response defined as the time from first study drug administration to the time the response criteria (complete response or partial response) are first met, for all cohorts
    • Patient-reported outcomes measured by EORTC QLQ-C30 and EQ-5D-5L questionnaires for all cohorts
    • Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs for all cohorts
    Per le coorti 1 e 2, le misure di efficacia saranno determinate utilizzando i criteri di Lugano (Cheson et al 2014) con modifica dei LYRIC per i farmaci immunomodulatori (Cheson et al 2016). Per la coorte 3, le misure di efficacia saranno determinate utilizzando le linee guida ISCL/EORTC (Olsen et al 2011). Tutte le misurazioni saranno valutate dallo sperimentatore.
    • Durata della risposta definita come l’intervallo di tempo dalla prima determinazione di una risposta obiettiva fino a progressione o decesso, a seconda di quale evento si verifichi prima, per tutte le coorti
    • Sopravvivenza libera da progressione, definita come l’intervallo di tempo dalla prima somministrazione del farmaco dello studio fino alla data di progressione della malattia o decesso, a seconda di quale evento si verifichi prima, per tutte le coorti
    • Sopravvivenza complessiva, definita come l’intervallo di tempo dalla prima somministrazione del farmaco dello studio fino alla data del decesso per qualsiasi motivo, per le coorti 1 e 2
    • Tasso di risposta completa o risposta metabolica completa, definito come la percentuale di pazienti che raggiungono una risposta completa o risposta metabolica completa come migliore risposta complessiva, per tutte le coorti
    • Tempo alla risposta, definito come l’intervallo di tempo dalla prima somministrazione del farmaco dello studio fino al momento in cui vengono soddisfatti per la prima volta i criteri di risposta (risposta completa o risposta parziale) per tutte le coorti
    • Esiti riferiti dal paziente misurati mediante i questionari QLQ-C30 di EORTC ed EQ-5D-5L per tutte le coorti
    • Parametri di sicurezza, compresi gli EA, gli eventi avversi seri (SAE), i test clinici di laboratorio, gli esami obiettivi e i segni vitali per tutte le coorti
    E.5.2.1Timepoint(s) of evaluation of this end point
    A) Duration of response until progression or death, whichever occurs first, for all cohorts
    B) Progression-free survival at selected timepoints, for all cohorts
    C) Overall Survival (OS) at selected timepoints, for cohorts 1 and 2
    D) Rate of complete response or complete metabolic response, for all cohorts
    E) Time-to-response at selected timepoints, for all cohorts
    F) The EORTC QLQ-C30 and EQ-5D-5L questionnaires will be summarized for each assessment timepoint, for all cohorts
    G) Safety and Pharmacokinetic parameters as assessed by investigator
    A) Durata della risposta fino a progressione o decesso, a seconda di quale evento si verifichi prima, per tutte le coorti
    B) Sopravvivenza libera da progressione in determinati punti temporali, per tutte le coorti
    C) Sopravvivenza complessiva (OS) in determinati punti temporali, per le coorti 1 e 2
    D) Tasso di risposta completa o risposta metabolica completa, per tutte le coorti
    E) Tempo alla risposta in determinati punti temporali, per tutte le coorti
    F) I questionari QLQ-C30 di EORTC ed EQ-5D-5L verranno riassunti per ciascun time point della valutazione, per tutte le coorti
    G) Parametri di sicurezza e farmacocinetica, valutati dallo sperimentatore
    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 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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    Canada
    China
    France
    Germany
    Hong Kong
    Italy
    Taiwan
    United States
    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
    Study termination is defined as the time point when data collection will stop and the final analysis of the study will occur. The study will continue until the last patient has died, becomes lost to follow-up, or withdraws from study, or until sponsor decides to terminate the study.


    La conclusione dello studio ¿ definita come il periodo in cui la raccolta dei dati si fermer¿ e si avr¿ l'analisi finale dello studio. Lo studio continuer¿ fino a quando l'ultimo paziente sar¿ deceduto, mostrer¿ perdita al follow up o ritirer¿ il consenso informato, o fino a quando il promotore decider¿ 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 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: 97
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 33
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 130
    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)
    There are no plans to provide study treatment after End of the study. Patients may be transferred to commercially available drug if available or other therapy as per investigator's medical judgment.
    Non ci sono programmi per il trattamento dopo la conclusione dello studio. I pazienti potranno essere trattati con un medicinale disponibile sul commercio in caso sia disponibile oppure con un'altra terapia sulla base del giudizio medico dello sperimentatore.
    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 Decision2018-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-16
    P. End of Trial
    P.End of Trial StatusOngoing
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