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    Summary
    EudraCT Number:2012-003005-10
    Sponsor's Protocol Code Number:IGR2012/1883
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-03-11
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2012-003005-10
    A.3Full title of the trial
    PHASE I-II STUDY OF VINBLASTINE IN COMBINATION WITH NILOTINIB IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH REFRACTORY OR RECURRENT LOW-GRADE GLIOMA
    Estudio Fase I-II de Vinblastina en Combinación con Nilotinib en Niños, Adolescentes, y Adultos jóvenes con Glioma de bajo grado Refractario o Recurrente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    LOW-GRADE GLIOMA
    Glioma de bajo grado
    A.3.2Name or abbreviated title of the trial where available
    Vinilo
    Vinilo
    A.4.1Sponsor's protocol code numberIGR2012/1883
    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 SponsorGustave Roussy
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFundació Sant Joan de Déu
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportGustave Roissy
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFundació Sant Joan de Deu
    B.5.2Functional name of contact pointUnidad de Ensayos Clínicos
    B.5.3 Address:
    B.5.3.1Street AddressC/ Santa Rosa, 39-57, 3a planta - Edifici Docent
    B.5.3.2Town/ cityEsplugues de Llobregat
    B.5.3.3Post code08950
    B.5.3.4CountrySpain
    B.5.4Telephone number+34936009751
    B.5.5Fax number+34936009771
    B.5.6E-mailrmorales@fsjd.org
    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 nameNilotinib
    D.3.2Product code AMN107
    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 INNNILOTINIB
    D.3.9.2Current sponsor codeAMN107
    D.3.9.3Other descriptive nameNILOTINIB HYDROCHLORIDE MONOHYDRATE
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tasigna 150mg
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNilotinib
    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 INNNILOTINIB
    D.3.9.3Other descriptive nameNILOTINIB HYDROCHLORIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB25647
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tasigna 200mg
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameNilotinib
    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 INNNILOTINIB
    D.3.9.3Other descriptive nameNILOTINIB HYDROCHLORIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB25647
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name VINBLASTINA
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratorio Stada, S.L.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameVinblastine
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNVINBLASTINA
    D.3.9.3Other descriptive nameVINBLASTINE SULPHATE
    D.3.9.4EV Substance CodeSUB12391MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Children, adolescents and young adults with refractory or recurrent low-grade gliomas
    Niños, Adolescentes, y Adultos jóvenes con Glioma de bajo grado Refractario o Recurrente
    E.1.1.1Medical condition in easily understood language
    Children, adolescents and young adults with refractory or recurrent low-grade gliomas
    Niños, Adolescentes, y Adultos jóvenes con Glioma de bajo grado Refractario o Recurrente
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10065443
    E.1.2Term Malignant glioma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10038111
    E.1.2Term Recurrent cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10070308
    E.1.2Term Refractory cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -Phase I part: to define the recommended dose (RD) of nilotinib and vinblastine when used in combination
    -Phase II part: to evaluate the efficacy of vinblastine in combination with nilotinib (VINILO) at the RD, as compared to vinblastine alone, in terms of progression-free survival, in children, adolescents, and young adults with refractory or recurrent low grade glioma.
    -Fase I. Esta parte del estudio definirá la dosis recomendada (RD = recommended dose) de Nilotinib y de vinblastina al utilizarse en combinación.
    -Fase II: Esta parte del estudio evaluará la eficacia de vinblastina en combinación con Nilotinib (VINILO) a la RD, comparada con monoterapia con vinblastina, en términos de progresión libre de eventos (PFS, progression-free survival), en niños, adolescentes, y adultos jóvenes con gliomas de bajo grado refractarios al tratamiento o recurrentes.
    E.2.2Secondary objectives of the trial
    1.To measure the impact of the VINILO combination compared to vinblastine alone, in terms of response rate (RR) , progression-free survival time ratio (PFS2/PFS1-ratio), time-to-treatment failure, overall survival (OS), long-term effects and patient-related outcome
    2.To describe and compare, on the whole duration of treatment, the toxicity related to the VINILO combination with that of vinblastine alone
    3.To describe the feasibility of the treatment and the compliance
    4. To provide pharmacokinetics data on both drugs when given in combination
    5. To identify the predictive value of early functional MRI changes
    6. To assess the inter-observers agreement of radiologic response assessment
    (Read the rest in protocol)
    1.Medir el impacto de la combinación VINILO comparada con monoterapia con vinblastina, en términos de tasa de respuesta (RR), ratio de progresión libre de eventos (progression-free survival time ratio PFS2/PFS1-ratio), tiempo hasta fracaso del tratamiento, supervivencia global (OS) efectos a largo plazo y resultados relacionados con el paciente.
    2.Describir y comparar, en toda la duración del tratamiento, la toxicidad relacionada con la combinación VINILO respecto a la que presenta la vinblastina sola.
    3.Describir la viabilidad del tratamiento y el cumplimiento.
    4.Proveer de datos de Farmacocinética de ambos fármacos cuando se administran en combinación.
    5.Identificar el valor predictivo de los cambios precoces funcionales en la RM
    6.Evaluar la concordancia inter-observadores en la valoración radiológica de la respuesta.
    (Leer el resto en el protocolo)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent signed by the patient, or parents or legal representative and assent of the minor child.
    2. Age: 6 months to < 21 years of age at time of study entry
    3. Histologically confirmed low-grade glioma in non-NF1 patients (no further biopsy is needed at study entry). For patients with NF1 and optic pathway glioma, no biopsy is required to confirm the radiological diagnosis of the low grade glioma.
    4. Relapse or refractory tumor after at least one first-line therapy, not taking into account surgery only.
    5. Evaluable Disease on morphologic MRI
    6. Karnofsky performance status score > or = to 70% for patients >12 years of age, or Lansky score > or = to 70% for patients < or = to 12 years of age, including patients with motor paresis due to disease.
    7. Life expectancy > or = to 3 months.
    8. Administration of stable dose of steroids for at least one week
    9.Adequate organ function:
    -Adequate hematopoietic function: neutrophils >1.0 x 109/L, platelets >100 x 109/L; hemoglobin >8 g/dL
    -Adequate renal function: serum creatinine < 1.5 x ULN for age
    In other cases where serum creatinine >1.5 ULN according to age, Glomerular filtration rate or creatinine clearance has to be > 70ml/min/1.73m2 or > 70% of the expected value.
    -Adequate electrolytes levels: potassium, magnesium, phosphor, total calcium > or = to Lower Limit of Normal (LLN)
    -Adequate hepatic function: total bilirubin < or = to 1.5 x ULN; AST and ALT < or = to 2.5 x ULN.
    -Absence of peripheral neuropathy > or = to grade 2 (Common Toxicity Criteria Adverse Event, NCI CTCAE v4.0)
    -Adequate cardiac function:
    Shortening Fraction (SF) > or = to 28% (35% for children <3 years) and Left Ventricular Ejection Fraction (LVEF) > or = to 50% at baseline, as determined by echocardiography
    Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the QTcF formula) or other clinically significant ventricular or atrial arrhythmia
    10.Wash-out period of at least
    -3 weeks in case of preliminary chemotherapy,
    -6 weeks in case of nitrosourea-containing chemotherapy,
    -2 weeks in the case of treatment with vincristine only
    -6 weeks in case of radiation therapy
    11.Possibility of receiving the therapeutic schedule as indicated in the protocol
    12.Patients with reproductive potential must use effective contraception during their treatment and for up to 90 days after the last dose. Females with reproductive potential must have a negative pregnancy test < or = to 7 days before starting Nilotinib and/or Vinblastine.
    13.Patients already treated with one of the two drugs can be enrolled in the trial provided that rechallenging them with the same drug could be considered acceptable
    1.Consentimiento informado firmado por el paciente, o sus padres o los representantes legales y asentimiento del menor.
    2.Edad: 6 meses a < 21 años de edad en el momento de la entrada en el estudio.
    3.Confirmación histológica de glioma de bajo grado en pacientes sin NF1 (no se precisa una biopsia adicional a la entrada del estudio). Para los pacientes diagnosticados de NF1 y glioma de vías ópticas, no se requiere biopsia para confirmar el diagnóstico radiológico del glioma de bajo grado.
    4.Tumor en recidiva o refractario después de al menos una primera línea de tratamiento, sin tener en cuenta sólo la cirugía.
    5.Enfermedad evaluable en la RM morfológica.
    6.Puntuación del estatus de performance por escala de Karnofsky > o = a 70% para los pacientes >12 años de edad, o puntuación de escala de Lansky > o = a 70% para los pacientes < o = a de 12 años de edad, incluyendo pacientes con paresias motoras debidas a la enfermedad.
    7.Esperanza de vida > o = a 3 meses.
    8.Administración de una dosis estable de corticoides por al menos una semana.
    9.Adecuada función orgánica:
    -Adecuada función hematopoyética: neutrófilos > o = a 1.0 x 109/L, plaquetas > o = a 100 x 109/L; hemoglobina > o = a 8 g/dL
    -Adecuada función renal: creatinina sérica < 1.5 x VSN (valores superiores de la normalidad) para la edad.
    -En otros casos cuando la creatinina sérica sea >1.5 VSN de acuerdo a la edad, la tasa de filtración glomerular o el aclaramiento de creatinina debe ser 70ml/min/1.73m2 del valor esperado.
    -Adecuados niveles de electrolitos: potasio, magnesio, fosforo, calcio total ? Límite inferior de la normalidad (LIN).
    -Adecuada función hepática: bilirrubina total < o = a 1.5 x VSN; AST y ALT < o = a 2.5 x VSN.
    -Ausencia de neuropatía periférica > o = a grade 2 (Common Toxicity Criteria Adverse Event, NCI CTCAE v4.0)
    -Adecuada función cardiaca:
    Fracción de acortamiento (FA) > o = a 28% (35% para niños <3 años) y fracción de eyección ventricular izquierda (FEVI) > o = a 50% basal, determinada mediante ecocardiografía.
    Ausencia de prolongación QTc (QTc > 450 msec en el ECG basal, utilizando la fórmula QTcF) o otras arritmias atriales o ventriculares clínicamente significativas.
    10. Periodo de lavado de al menos
    - 3 semanas en caso de quimioterapia preliminar,
    - 6 semanas en caso de quimioterapia que incluya nitrosoureas,
    - 2 semanas en caso de tratamiento sólo con vincristina,
    - 6 semanas en caso de radioterapia
    11.Posibilidad de recibir el esquema terapéutico tal como se indica en el protocolo.
    12.Pacientes con potencial reproductivo deben usar métodos eficaces de contracepción durante el tratamiento y hasta 90 días después de recibir la última dosis. Las mujeres con potencial reproductivo deben tener un test de embarazo negativo < o = a 7 días antes de comenzar Nilotinib y/o Vinblastina
    13.Los pacientes que ya fueron tratados con uno de los dos fármacos pueden ser incluidos en el ensayo si se considera que su re exposición al mismo medicamento pudiera ser considerado aceptable
    E.4Principal exclusion criteria
    1.Concomitant anti-tumor treatment
    2.Not recovered to <Grade 2 from the acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy
    3.Known intolerance or hypersensitivity to Vinblastine
    4.Existence of another severe systemic disease
    5.Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines,
    6.Any concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the patient
    7.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib.
    8.Simultaneous treatment with strong cytochromes P450 CYP3A4 inhibitors (e.g. antiepileptic drugs, see complete list in the Appendix 5).
    9.Simultaneous treatment with antiarrythmic drugs and other drugs known to prolong QT interval (cloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, cisapride and pimozide). A list of QT prolonging compounds can be found at http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm (Appendix 6)
    10.Impaired cardiac function including any one of the following:
    -Clinically significant resting brachycardia (<50 beats per minute).
    -QTc > 450 msec on baseline ECG. If QTc >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
    -Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension).
    -History of or presence of clinically significant ventricular or atrial tachyarrhythmias (including congenital long QT syndrome or a known family history of congenital long QT syndrome)
    1.Tratamiento anti-tumoral concomitante.
    2.Ausencia de recuperación de efectos agudos tóxicos de grade 2 o superior de cualquier quimioterapia, inmunoterapia o radioterapia previas.
    3.Conocida intolerancia o hipersensibilidad a la Vinblastina.
    4.Existencia de otra enfermedad sistémica grave.
    5.Infecciones no controladas, que no responden a antibióticos, medicación antiviral o antifúngicos.
    6.Cualquier enfermedad concurrente que en la opinión del investigador podría interferir con el tratamiento y la evaluación del paciente.
    7.Afectación de la función gastrointestinal (GI) o enfermedad GI que podría alterar de forma significativa la absorción de Nilotinib.
    8.Tratamiento simultaneo con inhibidores potentes de los citocromos P450 CYP3A4 (vg fármacos antiepilépticos, ver la lista completa en el Apéndice 5).
    9.Tratamiento simultaneo con fármacos antiarrítmicos y otros fármacos conocidos en prolongar el intervalo QT (cloroquina, halofantrina, claritromicina, haloperidol, metadona, moxifloxacino, bepridil, cisapride y pimozida). Una lista de compuestos con capacidad de prolongar el QT puede encontrarse en http://www.azcert.org/medical-pros/druglists/drug-lists.cfm (Apéndice 6).
    10.Función cardiaca alterada incluyendo cualquiera de los siguientes:
    -Bradicardia en reposo clínicamente significativa (<50 latidos por minuto)
    -QTc > 450 msec en el ECG basal. Si QTc >450 msec y los electrolitos están fuera del rango de normalidad, los electrolitos deben ser corregidos y entonces repetir en el paciente la valoración del QTc.
    -Otras enfermedades cardiológicas no controladas clínicamente significativas (vg. Angina inestable, fallo cardíaco congestivo o hipertensión arterial no controlada).
    -Historia de o presencia de taquiarritmias clínicamente significativas ventricular o atriales (incluyendo síndrome del QT largo congénito o historia familiar conocida de síndrome de QT largo congénito)
    E.5 End points
    E.5.1Primary end point(s)
    Phase I part ? Safety assessment
    Dose-Limiting Toxicity (DLT), assessed over the first 28-day cycle, defined as
    -Grade > 3 neutropenia (<1 x 109/L) for more than 7 days;
    -Grade > 2 thrombopenia (<75 x 109/L) during a time period of more than 7 days.
    -Grade 3 or grade 4 non-hematological toxicity, excluding grade 3 nausea, vomiting, fever, and hepatic toxicity that is rapidly reversible (i.e. returns to < 2.5 x ULN within 2 weeks after study drug discontinuation), and symptoms that are related to tumor progression.
    -Any study drug related toxicity occuring during the first cycle leading to a significant dose reduction considering the 1st cycle plus the following week (1st week of cycle 2), i.e.:
    -If the patient receive less than 80% of the planned dose of Nilotinib
    -If the patient receive less than 75% of the planned dose of Vinblastine

    Phase II part ? Efficacy assessment
    PFS computed as the time interval between the date of study entry and the date of tumor progression or death (whatever the cause of death). The progression will be defined either radiologically (>25% increase in two-dimension measurements or appearance of new lesions compared to the baseline or to the best response after initiation of therapy) or clinically by new symptoms related to tumor progression (significant decrease of visual acuity, new or worsening neurological deficit). Hydrocephalus is not considered as progression per se.
    Parte Fase ? Evaluación de seguridad

    Toxicidad dosis limitante (Dose-Limiting Toxicity = DLT), evaluada en el primer ciclo de 28 días, definida como

    -Neutropenia de grado > 3 (cifra <1 x 109/L) durante más de 7 días;
    -Trombopenia de grado > 2 (cifra <75 x 109/L) o trombopenia precisando transfusiones durante más de 7 días.
    -Cualquier toxicidad de grado 3 o grado 4 no hematológica, con exclusión de nausea, vomito o fiebre grado 3, y la toxicidad hepática que sea rápidamente reversible (i.e. vuelve a valores < 2.5 x VSN dentro de las dos semanas después de la discontinuación del fármaco); o síntomas que están relacionados con la progresión del tumor.
    -Cualquier toxicidad relacionada con los fármacos del estudio que aparezca durante el primer ciclo y que conduzca a una reducción de dosis significativa considerando el 1º ciclo y la siguiente semana a él (1ª semana del ciclo 2), i.e.
    si el paciente recibe menos del 80% de la dosis planeada de Nilotinib
    o si el paciente recibe menos del 75% de la dosis prevista de Vinblastina

    Parte Fase II ? Evaluación de la eficacia

    Se analizará la supervivencia libre de progresión (PFS) computada como el intervalo de tiempo entre la fecha de entrada al estudio y la fecha en la que sucede la progresión del tumor o la muerte (sea cual sea la causa de la muerte). La progresión se definirá tanto radiológicamente (definida como el aumento de >25%
    en medidas de dos dimensiones o la aparición de nuevas lesiones comparadas al estudio basal o a la mejor respuesta tras el inicio del tratamiento) o clínicamente por la aparición de nuevos síntomas relacionados con la progresión del tumor (disminución significativa de la agudeza visual, empeoramiento o aparición de déficit neurológico). La Hidrocefalia no se considera un signo de progresión por sí misma.
    E.5.1.1Timepoint(s) of evaluation of this end point
    For phase I: assessed over the first 28-day cycle

    For phase II: PFS computed as the time interval between the date of study entry and the date of tumor progression or death (whatever the cause of death).
    Para la Fase I: Evaluada sobre el primer ciclo-día 28
    Para la Fase II: PFS es medida desde la fecha de entrada en el estudio hasta la progresión tumoral o muerte.
    E.5.2Secondary end point(s)
    1) Safety monitoring during the treatment
    Clinical and laboratory toxicities / symptoms will be graded according to NCI-CTCAE v4.0 over the whole treatment duration. The adverse events which are not reported in the NCI-CTC will be graded as mild, moderate, severe, and life-threatening. In particular, cardiac function will be monitored with echocardiography and ECG.
    2) Efficacy criteria
    Tumor response will be based on two-dimension measurement and to RANO Criteria (van den Bent, Lancet Oncol 2011). The radiological imaging will be reanalyzed after the study by a radiologist panel, according to the RANO criteria and to the newly defined RAPNO Criteria, once they will be available.
    All tumor reduction >25% (CR or PR or MR) will be considered as success. Morphologic MRI will be performed every 3 months prior to the new cycle, apart from the week 4 early evaluations in case functional MRI is performed. Primary objective of the study is PFS and thus objective response does not need to be confirmed at 4 to 6 weeks. Baseline MRI and that related to the best response will be centrally reviewed by an independent international radiology panel.
    Growth modulation index or progression-free survival time ratio (PFS2/PFS1-ratio), defined as the ratio of a patient?s progression-free survival time from start of study treatment (VINILO or Vinblastine alone), PFS2, relative to the progression-free survival time observed from the patient?s most recent prior anticancer treatment, PFS1, which serves as the patient-specific historical control value.
    Time-to-treatment failure, defined as the time from date of study entry to the first date among death from any cause, PD, or study treatment discontinuation due to any reason other than ?protocol complete?. For patients who discontinue due to protocol complete, or for patient not known to have discontinued as of the data cut-off date, TtTF will be censored at the last contact date.
    Overall survival
    3) Dose intensity of each drug administered computed on the whole treatment duration and per month.
    4) Pharmacokinetics dosage of both drugs (for all patients recruited in the phase I and in 30 patients of each arm of the phase II part)
    5) Functional MRI (perfusion sequence). This dynamic imaging technique will be performed with contrast after 1 month and 3 months of treatment and compared to that performed at study entry. This evaluation will be performed in selected centers .
    6) Tumor biomarkers will be studied on paraffin tumor samples (histological subtype, vascular density with monoclonal antibody anti-CD105/endoglin, proliferation index MIB1, immunohistochemical expression of c-kit, PDGFR alpha and beta, and basic protein of myelin or MBP, telomeres length using Q-FISH technique, BRAF status).
    7) Pharmacogenetic biomarker (enzyme polymorphism)
    8) Immunological monitoring only for Phase 2 patients (according to section 1.10)
    9) Long-term follow-up: height, weight, pubertal growth, cardiac function, health status, and reporting health-related quality of life measured by HUI Mark 3.
    1)Monitorización de seguridad durante el tratamiento

    Las toxicidades clínicas y de laboratorio serán graduados de acuerdo a la clasificación NCI-CTCAE v4.0 durante toda la duración del tratamiento. Los eventos adversos que no estén reportados en el NCI-CTC se graduarán como leves, moderados, graves, y de riesgo mortal. En particular, la función cardiaca será vigilada con ecocardiografía y ECG.

    2) criterios de eficacia
    La respuesta del tumor se basará en la medida en dos dimensiones y en los criterios de la RANO (van den Bent, Lancet Oncol 2011). La imagen radiológica será re-analizada después del estudio por un panel de radiólogos, de acuerdo a los criterios de la RANO y a los criterios definidos nuevamente por la RAPNO, una vez estén disponibles.
    Toda la reducción del tumor >25% (CR o PR o MR) será considerada como éxito del tratamiento. La RM morfológica se realizará cada 3 meses antes de un nuevo ciclo; aparte de la evaluación precoz de la semana 4, efectuada en los casos que se realice RM funcional. El objetivo primario del estudio es la PFS y por tanto la respuesta objetiva no necesita confirmarse a las 4 a 6 semanas. La RM basal y la relacionada con la mejor respuesta se revisarán de forma centralizada por un panel de radiólogos internacionales independientes.
    El índice de modulación del crecimiento del tumor o la ratio de supervivencia libre de progresión (PFS2/PFS1-ratio), definido como la tasa de supervivencia libre de progresión de un paciente desde el inicio del tratamiento del estudio (brazo VINILO o brazo con Vinblastina), PFS2, relativa al tiempo de supervivencia libre de progresión observado desde el tratamiento previo antitumoral más reciente del paciente, PFS1, que sirve como un valor de control histórico específico para el paciente.
    El tiempo hasta el fracaso del tratamiento, definido como el tiempo desde la fecha de entrada al estudio a la primera fecha de muerte por cualquier causa, PD, o discontinuación del tratamiento del estudio debido a cualquier razón diferente de haber finalizado el protocolo. Para los pacientes que discontinúan el tratamiento debido a haber completado el protocolo, o para los pacientes que no se conozca que hayan discontinuado el tratamiento en la fecha de corte de datos, TtTF será censurado a la fecha del último contacto.

    Supervivencia global (OS, Overall survival)

    3) La intensidad de dosis de cada fármaco administrado cuenta en el total de la duración del tratamiento y por mes.
    4) La dosificación farmacocinetica de ambos fármacos (para 30 pacientes de cada brazo de la parte de Fase II)
    5) RM Funcional (secuencias de perfusión). Esta técnica de imagen dinámica se realizará con contraste después de un mes y de 3 meses de tratamiento y se comparará con la realizada en la entrada al estudio. Esta evaluación se realizará en centros seleccionados (ver el Apéndice 2).
    6) Los biomarcadores tumorales se estudiarán en las muestras de tumor fijadas en formol y preservadas en parafina (subtipo histológico, densidad vascular determinada con el anticuerpo monoclonal anti- CD105/endoglina, índice de proliferación MIB1, expresión inmunohistoquímica de c-kit, PDGFR alfa y beta, y proteína básica de mielina o MBP (mielin basic protein), alargamiento de telómeros utilizando técnica Q-FISH, estatus del BRAF).
    7) Biomarcador Farmacogenético (polimorfismo enzimático)
    8) Monitorización Inmunológica (de acuerdo a la sección 1.10, solo para los pacientes del ensayo Fase II)
    9) Seguimiento a largo plazo: altura, peso, crecimiento puberal, función cardiaca, y estado de salud (ver el Apéndice 7).
    E.5.2.1Timepoint(s) of evaluation of this end point
    over the whole study duration
    durante toda la duración del estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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
    Define the RD of nilotinib and vinblastine in combination
    Definir dosis recomendada de Nilotinib y de vinblastina al utilizarse en combinacion
    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 EEA60
    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
    Austria
    Denmark
    France
    Italy
    Netherlands
    Spain
    Switzerland
    United Kingdom
    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
    Last patient last visit
    Ultima Visita del Ultimo Paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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 Yes
    F.1.1Number of subjects for this age range: 148
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 30
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 88
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 22
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children from 28 days to 11 years
    Niños de 28 días a 11 años de edad
    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 170
    F.4.2.2In the whole clinical trial 170
    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)
    Not applicable
    No aplica
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Cancer Research UK Clinical Trials Unit (CRCTU) University of Birmingham
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation University of Padua
    G.4.3.4Network Country Italy
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation Erasmus MC/Sophia Children's Hospital
    G.4.3.4Network Country Netherlands
    G.4 Investigator Network to be involved in the Trial: 4
    G.4.1Name of Organisation Medical University of Vienna
    G.4.3.4Network Country Austria
    G.4 Investigator Network to be involved in the Trial: 5
    G.4.1Name of Organisation KKS Charité
    G.4.3.4Network Country Germany
    G.4 Investigator Network to be involved in the Trial: 6
    G.4.1Name of Organisation Fundació Sant Joan de Déu FSJD
    G.4.3.4Network Country Spain
    G.4 Investigator Network to be involved in the Trial: 7
    G.4.1Name of Organisation Rijkhospitalet de Copenhague
    G.4.3.4Network Country Denmark
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-05-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-15
    P. End of Trial
    P.End of Trial StatusOngoing
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