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    Summary
    EudraCT Number:2018-000108-41
    Sponsor's Protocol Code Number:062-HEM-102
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-11-04
    Trial results View 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 number2018-000108-41
    A.3Full title of the trial
    A Phase 1b/2 Dose-Escalation and Cohort-Expansion Study of the Noncovalent, Reversible Bruton's Tyrosine Kinase Inhibitor, SNS 062, in Patients With B-Lymphoid Malignancies
    Studio di fase 1b/2, di aumento della dose ed espansione di coorte sull’inibitore reversibile non covalente della tirosin-chinasi di Bruton, SNS-062, in pazienti affetti da malignità linfoidi B
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine the safety profile and recommended dose of SNS-062 for further evaluation of a new cancer agent to treatment relapsed or resistant B-lymphoid cancers
    Uno studio per determinare il profilo di sicurezza e la dose raccomandata di SNS-062 per un'ulteriore valutazione di un nuovo agente cancerogeno per il trattamento recidivo o tumori B-linfoidi resistenti
    A.3.2Name or abbreviated title of the trial where available
    N/A
    N/A
    A.4.1Sponsor's protocol code number062-HEM-102
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03037645
    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 SponsorSunesis Pharmaceuticals, 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 supportSunesis Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street AddressLe Dauphiné Part-Dieu
    B.5.3.2Town/ cityLyon
    B.5.3.3Post code69003
    B.5.3.4CountryFrance
    B.5.4Telephone number33426830067
    B.5.5Fax number330975188501
    B.5.6E-mailregsubmissions@medpace.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 nameVecabrutinib
    D.3.2Product code [SNS-062]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNvecabrutinib
    D.3.9.1CAS number 1947403-49-7
    D.3.9.2Current sponsor codeSNS-062
    D.3.9.3Other descriptive nameVECABRUTINIB SUCCINATE
    D.3.9.4EV Substance CodeSUB192223
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.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 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 nameVecabrutinib
    D.3.2Product code [SNS-062]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNvecabrutinib
    D.3.9.1CAS number 1947403-49-7
    D.3.9.2Current sponsor codeSNS-062
    D.3.9.3Other descriptive nameVECABRUTINIB SUCCINATE
    D.3.9.4EV Substance CodeSUB192223
    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 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
    Male or female adult patients with an advanced B-Lymphoid malignancies that have relapsed/progressed after appropriate prior therapy and have resistance and/or mutations that may respond to subsequent BTK inhibition using SNS-062.
    Pazienti adulti di sesso maschile o femminile con neoplasie B-linfoidi avanzate che hanno recidivato/progredito dopo appropriata precedente terapia e hanno resistenza e/o mutazioni che possono rispondere alla successiva inibizione di BTK usando SNS-062.
    E.1.1.1Medical condition in easily understood language
    Male or female adult patients with an advanced B-Lymphoid malignancies who have resistance and/or mutations that may respond to subsequent BTK inhibition using SNS-062.
    Pazienti adulti di sesso maschile o femminile con neoplasie maligne B-linfoidi con resistenza e/o mutazioni che possono rispondere alla successiva inibizione di BTK usando SNS-062.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10026798
    E.1.2Term Mantle cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level HLT
    E.1.2Classification code 10047802
    E.1.2Term Waldenstrom's macroglobulinaemias
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10008948
    E.1.2Term Chronic leukemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10012819
    E.1.2Term Diffuse large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10067070
    E.1.2Term Follicular B-cell non-Hodgkin's lymphoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1b: To determine the MTD and/or RD of SNS-062

    Phase 2: To evaluate the objective response rate (ORR) by cohort in subjects receiving SNS-062
    Fase 1b: determinare la MTD e/o l'RD di SNS-062

    Fase 2: valutare il tasso di risposta obiettiva (ORR) per coorte in soggetti che ricevono SNS-062
    E.2.2Secondary objectives of the trial
    Phase 1b:
    - To characterize the safety profile of SNS-062
    - To characterize the PK profile of SNS-062
    - To characterize the antitumor activity of SNS-062
    - To assess the preliminary effect of SNS-062 on the QTc interval

    Phase 2:
    - To further characterize additional antitumor activity by cohort in subjects receiving SNS-062
    - To characterize the safety profile of SNS-062
    - To characterize the plasma PK profile of SNS-062
    - To assess the preliminary effect of SNS-062 on the QTc interval
    Fase 1b:
    - Caratterizzare il profilo di sicurezza di SNS-062
    - Caratterizzare il profilo PK di SNS-062
    - Caratterizzare l'attività antitumorale di SNS-062
    - Valutare l'effetto preliminare di SNS-062 sull'intervallo QTc

    Fase 2:
    - Caratterizzare ulteriormente l'attività antitumorale aggiuntiva per coorte in soggetti che ricevono SNS-062
    - Caratterizzare il profilo di sicurezza di SNS-062
    - Caratterizzare il profilo PK plasmatico di SNS-062
    - Valutare l'effetto preliminare di SNS-062 sull'intervallo QTc
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Men and women of age >=18 years
    2) Eastern Cooperative Oncology Group (ECOG) Performance Status of <=2
    3) Histologically confirmed malignancy with relapsed/refractory disease:
    a) After >=2 lines of standard systemic therapy including prior BTK inhibitor therapy:
    i) CLL
    ii) LPL/WM
    iii) MCL
    b) After >=2 lines of standard systemic therapy:
    i) DLBCL-ABC
    ii) FL
    4) For subjects in:
    a) Phase 1b and 2:
    Availability of a peripheral blood sample or a bone marrow aspirate or a lymph node biopsy obtained during the screening period for evaluation of predictive/prognostic disease parameters and to determine if there is a functional BTK C481 mutation (ie BTK C481S) or a resistance or gain of function mutation(s) (ie, PLC¿2 R665W)
    b) Phase 2 only:
    i) For CLL: the presence of a functional BTK C481 mutation (ie, >=1% BTK C481 mutation), and absence of a resistance or gain of function mutation (ie, PLC¿2 R665W) or
    ii) For CLL: absence of a functional BTK C481mutation alone (<1% BTK C481 mutation)
    iii) For LPL/WM: no mutation requirement
    iv) For MCL: no mutation requirement
    5) Presence of measurable disease:
    a) For subjects with SLL, MCL, DLBCL-ABC, FL: presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy
    b) For subjects with LPL/WM: presence of serum monoclonal immunoglobulin protein (M-protein) >=1 g/dL (but subject does not have symptomatic hyperviscosity syndrome [HVS] and does not require immediate plasmapheresis for control of HVS)
    6) Current medical need for therapy of the B-lymphoid malignancy due to disease-related symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or PD
    7) An interval of >=3 half-lives (unless the last therapy was an antibody where 1 half-life or 14 days, whichever is shorter, is acceptable with demonstrated progression by standard guidelines) from the completion of all previous antitumor therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) to the start of study therapy
    8) All acute toxic effects of any prior antitumor therapy resolved to Grade 1 before the start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade <=2 permitted], or selected laboratory parameters [Grade <=2 permitted with exceptions noted below])
    9) Adequate thyroid function (TSH, T3, T4) with or without thyroid replacement (Grade <=2)
    10) Adequate hepatic profile:
    a) Serum alanine aminotransferase (ALT) <=3 × upper limit of normal (ULN) (Grade <=1)
    b) Serum aspartate aminotransferase (AST) <=3 × ULN (Grade< =1)
    c) Serum alkaline phosphatase (ALP) <=2.5 × ULN (Grade <=1)
    d) Serum bilirubin =1.5 × ULN (Grade <=1) except for subjects with Gilbert’s disease
    11) Adequate renal function:
    a) Estimated creatinine clearance (eClCR) >45 mL/minute (with eClCR to be calculated by the Cockcroft-Gault formula),
    OR
    b) Measured creatinine clearance >45 mL/minute (assessed with a 24 hour urine collection)
    12) Adequate pancreatic profile:
    a) Serum amylase <=1.5 × ULN (Grade <=1)
    b) Serum lipase <=1.5 × ULN (Grade <=1)
    13) Hematology Requirements:
    a) Platelet count >=50 × 109/L (Grade <=2) maintained for >=7 days after any prior transfusion
    b) For subjects without bone marrow involvement:
    i) Absolute neutrophil count (ANC) >=0.750 × 109/L
    ii) Hemoglobin (Hb) >=8.0 g/dL, stable for >=7 days
    c) For subjects with bone marrow involvement:
    i) Absolute neutrophil count (ANC) >=500 cells/µL
    14) Adequate coagulation profile:
    a) Prothrombin time (PT) <=1.5 × ULN (Grade <=1)
    b) Activated partial thromboplastin time (aPTT) <=1.5 × ULN (Grade <=1)
    15) Negative antiviral serology:
    a) Negative human immunodeficiency virus (HIV) antibody
    b) Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or undetectable hepatitis B virus (HBV) DNA by quantitative polymerase chain reaction (PCR) testing
    c) Negative hepatitis C virus (HCV) antibody or negative HCV RNA by quantitative PCR
    1) Uomini e donne di età >= 18 anni
    2) Stato di prestazione del gruppo di cooperazione oncologica orientale (ECOG) <= 2
    3) Malignità confermata istologicamente con malattia recidivante / refrattaria:
    a) Dopo >= 2 linee di terapia sistemica standard inclusa la precedente terapia con inibitori BTK:
    i) CLL
    ii) LPL/WM
    iii) MCL
    b) Dopo >= 2 linee di terapia sistemica standard:
    i) DLBCL-ABC
    ii) FL
    4) Per i soggetti in:
    a) Fase 1b e 2:
    Disponibilità di un campione di sangue periferico o di aspirato di midollo osseo o biopsia linfonodale ottenuta durante il periodo di screening per la valutazione dei parametri predittivi/prognostici della malattia e per determinare se esiste una mutazione BTK C481 (ovvero BTK C481S) o una mutazione di resistenza o di guadagno di funzione (ie, PLC¿2 R665W)
    b) Solo fase 2:
    i) Per CLL: presenza di una mutazione funzionale BTK C481 (cioè, >= 1% BTK C481 mutazione) e assenza di mutazione di resistenza o guadagno di funzione (cioè PLC¿2 R665W) o
    ii) Per CLL: assenza di una sola mutazione funzionale di BTK C481 (<1% di mutazione BTK C481)
    iii) Per LPL/WM: nessun requisito di mutazione
    iv) Per MCL: nessun requisito di mutazione
    5) Presenza di malattia misurabile:
    a) Per soggetti con SLL, MCL, DLBCL-ABC, FL: presenza di linfoadenopatia radiografica misurabile o neoplasia linfoide extranodale
    b) Per i soggetti con LPL/WM: presenza di proteina immunoglobulinica monoclonale (M-proteina) >= 1 g/dL
    6) Attuale necessità medica per la terapia della neoplasia B-linfoide a causa di sintomi correlati alla malattia, linfoadenopatia, organomegalia, coinvolgimento extranodale degli organi o PD
    7) Un intervallo di >= 3 emivite (a meno che l'ultima terapia fosse un anticorpo, nel qual caso è accettabile un intervallo di 1 emivita o di 14 giorni, a seconda di quale sia più breve, con progressione dimostrata da linee guida standard) dal completamento di tutte le precedenti terapie antitumorali all'inizio della terapia di studio
    8) Tutti gli effetti tossici acuti di qualsiasi precedente terapia antitumorale sono stati risolti al Grado 1 prima dell'inizio della terapia di studio (ad eccezione dell'alopecia, neurotossicità o parametri di laboratorio selezionati)
    9) Funzione tiroidea adeguata (TSH, T3, T4) con o senza sostituzione tiroidea (Grado <= 2)
    10) Profilo epatico adeguato:
    a) Siero alanina aminotransferasi (ALT) <= 3 × limite superiore della norma (ULN) (Grado <= 1)
    b) Aspartato aminotransferasi (AST) <= 3 × ULN (Grado <= 1)
    c) Fosfatasi alcalina sierica (ALP) <= 2,5 × ULN (Grado <= 1)
    d) Bilirubina sierica = 1,5 × ULN (Grado <= 1) ad eccezione dei soggetti con malattia di Gilbert
    11) Funzione renale adeguata:
    a) clearance della creatinina stimata (eClCR) >45 ml/minuto (con eClCR da calcolare con la formula di Cockcroft-Gault),
    O
    b) clearance misurata della creatinina > 45 ml/minuto (valutata con una raccolta di urina delle 24 ore)
    12) Profilo pancreatico adeguato:
    a) Amilasi sierica <= 1,5 × ULN (Grado <= 1)
    b) Lipasi sierica <= 1,5 × ULN (Grado <= 1)
    13) Requisiti di ematologia:
    a) Conta piastrinica >= 50 × 109/L (Grado <= 2) mantenuta per >= 7 giorni dopo ogni precedente trasfusione
    b) Per i soggetti senza coinvolgimento del midollo osseo:
    i) Conteggio assoluto dei neutrofili (ANC) >= 0,750 × 109/L
    ii) Emoglobina (Hb) >= 8,0 g/dL, stabile per >= 7 giorni
    c) Per soggetti con coinvolgimento del midollo osseo:
    i) Conteggio assoluto dei neutrofili (ANC) >= 500 cellule/µL
    14) Profilo di coagulazione adeguato:
    a) Tempo di protrombina (PT) <= 1,5 × ULN (Grado <= 1)
    b) Tempo di tromboplastina parziale attivato (aPTT) <= 1,5 × ULN (Grado <= 1)
    15) sierologia antivirale negativa:
    a) Anticorpo del virus dell'immunodeficienza umana (HIV) negativo
    b) Anticorpo di superficie dell'epatite B (HBsAg) negativo e anticorpo del nucleo di epatite B (HBc) negativo o virus dell'epatite B non rilevabile (HBV) mediante PCR
    c) Anticorpo del virus dell'epatite C (HCV) negativo o RNA dell'HCV negativo mediante qPCR
    E.4Principal exclusion criteria
    1) Transformed disease at time of screening (eg, Richter’s transformation or of blastoid variant MCL)
    2) Known central nervous system malignancy
    Note: Central nervous system imaging is only required in subjects with suspected central nervous system malignancy.
    3) History of another malignancy except for the following adequately treated:
    a) Local basal cell or squamous cell carcinoma of the skin
    b) Carcinoma in situ of the cervix or breast
    c) Papillary, noninvasive bladder cancer
    d) Prostate cancer Stage 1 and 2 for which observation is clinically indicated with stable prostate-specific antigen (PSA) for 6 months
    e) Other Stage 1 or 2 cancers currently in complete remission
    f) Any other cancer that has been in complete remission for 2 years or surgically cured
    4) Significant cardiovascular disease
    a) Myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism within 6 months prior to start of study therapy
    b) Symptomatic angina
    c) Symptomatic peripheral vascular disease
    d) New York Heart Association Class >=3 congestive heart failure
    e) Uncontrolled Grade >=3 hypertension (diastolic blood pressure >=100 mmHg or systolic blood pressure >=160 mmHg) despite antihypertensive therapy
    f) Uncontrolled arrhythmia
    5) Significant screening ECG abnormalities:
    a) Left bundle branch block
    b) 2nd or 3rd-degree Atrioventricular block Type 2
    c) Grade >=2 bradycardia
    d) QTc by either Bazett or Fridericia method (QTcB or QTcF) >450 msec (for men) or >470 msec (for women)
    6) Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic diarrheal illness, bowel obstruction) that might interfere with drug absorption or with interpretation of gastrointestinal AEs
    7) Ongoing risk for bleeding due to any of the following:
    a) Bleeding diathesis
    b) Known platelet function disorder
    c) Uncontrolled peptic ulcer disease
    d) Oral anticoagulation (eg, warfarin, apixaban, rivaroxaban, dabigatran etexilate)
    e) Heparin, low-molecular-weight heparin or heparin fractions (eg, enoxaparin, dalteparin, fondaparinux)
    Note: Use of heparin or thrombolytic agents for local maintenance or clearance of a central venous catheter is permitted.
    8) Evidence of an uncontrolled systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of study therapy
    Note: Subjects with localized fungal infections of skin or nails are eligible.
    9) Demonstrated intolerance to a BTK inhibitor as evidenced by discontinuation of BTK inhibitor due to AE or required dose reduction due to AE
    10) Transplant
    a) Evidence of ongoing graft-versus-host disease after prior stem cell transplant
    b) Prior solid organ transplant
    11) Pregnancy or breastfeeding
    12) Major surgery within 4 weeks before the start of study therapy
    13) Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids except as noted
    Note: At screening, subjects may be using systemic corticosteroids (at physiologic doses of <=10 mg/day of prednisone or equivalent) or topical or inhaled corticosteroids.
    14) Use of a moderate or strong inhibitor or inducer of CYP3A4 within 7 days prior to the start of study therapy or expected requirement for use during study therapy
    15) Use of substrates of CYP2C8, CYP3A4, CYP2B6, CYP2C9 and CYP2D6 with narrow therapeutic index within 7 days prior to the start of study therapy or expected requirement for use during study therapy
    16) Any illness, medical condition, organ system dysfunction, or social situation, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a subject’s ability to sign informed consent, adversely affect the subject’s ability to cooperate and participate in the study, or compromise the interpretation of study results
    1) Malattia trasformata al momento dello screening
    2) Nota malignità del sistema nervoso centrale
    3) Storia di un'altra neoplasia tranne che per i seguenti trattati adeguatamente trattati:
    a) Carcinoma cutaneo basocellulare o squamocellulare localizzato della pelle
    b) Carcinoma in situ della cervice o della mammella
    c) Cancro alla vescica papillare e non invasivo
    d) Cancro prostatico stadio 1 e 2 per i quali l'osservazione è clinicamente indicata con un antigene prostatico specifico (PSA) stabile per 6 mesi
    e) Altri tumori di stadio 1 o 2 attualmente in remissione completa
    f) Qualsiasi altro tumore che è stato in completa remissione per 2 anni o guarito chirurgicamente
    4) Malattia cardiovascolare significativa
    a) Infarto miocardico, tromboembolia arteriosa o tromboembolia cerebrovascolare entro 6 mesi prima dell'inizio della terapia di studio
    b) angina sintomatica
    c) malattia vascolare periferica sintomatica
    d) Insufficienza cardiaca congestizia di classe >=3 secondo la New York Heart Association
    e) Ipertensione non controllata grado >= 3 nonostante la terapia antipertensiva
    f) aritmia incontrollata
    5) Anomalie ECG significative dello screening:
    a) Blocco di branca sinistro
    b) Blocco atrioventricolare di 2° o 3° grado di tipo 2
    c) bradicardia di grado > = 2
    d) QTc con metodo Bazett o Fridericia (QTcB o QTcF) >450 msec (uomini) o >470 msec (donne)
    6) Malattia gastrointestinale (ad es. Chirurgia di bypass gastrico o intestinale, insufficienza di enzimi pancreatici, sindrome da malassorbimento, ecc.) che potrebbe interferire con l'assorbimento del farmaco o con l'interpretazione degli EA gastrointestinali
    7) Rischio continuo di sanguinamento dovuto a uno dei seguenti:
    a) Diatesi sanguinante
    b) Disturbo della funzione piastrinica nota
    c) Malattia ulcera peptica incontrollata
    d) anticoagulazione orale (ad es. warfarin, apixaban, rivaroxaban, dabigatran etexilato)
    e) Eparina, frazione di eparina a basso peso molecolare o frazione di eparina (ad es. enoxaparina, dalteparina, fondaparinux)
    Nota: l'uso di eparina o di agenti trombolitici per la manutenzione locale o l'eliminazione di un catetere venoso centrale è consentito.
    8) Evidenza di un'infezione sistemica batterica, fungina o virale incontrollata (comprese le infezioni del tratto respiratorio superiore) al momento dell'inizio della terapia di studio
    Nota: sono ammessi i soggetti con infezioni fungine localizzate della pelle o delle unghie.
    9) Dimostrato intolleranza ad un inibitore BTK come evidenziato dalla sospensione dell'inibitore BTK dovuto ad AE o riduzione della dose richiesta a causa di AE
    10) Trapianto
    a) Evidenza della malattia del trapianto contro l'ospite in corso dopo il precedente trapianto di cellule staminali
    b) Trapianto di organi solidi precedenti
    11) Gravidanza o allattamento
    12) Chirurgia maggiore entro 4 settimane prima dell'inizio della terapia di studio
    13) Terapia immunosoppressiva in corso, inclusi corticosteroidi sistemici o enterici, eccetto per quanto osservato
    Nota: allo screening, i soggetti possono usare corticosteroidi sistemici (a dosi fisiologiche <= 10 mg / die di prednisone o equivalenti) o corticosteroidi topici o inalati.
    14) Uso di un inibitore moderato o forte o di un induttore di CYP3A4 entro 7 giorni prima dell'inizio della terapia di studio o del requisito previsto per l'uso durante la terapia di studio
    15) Uso di substrati di CYP2C8, CYP3A4, CYP2B6, CYP2C9 e CYP2D6 con indice terapeutico stretto entro 7 giorni prima dell'inizio della terapia di studio o requisito previsto per l'uso durante la terapia di studio
    16) Qualsiasi malattia, condizione medica, disfunzione del sistema degli organi o situazione sociale, inclusa la malattia mentale o abuso di sostanze, ritenuta dallo sperimentatore in grado di interferire con la capacità di un soggetto di firmare il consenso informato, influire negativamente sulla capacità del soggetto di cooperare e partecipare nello studio, o compromettere l'interpretazione dei risultati dello studio
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b: MTD and/or RD within the tested SNS-062 dose range

    Phase 2: ORR by cohort as evaluated by standard response and progression criteria for each tumor type
    Fase 1b: MTD e /o RD entro il range di dosaggio SNS-062 testato

    Fase 2: ORR per coorte come valutata dalla risposta standard e criteri di progressione per ciascun tipo di tumore
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the trial
    Durante tutta la sperimentazione
    E.5.2Secondary end point(s)
    Phase 1b:
    - Type, frequency, severity, and relatedness to study drug of treatment emergent adverse events (TEAEs), laboratory abnormalities, or electrocardiogram (ECG) findings
    - SNS-062 plasma PK parameters (including area under the plasma concentration-time curve [AUC], maximum concentration [Cmax], time of maximum concentration [Tmax], half-life [t1/2], apparent volume of distribution [Vd/F], terminal elimination rate constant [¿z], and apparent clearance [Cl/F])
    - ORR, time to response (TTR), duration of response (DOR), progressionfree-survival (PFS), as evaluated by standard response and progression criteria for each tumor type
    - QTc interval parameters, including changes from baseline and absolute increases in QTc interval

    Phase 2b
    - TTR, DOR, PFS, and OS by cohort as evaluate and progression criteria for each tumor type
    - Type, frequency, severity, and relatedness to study drug of TEAEs, laboratory abnormalities, or ECG findings
    - SNS 062 plasma PK parameters (including AUC, Cmax, Tmax, t1/2,Vd/FF, ¿z, and Cl/F)
    - QTc interval parameters, including changes from baseline and absolute increases in QTc interval
    Fase 1b:
    - Tipo, frequenza, gravità e correlazione allo studio di eventi avversi emergenti (TEAE) del farmaco, anomalie di laboratorio o risultati dell'elettrocardiogramma (ECG)
    - Parametri PK plasmatici SNS-062 (compresa area sotto la curva concentrazione plasmatica-tempo [AUC], concentrazione massima [Cmax], tempo di concentrazione massima [Tmax], tempo di dimezzamento [t1 / 2], volume apparente di distribuzione [Vd / F], costante velocità di eliminazione terminale [¿z] e clearance apparente [Cl / F])
    - ORR, time to response (TTR), durata della risposta (DOR), progressionfree-survival (PFS), come valutato dalla risposta standard e dai criteri di progressione per ciascun tipo di tumore
    - Parametri dell'intervallo QTc, comprese le variazioni rispetto al basale e gli aumenti assoluti dell'intervallo QTc

    Fase 2b
    - TTR, DOR, PFS e OS per coorte come criteri di valutazione e di progressione per ciascun tipo di tumore
    - Tipo, frequenza, gravità e correlazione al farmaco in studio di TEAE, anomalie di laboratorio o risultati ECG
    - Parametri PK plasmatici SNS 062 (inclusi AUC, Cmax, Tmax, t1 / 2, Vd / FF, ¿z e Cl / F)
    - Parametri dell'intervallo QTc, comprese le variazioni rispetto al basale e gli aumenti assoluti dell'intervallo QTc
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Type, frequency, severity, and relatedness to study drug of TEAEs, laboratory abnormalities, or ECG findings: thoughout the trial
    - SNS 062 plasma PK parameters: Cycle 1 days 1, 2, 8, 15, Cycle 2 Day 1
    - ORR, TTR, DOR, PFS, and OS : throughout the trial
    - QTc : Cycle 1 days 1, 2, 8, 15, Cycle 2 Day 1 to Cycle X day 1, EoT
    - Tipo, frequenza, gravità e correlazione al farmaco in studio di TEAE, anomalie di laboratorio o risultati ECG: durante lo studio
    - Parametri PK plasmatici SNS 062: ciclo 1 giorni 1, 2, 8, 15, ciclo 2 giorno 1
    - ORR, TTR, DOR, PFS e SO: durante la prova
    - QTc: ciclo 1 giorno 1, 2, 8, 15, ciclo 2 giorno 1 a ciclo X giorno 1, EoT
    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 Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation and Dose expansion
    Aumento della dose ed espansione di coorte
    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
    In aperto
    Open
    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 EEA34
    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
    France
    Germany
    Italy
    Spain
    United Kingdom
    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
    LVLS
    Ultima visita dell'ultimo paziente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    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: 37
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 87
    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 72
    F.4.2.2In the whole clinical trial 124
    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)
    A Post Therapy Follow Up visit 30 days after the last dose of study drug will occur to check on the status of unresolved AEs. All patients will enter Long Term Follow up (appr. every 3 months for up to two years) for the purpose of confirming the resolution of any AEs, subsequent anticancer therapy(ies), and survival. LTFU may be conducted by phone.
    Una visita di follow-up post terapia 30 giorni dopo l'ultima dose del farmaco in studio per verificare lo stato degli eventi avversi non risolti. Tutti i pazienti entreranno nel follow-up a lungo termine (circa ogni 3 mesi per un massimo di due anni) allo scopo di confermare la risoluzione di eventuali eventi avversi, la/e successiva/e terapia/e antitumorale/i e la sopravvivenza. LTFU può essere condotto per telefono.
    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 Decision2019-05-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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