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    Summary
    EudraCT Number:2011-000266-35
    Sponsor's Protocol Code Number:CTKI258A2211
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-03-28
    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 number2011-000266-35
    A.3Full title of the trial
    A phase II, open-label, single-arm, non-randomized, multi-center study to evaluate the efficacy of oral TKI258 as second-line therapy in patients with either FGFR2 mutated or wild-type advanced and/or metastatic endometrial cancer
    Estudio de fase II, abierto, de un brazo único, no aleatorizado, multicéntrico para evaluar la eficacia de TKI258 oral como terapia en segunda línea en pacientes con cáncer de endometrio avanzado y/o metastásico con FGFR2 mutado o wild-type
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial investigating the efficacy of TKI258 in patients with cancer of the endometrium that has progressed after prior therapy
    Ensayo clínico que investiga la eficacia del TKI258 en pacientes con cáncer de endometrio que ha progresado tras la primera línea de terapia.
    A.4.1Sponsor's protocol code numberCTKI258A2211
    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 SponsorNovartis Farmacéutica S.A
    B.1.3.4CountrySpain
    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 supportNovartis Farmacéutica S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica S.A.
    B.5.2Functional name of contact pointJavier Malpesa
    B.5.3 Address:
    B.5.3.1Street AddressC/ Gran Via de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number+34933064464
    B.5.5Fax number+3493 306 42 90
    B.5.6E-maileecc.novartis@novartis.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 nameDovitinib
    D.3.2Product code TKI258
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNdovitinib
    D.3.9.1CAS number 915769-50-5
    D.3.9.2Current sponsor codeTKI258
    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 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
    Advanced and/or metastatic endometrial carcinoma
    cáncer de endometrio avanzado y/o metastásico
    E.1.1.1Medical condition in easily understood language
    Advanced cancer which originates in the inner lining of the uterus
    Cancer avanzado que se origina en el útero
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10014736
    E.1.2Term Endometrial cancer recurrent
    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
    To assess the antitumor activity of TKI258, as measured by an 18-week progression free survival (PFS) rate, in patients with pre-treated endometrial cancer, with or without FGFR2 mutation.
    Evaluar la actividad antitumoral de TKI258, medida mediante una tasa de supervivencia libre de progresión (SLP) a las 18 semanas en pacientes con cáncer de endometrio previamente tratado, con o sin mutación de FGFR2
    E.2.2Secondary objectives of the trial
    ? To evaluate the following ancillary efficacy parameters in patients with advanced and/or metastatic endometrial cancer, with or without FGFR2 mutation: Overall Response Rate, Disease Control Rate, Duration of Response, Progression Free Survival, Overall Survival
    ? To characterize the safety and tolerability of TKI258 in patients with advanced and/or metastatic endometrial cancer, with or without FGFR2 mutation
    ? To determine the trough plasma concentration of TKI258 in patients with advanced and/or metastatic endometrial cancer, with or without FGFR2 mutation
    ? To assess the pharmacodynamic (PD) effect of TKI258 on soluble plasma biomarker expression levels
    ? Evaluar los siguientes parámetros complementarios de eficacia en pacientes con cáncer de endometrio avanzado y/o metastásico, con o sin mutación de FGFR2: Tasa de respuesta global, Tasa de control de la enfermedad, Duración de la respuesta, Supervivencia libre de progresión, Supervivencia global
    ? Caracterizar la seguridad y tolerabilidad de TKI258 en pacientes con cáncer de endometrio avanzado y/o metastásico, con o sin mutación de FGFR2
    ? Determinar la concentración valle en plasma de TKI258 en pacientes con cáncer de endometrio avanzado y/o metastásico, con o sin mutación de FGFR2
    ? Evaluar el efecto farmacodinámico (PD) de TKI258 en niveles de expresión de biomarcadores plasmáticos solubles (incluidos, pero no limitados a bFGF, VEGF, PLGF, sVEGFR1 y sVEGFR2)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ? Patients with histologically confirmed diagnosis of advanced and/or metastatic endometrial cancer with available tissue specimen (either archival tissue or fixed fresh biopsy)
    ? Female patients >= 18 years old
    ? Documented radiologically confirmed progression of disease after prior first-line treatment evidence of progressive disease
    ? ECOG (Eastern Cooperative Oncology Group) performance status ? 2
    ? At least one measurable lesion as per RECIST

    Other protocol-defined inclusion criteria may apply
    ? Pacientes mujeres de ? 18 años de edad
    ? Diagnóstico histológicamente confirmado de cáncer de endometrio avanzado y/o metastásico
    ? Disponer de muestras de tejido, ya sea de tejido almacenado o una biopsia en fresco fijada, para la evaluación de la mutación de FGFR2
    ? Evidencia radiológica documentada de enfermedad progresiva según los RECIST v1.1 tras el tratamiento antineoplásico en primera línea para el cáncer de endometrio avanzado y/o metastásico
    ? El paciente presenta al menos una lesión medible en base a los RECIST v1.1 según lo determine el investigador
    ? Estado Funcional ECOG ? 2
    ? Las pacientes deben tener los siguientes valores de laboratorio: ANC ? 1,5 x 109/L; plaquetas ? 100 x 109/L; hemoglobina > 9 g/dL; bilirrubina total en suero ? 1,5 x LSN; ALT y AST ? 3,0 x LSN; creatinina sérica ? 1,5 x LSN
    Ver listado completo de criterios de inclusión definidos en el protocolo
    E.4Principal exclusion criteria
    ? Previous treatment with an FGFR inhibitor
    ? More than one line of treatment for advanced or metastatic disease
    ? Patients with uterine sarcomas, adenosarcoma, and malignant Mullerian tumors
    ? Patients with isolated recurrences (vaginal, pelvic, or para-aortic) potentially curative with radiation therapy or surgery
    ? Known central nervous system (CNS) metastases
    ? Malignancy within 3 years of study enrollment

    Other protocol-defined exclusion criteria may apply
    1. Pacientes que hayan recibido terapia antineoplásica previa con un inhibidor de FGFR
    2. Pacientes que han recibido > 1 línea(s) previa(s) de tratamiento antineoplásico para enfermedad metastásica avanzada (terapia neoadyuvante/adyuvante no considerada como una línea según el criterio de inclusión 4)
    3. Pacientes con sarcomas uterinos, adenosarcoma, y tumores mullerianos malignos
    4. Pacientes con recurrencias aisladas (vaginales, pélvicas, o paraaórticas) potencialmente curativas con radioterapia o cirugía
    5. Pacientes con metástasis cerebrales conocidas
    6. Pacientes con otro tumor maligno primario en los 3 años previos al inicio del tratamiento del estudio, excepto carcinoma basocelular debidamente tratado, carcinoma de células escamosas u otro tipo de cáncer de piel no melanomatoso o carcinoma in situ de cuello uterino
    7. Pacientes que han participado en un estudio de investigación de antineoplásicos ? 30 días antes del reclutamiento o ? 5 semividas del producto antineoplásico en investigación, lo que sea más largo
    8. Pacientes que han recibido la última administración de terapia antineoplásica dirigida con moléculas pequeñas (p. ej., sunitinib, sorafenib, pazopanib, axitinib, everolimus, temsirolimus, ridaforolimus) ? 2 semanas antes de iniciar la medicación del estudio o que no se hayan recuperado de los efectos secundarios de dicha terapia
    9. Pacientes que han recibido la última administración de un anticuerpo monoclonal contra el cáncer, inmunoterapia, terapia hormonal, o quimioterapia (excepto nitrosoureas y mitomicina C) ? 4 semanas antes de iniciar la medicación del estudio o que no se hayan recuperado de los efectos secundarios de dicha terapia
    10. Pacientes que han recibido la última administración de nitrosourea o mitomicina C ? 6 semanas antes de iniciar la medicación del estudio o que no se hayan recuperado de los efectos secundarios de dicha terapia
    11. Pacientes que han recibido radioterapia ? 4 semanas antes de iniciar la medicación del estudio o que no se han recuperado de las toxicidades relacionadas con la radioterapia (nota: se permite la radioterapia paliativa para lesiones óseas ? 2 semanas antes de iniciar la medicación del estudio
    12. Pacientes que hayan sido sometidas a cirugía mayor (p. ej., intratorácica, intraabdominal, o intrapélvica) ? 4 semanas antes de iniciar la medicación del estudio, o que no se hayan recuperado de los efectos secundarios de dicha terapia
    13. Pacientes con antecedentes de embolismo pulmonar o trombosis venosa profunda no tratada ? 6 meses antes de iniciar la medicación del estudio
    14. Alteración de la función cardíaca o cardiopatías clínicamente significativas,
    15. Deterioro de la función gastrointestinal o enfermedad gastrointestinal que pueda alterar significativamente la absorción de TKI258 (p. ej., enfermedad ulcerativa, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción, resección del intestino delgado)
    16. Cirrosis, hepatitis activa crónica o hepatitis persistente crónica
    17. Antecedentes conocidos de infección por VIH (no es obligatoria la prueba del VIH).
    18. Pacientes que actualmente estén recibiendo prasugrel, clopidogrel, o tratamiento con la dosis plena de anticoagulante con dosis terapéuticas de warfarina Sin embargo, se permite el tratamiento con dosis bajas de warfarina (p. ej., ?2 mg/día) o dosis bajas localmente aceptadas de ácido acetilsalicílico (hasta 100 mg al día) para prevenir acontecimientos cardiovasculares o ictus
    19. Otras enfermedades concurrentes severas y/o concomitantes no controladas (p. ej., infección activa o no controlada, diabetes no controlada) que podrían provocar riesgos inaceptables de seguridad o que comprometerían el cumplimiento del protocolo
    20. Mujeres embarazadas o en período de lactancia
    21. Mujeres en edad fértil, que sean biológicamente capaces de concebir, que no estén utilizando dos métodos anticonceptivos altamente eficaces.
    ? 22. Pacientes que no estén dispuestas o no puedan cumplir con el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    The 18-week PFS rate as defined as the percentage of patients who do not have a progression event at week 18.
    Supervivencia libre de progresión a las 18 semanas, definida como porcentaje de pacientes que no han progresado a la semana 18.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 18 weeks after the first dose of study drug.
    A las 18 semanas tras la primera toma de medicación de estudio.
    E.5.2Secondary end point(s)
    ? To evaluate the following ancillary efficacy parameters in patients with advanced and/or metastatic endometrial cancer, with or without FGFR2 mutation:
    -Overall Response Rate (key secondary objective)
    -Disease Control Rate
    -Duration of Response
    -Progression Free Survival
    -Overall Survival

    ? To characterize the safety and tolerability of TKI258 in patients with advanced and/or metastatic endometrial cancer, with or without FGFR2 mutation
    ? To determine the trough plasma concentration of TKI258 in patients with advanced and/or metastatic endometrial cancer, with or without FGFR2 mutation
    ? To assess the pharmacodynamic (PD) effect of TKI258 on soluble plasma biomarker expression levels
    ? Evaluar los siguientes parámetros complementarios de eficacia en pacientes con cáncer de endometrio avanzado y/o metastásico, con o sin mutación de FGFR2:
    ? Tasa de respuesta global (objetivo secundario clave)
    ? Tasa de control de la enfermedad
    ? Duración de la respuesta
    ? Supervivencia libe de progresión
    ? Supervivencia global
    ? Caracterizar la seguridad y tolerabilidad de TKI258 en pacientes con cáncer de endometrio avanzado y/o metastásico, con o sin mutación de FGFR2
    ? Determinar la concentración valle en plasma de TKI258 en pacientes con cáncer de endometrio avanzado y/o metastásico, con o sin mutación de FGFR2
    ? Evaluar el efecto farmacodinámico (PD) de TKI258 en niveles de expresión de biomarcadores plasmáticos solubles
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy: baseline and every 6 weeks until disease progression
    Safety: up to 30 days after the last dose of study drug
    Eficacia: Desde la entrada en el estudio, cada 6 semanas hasta progresión de la enfermedad.
    Seguridad: Hasta 30 días después de la última dosis de fármaco de 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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Canada
    China
    Egypt
    Italy
    Japan
    New Zealand
    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
    Patients may receive treatment with TKI258 until disease progression, unacceptable toxicity,
    death, or discontinuation from the study treatment due to any other reason.
    Las pacientes pueden recibir tratamiento con TKI258 hasta que se presente progresión de la enfermedad, toxicidad inaceptable, muerte, o retirada del tratamiento del estudio debido a cualquier otro motivo
    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 months1
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days1
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 26
    F.4.2.2In the whole clinical trial 80
    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)
    NA
    NA
    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 Decision2012-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-05-22
    P. End of Trial
    P.End of Trial StatusCompleted
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