Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42758   clinical trials with a EudraCT protocol, of which   7042   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2018-000108-41
    Sponsor's Protocol Code Number:062-HEM-102
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-01-10
    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 ConcernedSpain - AEMPS
    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.
    Estudio en fase Ib/II de aumento progresivo de la dosis y ampliación de cohortes del inhibidor no covalente reversible de la tirosina-cinasa de Bruton —SNS062— en pacientes con neoplasias malignas linfoides 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.
    Estudio para determinar el perfil de seguridad y la dosis recomendada de SNS-062 para la posterior evaluación de un nuevo fármaco antineoplásico para el tratamiento de neoplasias malignas linfoides B en recidiva o resistentes.
    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 number3309 75 18 85 01
    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
    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 194740-349-7
    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 number82
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.
    Pacientes adultos de ambos sexos con neoplasias malignas linfoides B avanzadas que hayan experimentado recidiva o progresión después de un tratamiento previo adecuado y que presenten resistencia o mutaciones que puedan responder a la inhibición posterior de la BTK con SNS-062.
    E.1.1.1Medical condition in easily understood language
    Male or female adult patients with advanced B-Lymphoid malignancies who have resistance and/or mutations that may respond to subsequent BTK inhibition using SNS-062.
    Pacientes adultos de ambos sexos con neoplasias malignas linfoides B avanzadas que presenten resistencia o mutaciones que puedan responder a la inhibición posterior de la BTK con 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 vecabrutinib.

    Phase 2: To evaluate the anti-tumor activity in patients receiving vecabrutinib, as assessed by overall response rate (ORR) (complete remission [CR] + complete remission with incomplete blood count recovery [CRi] + partial remission [PR]).
    Fase 1b: Determinar la DMT y/o la DR de vecabrutinib.

    Fase 2: Evaluar la actividad antitumoral en pacientes tratados con vecabrutinib, determinada mediante la tasa de respuesta global (TRG) (remisión completa [RC] + remisión completa con recuperación incompleta del hemograma [RCi] + remisión parcial [RP]).
    E.2.2Secondary objectives of the trial
    Phase 1b:
    • To characterize the safety profile of vecabrutinib
    • To characterize the PK profile of vecabrutinib
    • To characterize the antitumor activity of vecabrutinib
    • To assess the preliminary effect of vecabrutinib on the QTc interval

    Phase 2:
    •To evaluate additional antitumor activity by assessment of
    • Time to response (TTR)
    • Duration of response (DOR)
    • Response rate (RR) (CR + CRi + PR + partial remission with lymphocytosis [PR-L])
    • Disease control rate (DCR) (CR + CRi + PR + PR-L + stable disease [SD])
    • Progression free survival (PFS)
    • OS
    • To characterize the safety profile of vecabrutinib
    • To characterize the plasma PK profile of vecabrutinib
    Fase 1b:
    • Caracterizar el perfil de seguridad de vecabrutinib.
    • Caracterizar el perfil farmacocinético de vecabrutinib
    • Caracterizar la actividad antitumoral de vecabrutinib.
    • Evaluar el efecto preliminar de vecabrutinib sobre el intervalo QTc.

    Fase 2:
    • Evaluar la actividad antitumoral adicional mediante:
    • Tiempo transcurrido hasta la respuesta (THR).
    • Duración de la respuesta (DDR).
    • Tasa de respuesta (TR) (RC + RCi + RP + remisión parcial con linfocitosis [RP L]).
    • Tasa de control de la enfermedad (TCE) (RC + RCi + RP + RP L + enfermedad estable [EE]).
    • Supervivencia sin progresión (SSP).
    • SG.
    • Caracterizar el perfil de seguridad de vecabrutinib.
    • Caracterizar el perfil farmacocinético en plasma de vecabrutinib.
    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:
    Phase Ib:
    i) CLL/SLL
    ii) LPL/WM
    iii) MCL
    iv) MZL
    v) DLBCL-ABC
    vi) FL
    Phase 2:
    Cohort 1: Patients with CLL/SLL who have received ≥1 prior regimen that included a covalent BTKi (single agent or in combination) AND
    • relapsed on or following discontinuation of this BTKi-containing
    regimen
    • have a BTK C481 mutation (≥5% VAF)
    Cohort 2: Patients with CLL/SLL who have received ≥1 prior regimen that included a covalent BTKi (single agent or in combination) AND
    • relapsed on or following discontinuation of this BTKi-containing regimen
    • do not have a BTK C481 mutation (<5% VAF).
    Cohort 3: Patients with relapsed or refractory CLL/SLL who have received ≥2 prior regimens, including having relapsed from a covalent BTKi (single agent or in combination) AND
    • the most recent regimen was not a covalent BTKi
    • have a BTK C481 mutation (≥5% VAF).
    Cohort 4: Patients with CLL/SLL who have received ≥1 prior regimen where the most recent regimen was a covalent BTKi (single agent or in combination) and discontinued therapy due to BTKi treatment intolerance (ie, discontinued due to AE or unacceptable toxicity as determined by the investigator). Patients must have a need for treatment (inclusion criterion 6) but relapsed or refractory disease is not required.
    4) For both Phase 1b and 2, availability of a peripheral blood sample and/or a bone marrow aspirate and/or a lymph node biopsy obtained during the screening period for evaluation of predictive/prognostic disease parameters and to determine if there is a BTK C481 mutation or other resistance mutations
    5) Presence of measurable disease:
    a) For patients with SLL, MCL, MZL, DLBCL-ABC, or FL: presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (Cheson, 2014)
    b) For patients with LPL/WM: presence of serum immunoglobulin M (IgM) with a minimum IgM level >2 times the upper limit of normal (ULN) of each institution (but patient 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-cell malignancy
    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 to the start of study therapy
    8) All acute toxic effects of any prior antitumor therapy resolved to Grade 1 (or baseline) 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, free T3, free T4) with or without thyroid replacement (Grade ≤2)
    10) Adequate hepatic profile:a) Serum alanine aminotransferase (ALT) ≤3 × 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 patients 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 [Appendix 3]),
    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 ≥30 × 109/L (Grade ≤2), without transfusion support, evidence of mucosal bleeding, known history of mucosal bleeding episode within 3 months of screening, and history of bleeding disorder
    b) For patients without bone marrow involvement:
    i) Absolute neutrophil count (ANC) ≥0.75 × 109/L
    ii) Hemoglobin (Hb) ≥8.0 g/dL, stable for ≥ 7 days
    c) For patients with bone marrow involvement:
    i) ANC ≥0.5 × 109/L
    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) No history of human immunodeficiency virus (HIV) and negative serology and/or undetectable virus by polymerase chain reaction (PCR) for both hepatitis B virus (HBV) and hepatitis C virus (HCV) at screening
    16) For female patients of childbearing potential:
    a) A negative serum pregnancy test prior to start of study therapy
    b) Willingness to use a protocol-recommended method of contraception from the start of the screening period until ≥30 days after the final dose of study therapy
    17) For male patients who can father a child: willingness to use a protocol recommended method of contraception and to refrain from sperm donation from the start of study therapy until ≥90 days after the final dose of study therapy
    1)Varón y mujer ≥ 18 años
    2)ECOG ≤ 2
    3)Neoplasia maligna confirmad histológicamente con enf recidivante/resistente:
    Fase Ib:
    i)LLC/LLCP
    ii)LLP/MW LPL/WM
    iii)LCM
    iv)LZM
    v)LBDCG-LBA
    vi)LF
    Fase 2:
    Cohorte 1: Pacients con LLC/LLCP q han recibido ≥1 pautas previas q incluya BTKi covalente (en monoterapia o en combinación) Y
    •recidiva durante o desp d la suspensión d esta pauta con iBTK
    •presentan mutación C481 de BTK (FAV ≥ 5%)
    Cohorte 2: Pacients con LLC/LLCP q han recibido ≥1 pautas previas q incluya BTKi covalente (monoterapia o en combinación) Y
    •recidiva durante o desp d la suspensión d esta pauta con iBTK
    •no presentan mutación C481 de BTK (FAV < 5%)
    Cohorte 3: Pacients con LLC/LLCP recidivante o resistente q han recibido ≥2 pautas previas, incluida 1 recidiva con iBTK covalente (monoterapia o combinación)Y
    • La pauta más reciente no ha sido iBTK covalente
    • Presentan mutación C481 de BTK (FAV ≥ 5%)
    Cohorte 4: Pacients con LLC/LLCP q han recibido ≥1 pautas previas, siendo la más reciente iBTK (en monoterapia o en combinación) y han suspendido tto por intolerancia al iBTK (es decir, suspensión por un AA o toxicidad inaceptable según lo determinado por el investigador). Los pacientes deben tener necesidad d tto (criterio de inclusión nº6), pero no se exige enf recidivante o resistente
    4) Enfases 1b y 2, disponibilidad d 1muestra d sangre periférica y/o 1aspirado d médula ósea y/o 1biopsia ganglionar obtenida durante selección para evaluar parámetros predictivos/pronósticos d la enf para determinar si existe mutación C481d la BTK u otras mutaciones d resistencia
    5) Presencia d enf mensurable:
    a) Pacientes con LLCP, LCM, LZM, LBDCG LBA o LF: presencia d adenopatías o neoplasia maligna linfoide extraganglionar radiológicamente mensurables (Cheson, 2014)
    b) Pacientes con LLP/MW: presencia d inmunoglobulina M (IgM) sérica con concentración mín de IgM >2 vcs el lím superior d la normalidad (LSN) d cada centro (pero el paciente no presenta síndrome de hiperviscosidad [SHV] sintomático y no requiere plasmaféresis inmediata para controlar el SHV)
    6)Necesidad médica actual d tto para la neoplasia maligna d linfocitosB
    7)Intervalo ≥ 3 semividas (a menos q el último tto fuese un anticuerpo, en cuyo caso 1 semivida o 14 días, lo q suponga menos tiempo, son aceptables en presencia d progresión demostrada según las directrices habituales) dsde la finalización d todo tto antitumoral previo hasta el comienzo del tto del estudio.
    8)Resolución d todos los efectos tóxicos agudos d cualquier tto antitumoral previo a grado 1 (o a la situación basal) antes del comienzo del tto del estudio (con la excepción de alopecia [grado 1 o 2 permitido], neurotoxicidad [grado ≤ 2 permitido] o determinados parámetros analíticos [grado ≤ 2 permitido, con las excepciones q se indican a continuación])
    9)Función tiroidea adecuada (TSH, T3 libre, T4 libre) con o sin terapia d reposición tiroidea (grado ≤ 2)
    10) Perfil hepático adecuado
    a)ALT sérica ≤ 3 el LSN (grado ≤ 1).
    b)AST sérica ≤ 3 el LSN (grado ≤ 1).
    c)FA sérica ≤ 2,5 el LSN (grado ≤ 1).
    d)Bilirrubina sérica ≤ 1,5 el LSN (grado ≤ 1), excepto en pacientes con enf d Gilbert.
    11) Función renal adecuada:
    a)Aclaramiento de creatinina estimado (ClCRe) > 45 ml/min(ClCRe se calculará mediante la fórmula d Cockcroft Gault [Apénd 3])
    O
    b) Aclaramiento de creatinina medido > 45 ml/min (evaluado con muestra d orina d 24 hrs).
    12) Perfil pancreático adecuado:
    a)Amilasa sérica ≤ 1,5 el LSN (grado ≤ 1).
    b)Lipasa sérica ≤ 1,5 el LSN (grado ≤ 1).
    13)Requisitos hematológicos:
    a)Recuento d plaquetas ≥ 30 × 109/l (grado ≤ 2), sin apoyo con transfusiones, signos d hemorragias mucosas, antecedentes conocidos d hemorragias mucosas en los 3 meses previos a la selección y antecedentes d trastorno hemorrágico.
    b)Pacientes sin afectación d la médula ósea:
    i)Recuento absoluto d neutrófilos (RAN) ≥ 0,75 × 109/l.
    ii)Hemoglobina (Hb) ≥ 8,0 g/dl, estable durante ≥ 7 días.
    c)Pacientes con afectación d médula ósea:
    i)RAN ≥ 0,5 × 109/l.
    14)Perfil d coagulación adecuado:
    a)Tiempo d protrombina (TP) ≤ 1,5 el LSN (grado ≤ 1).
    b)iempo d tromboplastina parcial activado (TTPa) ≤ 1,5 el LSN (grado ≤ 1).
    15)Ausencia d antecedentes d infección por el virus d la inmunodeficiencia humana (VIH) y serología negativa o virus indetectable mediante reacción en cadena d la polimerasa (PCR) para el virus d la hepatitis B (VHB) y el virus d la hepatitis C (VHC) en la selección.
    16)En las mujeres en edad fértil:
    a)Prueba d embarazo en suero negativa antes del comienzo del tto del estudio.
    b)Disposición a utilizar un método anticonceptivo recomendado por el protocolo desde el comienzo del período deselección hasta ≥30 días después d la últ dosis del tto del estudio.
    17)Varones q puedan engendrar hijo: disposición a utilizar método anticonceptivo recomendado y abstenerse d donar semen por el protocolo desde el comienzo del tto del estudio hasta mín d 90d desp d l últ dosis del tto del estudio
    E.4Principal exclusion criteria
    1) Transformed disease at time of screening (eg, Richter’s transformation or blastoid variant of MCL)
    2) Active central nervous system involvement
    3) History of a second primary malignancy that has progressed or required systemic treatment in the past 2 years. Exceptions that do not require a 2- year remission include:
    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. Hormone-sensitive prostate cancer with stable prostate-specific antigen (PSA) for ≥3 months
    e. Other localized solid tumors in situ or other low-risk cancers may also be exempt after discussion with the sponsor’s medical monitor
    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 mm Hg, or systolic blood pressure ≥160 mm Hg), 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 >480 msec
    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) Uncontrolled systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of study therapy.
    Note: Patients with localized fungal infections of skin or nails are eligible.
    9) Previously documented intolerance to a covalent BTKi, as evidenced by discontinuation of covalent BTKi due to AE (applies to Phase 1b, and to Phase 2, until Cohort 4 accrual is initiated)
    10) Transplant
    a) Prior solid organ transplant is excluded
    b) Prior autologous or allogeneic stem-cell transplant is permitted, provided that the patient has been off immunosuppressive therapy for at least 14 days and has no evidence of active graft-versus-host disease (GVHD)
    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, patients 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 a 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 patient’s ability to sign informed consent, adversely affect the patient’s ability to cooperate and participate in the study, or compromise the interpretation of study results
    1)Enfermedad transformada en el momento de la selección (por ejemplo, transformación de Richter o variante blastoide del LCM)
    2) Afectación activa del sistema nervioso central
    3) Antecedentes de una segunda neoplasia maligna primaria que haya progresado o que haya precisado tratamiento sistémico en los 2 últimos años. Las excepciones que no requieren una remisión de 2 años son:
    a.Carcinoma basocelular o espinocelular local de piel.
    b.Carcinoma in situ de cuello uterino o mama.
    c.Cáncer de vejiga papilar no invasivo.
    d.Cáncer de próstata hormonosensible con antígeno prostático específico (PSA) estable durante ≥ 3 meses.
    e.Otros tumores sólidos localizados in situ u otros cánceres de bajo riesgo también pueden estar exentos tras consultarlo con el monitor médico del promotor.
    4)Enfermedad cardiovascular importante:
    a)Infarto de miocardio, tromboembolia arterial o tromboembolia cerebrovascular en los 6 meses previos al comienzo del tratamiento del estudio.
    b)Angina de pecho sintomática.
    c)Vasculopatía periférica sintomática.
    d)Insuficiencia cardíaca congestiva de clase ≥ 3 de la New York Heart Association.
    e)Hipertensión de grado ≥ 3 no controlada (presión arterial diastólica ≥ 100 mm Hg o presión arterial sistólica ≥ 160 mm Hg), a pesar del tratamiento antihipertensivo.
    f)Arritmia no controlada
    5)Anomalías electrocardiográficas significativas de selección:
    a)Bloqueo de rama izquierda.
    b)Bloqueo auriculoventricular de segundo o tercer grado de tipo 2.
    c)Bradicardia de grado ≥ 2.
    d)Intervalo QTc > 480 ms
    6)Enfermedad digestiva (por ejemplo, cirugía de derivación gástrica o intestinal, insuficiencia de enzimas pancreáticas, síndrome de malabsorción, enfermedad inflamatoria intestinal sintomática, enfermedad diarreica crónica u obstrucción intestinal) que pueda interferir en la absorción del fármaco o en la interpretación de los AA digestivos.
    7)Riesgo activo de hemorragia por cualquiera de las circunstancias siguientes:
    a)Diátesis hemorrágica.
    b)Trastorno conocido de la función plaquetaria.
    c)Enfermedad ulcerosa péptica no controlada.
    d)Anticoagulación oral (p. ej., warfarina, apixabán, rivaroxabán, etexilato de dabigatrán).
    e)Heparina, heparina de bajo peso molecular o fracciones de heparina (p. ej., enoxaparina, dalteparina, fondaparinux).
    Nota: Se permite el uso de heparina o trombolíticos para el mantenimiento local o la limpieza de un catéter venoso central.
    8)Infección bacteriana, micótica o vírica sistémica no controlada (incluidas las infecciones de las vías respiratorias superiores) al comienzo del tratamiento del estudio.
    Nota: Podrán participar pacientes con micosis localizadas de la piel o las uñas.
    9)Intolerancia previamente documentada a un iBTK covalente, demostrada por la suspensión del iBTK covalente por AA (se aplica a la fase 1b, así como a la fase 2 hasta que se inicie el reclutamiento de pacientes en la cohorte 4).
    10)Trasplante.
    a)Se excluye el trasplante previo de órgano sólido.
    b)Se permite el auto o alotrasplante de células madre hematopoyéticas previo, siempre que el paciente haya estado sin tratamiento inmunodepresor durante al menos 14 días y no presente signos de enfermedad del injerto contra el huésped (EICH) activa.
    11) Embarazo o lactancia.
    12)Intervención de cirugía mayor en las 4 semanas previas al comienzo del tratamiento del estudio.
    13)Tratamiento inmunodepresor en curso, incluidos corticoides sistémicos o entéricos, excepto cuando se indique lo contrario.
    Nota: En la selección, los pacientes podrán estar utilizando corticoides sistémicos (en dosis fisiológicas ≤ 10 mg/día de prednisona o equivalente), tópicos o inhalados.
    14) Uso de un inhibidor o inductor moderado o potente de la enzima CYP3A4 en los 7 días previos al comienzo del tratamiento del estudio, o necesidad prevista de su uso durante el tratamiento del estudio
    15)Uso de sustratos de las enzimas CYP2C8, CYP3A4, CYP2B6, CYP2C9 y CYP2D6 con un índice terapéutico estrecho en los 7 días previos al comienzo del tratamiento del estudio, o necesidad prevista de su uso durante el tratamiento del estudio
    16)Cualquier enfermedad, trastorno médico, disfunción de sistemas orgánicos o situación social, como enfermedad mental o abuso de sustancias, que, en opinión del investigador, podría interferir probablemente en la capacidad del paciente para firmar el consentimiento informado, afectar negativamente a su capacidad para cooperar y participar en el estudio o comprometer la interpretación de los resultados del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b: MTD and/or RD within the tested vecabrutinib dose range.

    Phase 2: ORR by cohort as evaluated by standard response and progression criteria for CLL/SLL.
    Fase 1b: DMT o DR dentro del intervalo de dosis de vecabrutinib evaluado.

    Fase 2: TRG por cohorte, evaluada según los criterios habituales de respuesta y progresión en la LLC/LLCP.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the trial.
    Durante todo el ensayo.
    E.5.2Secondary end point(s)
    Phase 1b:
    • Type, frequency, severity, and relatedness to study drug of treatment-emergent adverse events (TEAEs), laboratory abnormalities, and electrocardiogram (ECG) findings
    • Vecabrutinib plasma PK parameters (including area under the plasma concentration-time curve [AUC], Cmax, time of maximum concentration [Tmax]), and minimum plasma concentration during a dosing interval at steady state [Cmin,ss])
    • ORR, TTR, DOR, RR, DCR, and 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, RR, DCR, PFS, and OS by cohort as evaluated by standard response and progression criteria for CLL/SLL
    • Safety by assessment of type, frequency, severity, and relatedness to study drug of TEAEs, laboratory abnormalities, and ECG findings
    • Vecabrutinib plasma PK parameters (including AUC, Cmax, Tmax, Cmin,ss)
    Fase 1b:
    •Tipo, frecuencia, intensidad y relación con el fármaco del estudio de los acontecimientos adversos aparecidos durante el tratamiento (AAAT), anomalías analíticas y hallazgos electrocardiográficos (ECG).
    •Parámetros farmacocinéticos en plasma de vecabrutinib (como área bajo la curva de concentración plasmática tiempo [AUC], Cmáx, tiempo en alcanzar la concentración máxima [Tmáx]) y concentración plasmática mínima durante un intervalo de administración en estado de equilibrio [Cmín,ss]).
    •TRG, THR, DDR, TCE y SSP, evaluados mediante los criterios habituales de respuesta y progresión en cada tipo de tumor (Apéndice 1).
    •Parámetros del intervalo QTc, incluidas las variaciones con respecto al momento basal y los aumentos absolutos del intervalo QTc.

    Fase 2b:
    •THR, DDR, TCE, SSP y SG por cohorte, evaluados según los criterios habituales de respuesta y progresión en la LLC/LLCP.
    •Seguridad según la evaluación del tipo, la frecuencia, la intensidad y la relación con el fármaco del estudio de los AAAT, las anomalías analíticas y los hallazgos electrocardiográficos.
    •Parámetros farmacocinéticos en plasma de vecabrutinib (como AUC, Cmáx, Tmáx y Cmín,ss).
    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
    - Vecabrutinib plasma PK parameters:
    Phase 1b - Cycle 1 days 1, 8, 15, Cycle 2 Day 1
    Phase 2 - Cycle 1 days 1, 15, Cycle 2 and ≥3 Day 1
    - ORR, TTR, DOR, PFS, and OS : throughout the trial
    - QTc :
    Phase 1b - C1D1, C1D8, C2D1, D1 of each ≥C3 visit, EOT visit.
    Phase 2- D1 of each cycle, EOT visit
    - Tipo, frecuencia, intensidad y relación con el fármaco del estudio de los acontecimientos adversos aparecidos durante el tratamiento (AAAT), anomalías analíticas y hallazgos electrocardiográficos (ECG): a lo largo del ensayo
    - Parámetros farmacocinéticos en plasma de vecabrutinib:
    Fase 1b - Ciclo 1 Día 1, 8, 15, Ciclo 2 Día 1
    Fase 2 - Ciclo 1 Día 1, 15, Ciclo 2 and ≥3 Día 1
    - TRG, THR, DDR, SSP, and SG: a lo largo del ensayo
    - QTc :
    Fase 1b - C1D1, C1D8, C2D1, D1 de cada ≥C3 visita, EOT visita.
    Fase 2- D1 de cada ciclo, EOT visit
    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 de dosis y ampliación de dosis
    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 Yes
    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.8.3 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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 No
    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
    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
    UVUP (última visita ultimo paciente)
    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 months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    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: 52
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 122
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 72
    F.4.2.2In the whole clinical trial 174
    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.
    Se realizará una visita de seguimiento posterior al tratamiento 30 días después de la última dosis del fármaco del estudio para comprobar el estado de los AA no resueltos. Todos los pacientes se incorporarán al seguimiento a largo plazo (aprox. cada 3 meses durante un máximo de dos años) con el fin de confirmar la resolución de cualquier AA y constatar los tratamientos antineoplásicos posteriores y la supervivencia. El seguimiento a largo plazo podrá realizarse por teléfono.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-02-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-06-23
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA