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    Summary
    EudraCT Number:2015-004225-14
    Sponsor's Protocol Code Number:PQR309-007
    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:2015-11-12
    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 number2015-004225-14
    A.3Full title of the trial
    An open label, non-randomized, multicenter phase 1/2b study investigating safety and efficacy of PQR309 and eribulin combination in patients with locally advanced or metastatic HER2 negative and triple-negative breast cancer
    Ensayo clínico abierto, multicentrico, fase 1/2b, no aleatorizado para investigar la seguridad y eficacia de la combinación de eribulina con PQR309 en pacientes con cáncer de mama HER2 negativo y triple negativo localmente avanzado o metastásico.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study investigating safety and efficacy of PQR309 and eribulin combination in patients with locally advanced or metastatic HER2 negative and triple-negative breast cancer
    Ensayo clínico para investigar la seguridad y eficacia de la combinación de eribulina con PQR309 en pacientes con cáncer de mama HER2 negativo y triple negativo localmente avanzado o metastásico.
    A.3.2Name or abbreviated title of the trial where available
    PQR309-007
    PQR309-007
    A.4.1Sponsor's protocol code numberPQR309-007
    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 SponsorPIQUR Therapeutics AG
    B.1.3.4CountrySwitzerland
    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 supportPIQUR Therapeutics AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedica Scientia Innovation Research (MedSIR ARO)
    B.5.2Functional name of contact pointMedSIR ARO
    B.5.3 Address:
    B.5.3.1Street AddressRambla de Catalunya, 2 2D
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08007
    B.5.3.4CountrySpain
    B.5.4Telephone number003493221 41 35
    B.5.5Fax number003493299 23 82
    B.5.6E-mailanna.gibernau@medsir.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 namePQR309
    D.3.2Product code PQR309
    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 INNNot available yet
    D.3.9.1CAS number 1225037-39-7
    D.3.9.2Current sponsor codePQR309
    D.3.9.3Other descriptive name5-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)-2-pyridinamine
    D.3.9.4EV Substance CodeSUB172213
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 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 namePQR309
    D.3.2Product code PQR309
    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 INNNot available yet
    D.3.9.1CAS number 1225037-39-7
    D.3.9.2Current sponsor codePQR309
    D.3.9.3Other descriptive name5-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)-2-pyridinamine
    D.3.9.4EV Substance CodeSUB172213
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 HALAVEN
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe Ltd
    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 nameHalaven
    D.3.4Pharmaceutical form Solution for injection
    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 INNERIBULIN MESYLATE
    D.3.9.1CAS number 441045-17-6
    D.3.9.3Other descriptive nameERIBULIN MESYLATE
    D.3.9.4EV Substance CodeSUB31126
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.44
    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
    Locally advanced or metastatic HER2 negative and triple-negative breast cancer
    Cáncer de mama HER2 negativo y triple negativo localmente avanzado o metastásico
    E.1.1.1Medical condition in easily understood language
    Locally advanced or metastatic HER2 negative and triple-negative breast cancer
    Cáncer de mama HER2 negativo y triple negativo localmente avanzado o metastásico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10072740
    E.1.2Term Locally advanced breast cancer
    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
    For the escalation part: To identify maximum tolerated dose (MTD) of
    PQR309 administered in combination with eribulin in patients with HER2 negative BC.
    For the expansion part: To evaluate efficacy of PQR309 in combination with eribulin in patients with TNBC
    En la parte de escalada: Identificar la dosis máxima tolerada (MTD) de PQR309 administrado en combinación con eribulina en pacientes con CM HER2 negativo.
    En la parte de expansión: Evaluar la eficacia de PQR309 en combinación con eribulina en pacientes con CMTN.
    E.2.2Secondary objectives of the trial
    To assess safety and tolerability of the combination
    To assess the pharmacokinetics (PK) of PQR309 in combination with eribulin and to investigate the potential effect of PQR309 on the pharmacokinetics of eribulin
    Evaluar la seguridad y la tolerabilidad de la combinación.
    Evaluar la farmacocinética (PK) de PQR309 en combinación con eribulina e investigar el posible efecto de PQR309 en la farmacocinética de eribulina.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Female ? 18 years old at the time of informed consent.
    2. Histologically/cytologically confirmed diagnosis of breast cancer.
    3. Radiological evidence of inoperable locally advanced or metastatic breast cancer.
    4. HER2 negative breast cancer (based on the most recent analyzed biopsy) defined as a negative in situ hybridization test (ISH) or an immunohistochemistry (IHC) status of 0, 1+ or 2+ (if IHC 2+, a negative in situ hybridization test is required) by local laboratory testing.
    5. Negative estrogen receptor and progesterone receptor status known as per local laboratory testing.
    6. Received at least 2 and no more than 5 prior chemotherapeutic regimens in locally advanced and/or metastatic setting. Prior therapy has to include an anthracycline and a taxane in any combination or order (unless contraindicated for a certain patient). Prior anti-hormonal therapy is allowed.
    7. Stable Eastern Cooperative Oncology Group (ECOG) performance status ? 2.
    8. More than 4 weeks from any investigational agent.
    9. Adequate bone marrow and organ function as defined by the following laboratory values:
    - Absolute neutrophil count (ANC) ? 1.5x10^9/l, platelets ? 100x10^9/l, hemoglobin ? 100g/L.
    - Potassium, calcium (corrected for serum albumin) and magnesium within normal limits (WNL) for the institution.
    - Total bilirubin ? 1.5 times the upper limit of normal (ULN).
    - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 2.5 times ULN or ? 5.0 x ULN if liver metastases are present.
    - Serum creatinine ? 1.5 times ULN.
    - Fasting plasma glucose ? 125 mg/dL (? 7 mmol/L) or HbA1c ? 7%.
    10. Able and willing to swallow and retain oral medication.
    11. Written informed consent obtained according to local guidelines.
    Expansion part:
    12. Triple-negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+ (if IHC 2+, a negative in situ hybridization is required), ER and PR status < 10% by local laboratory testing.
    13. Measurable disease according to RECIST v.1.1 or non-measurable lytic or mixed (lytic + blastic) bone lesions with an identifiable soft tissue component that meets the measurability criteria per RECIST v.1.1
    1. Mujeres ? 18 años de edad en el momento de la firma del consentimiento informado.
    2. Diagnóstico histológicamente/citológicamente confirmado de cáncer de mama.
    3. Pruebas radiológicas de cáncer de mama metastásico o localmente avanzado inoperable.
    4. Cáncer de mama HER2 negativo (basado en la biopsia analizada más reciente) definido como prueba de hibridación in situ (ISH) con un resultado negativo o estado de inmunohistoquímica (IHC) de 0, 1+ o 2+ (en caso de IHC 2+, será necesario realizar una prueba de hibridación in situ con un resultado negativo) mediante pruebas analíticas locales.
    5. Estado de receptor de estrógenos y receptor de progesterona negativo conocido según las pruebas analíticas locales.
    6. Haber recibido entre 2 y 5 regímenes quimioterapéuticos previos en un marco localmente avanzado y/o metastásico. El tratamiento previo debe incluir una antraciclina y un taxano en cualquier combinación u orden (salvo que esté contraindicado para alguna paciente). Se permite tratamiento antihormonal previo.
    7. Estado funcional del Eastern Cooperative Oncology Group (ECOG) estable ? 2.
    8. Más de 4 semanas desde cualquier fármaco en investigación.
    9. Función adecuada de la médula ósea y los órganos definida por los siguientes valores de laboratorio:
    -Recuento absoluto de neutrófilos (RAN) ? 1,5 x 10^9/l, plaquetas ? 100 x 10^9/l, hemoglobina ? 100 g/l.
    -Potasio, calcio (corregido para la albúmina sérica) y magnesio dentro de los límites normales (DLN) del centro.
    -Bilirrubina total ? 1,5 veces el límite superior normal (LSN).
    -Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) ? 2,5 veces el LSN o ? 5,0 x LSN en caso de metástasis hepáticas.
    -Creatinina sérica ? 1,5 veces el LSN.
    -Glucosa plasmática en ayunas ? 125 mg/dl (? 7 mmol/l) o HbA1c ? 7 %.
    10. Pacientes que puedan y deseen deglutir y retener la medicación oral.
    11. Consentimiento informado escrito obtenido según las directrices locales.
    Parte de expansión:
    12. Cáncer de mama triple negativo (basado en la biopsia analizada más recientemente) definido como prueba de hibridación in situ con un resultado negativo o estado de IHC de 0, 1+ o 2+ (en caso de IHC 2+, será necesario realizar una prueba de hibridación in situ con un resultado negativo) y estado de ER y RP < 10% mediante pruebas analíticas locales.
    13. Enfermedad medible según RECIST v.1.1 o lesiones óseas líticas o mixtas (líticas + blásticas) no medibles con un componente de tejido blando identificable que cumpla los criterios de medición de RECIST v.1.1
    E.4Principal exclusion criteria
    1. Previous systemic treatment with PI3K, mTOR or AKT inhibitors (allowed in the escalation part).
    2. Previous treatment with eribulin (allowed in the escalation part).
    3. Known hypersensitivity to any of the excipients of PQR309 or eribulin.
    4. Concurrent treatment with other approved or investigational antineoplastic agent.
    5. Symptomatic CNS metastases. The patient must have completed any prior local treatment for CNS metastases ? 28 days prior to first dose of the study drug (including radiotherapy and/or surgery).
    6. Clinically manifested diabetes mellitus (treated and/or clinical signs with fasting glucose > 125 mg/dl or HbA1c >7%), or documented steroid induced diabetes mellitus.
    7. Peripheral neuropathy ? CTC AE grade 2.
    8. Anxiety ? CTC AE grade 3.
    9. Concurrent malignancy other than HER2 negative BC or malignancy within 3 years of study enrollment (with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer).
    10. Received radiotherapy ? 3 weeks or limited field radiation for palliation ? 2 weeks prior to starting study drug, and not recovered or improved to grade 1 from related side effects of such therapy (exceptions include alopecia) and/or from whom ? 30% of the bone marrow was irradiated.
    11. Not recovered or improved to grade 1 from related side effects (except alopecia) of any prior antineoplastic therapy.
    12. Major surgery within 14 days prior to first dose of the study drug or not recovered from major side effects.
    13. Received systemically high doses of corticosteroids ? 2 weeks prior to starting study drug, or not fully recovered from side effects of such treatment.
    Stable doses of corticosteroids, no more than 1 mg of dexamethasone a day or equivalent, e.g. 6 mg prednisone or 25 mg hydrocortisone for at least 5 days prior to first dose of the study drug is allowed.
    14. Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
    15. Treatment with medicinal products that increase the pH (reduce acidity) of the upper Gastro-Intestinal (GI) tract, including, but not limited to: protonpump inhibitors (e.g. omeprazole), H2-antagonists (e.g. ranitidine) and antacids. Patients may be enrolled in the study after a wash out period sufficient to terminate their effect.
    16. Using herbal preparations or medications within ? 7 days prior to first dose of the study drug.
    17. Any severe or uncontrolled cardiac disease or history of cardiac dysfunction (Section 9.3 of protocol).
    18. Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
    19. Cardiac conduction abnormalities (Section 9.3 of protocol).
    20. QTcF > 480 msec on the screening ECG (using the QTcF formula).
    21. Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to randomization.
    22. Impairment of hepatic function (Child-Pugh score > 5).
    23. Severe impairment of kidney function (CrCL: 15-29 mL/min - according to Cockcroft-Gault formula).
    24. Gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PQR309.
    25. Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate participation in the clinical study (e.g. chronic pancreatitis, chronic active hepatitis, etc.).
    26. Known history of HIV infection (testing not mandatory).
    27. Women able to concive and do not agree to practice an effective method of birth control from screening until 90 days after discontinuing study treatment (women of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of study treatment).
    28. History of non-compliance to medical regimen
    1. Tratamiento sistémico previo con inhibidores PI3K, mTOR o AKT (permitidos en la parte de escalada).
    2. Tratamiento previo con eribulina (permitida en la parte de escalada).
    3. Hipersensibilidad conocida a cualquiera de los excipientes de PQR309 o eribulina.
    4. Tratamiento concomitante con otro fármaco antineoplásico aprobado o en investigación.
    5. Metástasis sintomáticas del SNC. La paciente debe haber completado cualquier tratamiento local previo para las metástasis del SNC ? 28 días antes de la primera dosis del fármaco del estudio (incluida radioterapia y/o cirugía).
    6. Diabetes mellitus clínicamente manifestada (tratada y/o con signos clínicos de glucosa en ayunas > 125 mg/dl o HbA1c >7 %) o diabetes mellitus inducida por esteroides documentada.
    7. Neuropatía periférica de grado ? 2 de los CTCAE.
    8. Ansiedad de grado ? 3 de los CTCAE.
    9. Tumor maligno concurrente, salvo CM HER2 negativo, o tumor maligno durante los 3 años de inclusión en el estudio (salvo un carcinoma de células basales o escamosas adecuadamente tratado, cáncer de piel no melanomatoso o cáncer de cuello uterino resecado de forma curativa).
    10. Radioterapia recibida durante ? 3 semanas o radiación de campo limitado para paliación ? 2 semanas antes del inicio del fármaco del estudio y que no se haya recuperado ni mejorado a grado 1 de los efectos secundarios relacionados de dicho tratamiento (entre las excepciones se incluye alopecia) y/o en los que se haya irradiado ? 30% de la médula ósea.
    11. Ausencia de recuperación o mejora a grado 1 de los efectos secundarios relacionados (salvo alopecia) de cualquier tratamiento antineoplásico previo.
    12. Cirugía mayor durante los 14 días anteriores a la primera dosis del fármaco del estudio o que no se hayan recuperado de los efectos secundarios principales.
    13. Recepción de dosis altas de corticosteroides sistémicos ? 2 semanas antes de empezar a tomar el fármaco del estudio o aquellas que no se hayan recuperado completamente de los efectos secundarios de dicho tratamiento. Se permiten dosis estables de corticosteroides, no más de 1 mg de dexametasona al día o equivalente, p.ej., 6 mg de prednisona o 25 mg de hidrocortisona durante al menos 5 días antes de la primera dosis del fármaco del estudio.
    14. Recibir actualmente warfarina u otro anticoagulante derivado de la cumarina para tratamiento, profilaxis u otro. El tratamiento con heparina, heparina de bajo peso molecular (HBPM) o fondaparinux está permitido.
    15. Tratamiento con productos medicinales que aumenten el pH (reducen la acidez) del tracto gastrointestinal (GI) superior, incluidos entre otros, inhibidores de la bomba de protones (p. ej., omeprazol), antagonistas H2 (p. ej., ranitidina) y antiácidos. Las pacientes pueden ser incluidas en el estudio después de un periodo de lavado suficiente para terminar su efecto.
    16. Uso de preparaciones a base de plantas medicinales o medicación durante ? 7 días antes de la primera dosis del fármaco del estudio.
    17. Cualquier enfermedad cardíaca grave o no controlada o antecedentes de disfunción cardíaca (apartado 9.3 del protocolo).
    18. Fracción de eyección del ventrículo izquierdo (FEVI) < 50 % según determina una ventriculografía isotópica (MUGA) o una ecocardiografía (ECO).
    19. Anomalías en la conducción cardíaca (apartado 9.3 del protocolo).
    20. QTcF > 480 ms en el ECG de la visita de selección (utilizando la fórmula QTcF).
    21. Recepción actual de tratamiento con medicación que conlleve un riesgo conocido de prolongar el intervalo QT o inducir Torsade de Pointe; dicho tratamiento no puede retirarse o cambiarse por una medicación diferente antes de la aleatorización.
    22. Alteración de la función hepática (puntuación de Child-Pugh > 5).
    23. Alteración grave de la función renal (Clcr: 15-29 ml/min - según la fórmula de Cockcroft-Gault).
    24. Función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de PQR309.
    25. Cualquier otra enfermedad grave y/o no controlada concurrente que, según el criterio del investigador, podría contraindicar la participación en el estudio clínico (p. ej., pancreatitis crónica, hepatitis activa crónica, etc.).
    26. Antecedentes conocidos de infección por VIH (no es obligatorio realizar pruebas).
    27. Las mujeres que puedan concebir y no se comprometan a utilizar un método anticonceptivo efectivo desde la selección hasta 90 días después de la retirada del tratamiento del estudio (las mujeres en edad fértil deben presentar un resultado negativo en la prueba de embarazo en suero durante los 7 días anteriores a la primera dosis del tratamiento del estudio).
    28. Antecedentes de falta de cumplimiento del régimen médico.
    E.5 End points
    E.5.1Primary end point(s)
    In the escalation part: MTD based on the incidence of dose limiting toxicities (DLTs)
    In the expansion part: Clinical Benefit Rate (CBR) including complete
    response (CR), partial response (PR) and stable disease (SD) according to the response evaluation criteria in solid tumors (RECIST), version 1.1
    En la parte de escalada: MTD basada en la incidencia de las toxicidades limitantes de dosis (DLT).
    En la parte de expansión: La tasa de beneficio clínico (TBC) incluida la respuesta completa (RC), la respuesta parcial (RP) y la enfermedad estable (EE) según los criterios de evaluación de respuesta en tumores sólidos (RECIST), versión 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    In the escalation part: Weekly
    In the expansion part: every 6 weeks for the first 24 weeks, then every 9 weeks
    En la parte de escalada: Semanalmente
    En la parte de expansión: cada 6 semanas durante los 24 primeras semanas, y después cada 9 semanas
    E.5.2Secondary end point(s)
    Safety and tolerability:
    - Incidence and severity of AEs including SAEs
    - Changes in vital signs (heart rate, blood pressure, body temperature), ECOG status, physical examinations, body weight, and ECG
    - Changes of routine laboratory assessments (hematology, blood chemistry, urinalysis)
    Additional Clinical Efficacy:
    - Overall response rate (ORR), time to response (TTR), duration of response (DOR), time to treatment failure (TTF), progression-free survival (PFS) and 1-year survival rates.
    Pharmacokinetics (PK):
    - PQR309 and eribulin plasma concentration, PK parameters: Cmax, tmax,AUC0-24, AUC0??, t1/2 and RAC
    Seguridad y tolerabilidad:
    -Incidencia e intensidad de los AA, incluidos los AAG.
    -Cambios en las constantes vitales (frecuencia cardíaca, presión arterial, temperatura corporal), estado ECOG, exploraciones físicas, peso corporal y ECG.
    -Cambios en las pruebas analíticas rutinarias (hematología, análisis bioquímico de sangre, análisis de orina).
    Eficacia clínica adicional:
    -Tasa de respuesta global (TRG), tiempo hasta la respuesta (TR) y duración de respuesta (DR), tiempo hasta el fracaso del tratamiento (TFT), supervivencia libre de progresión (PFS) y tasas de supervivencia de 1 año.
    Farmacocinética (PK):
    -Concentración plasmática de PQR309 y eribulina, parámetros PK: Cmax, tmax, AUC0-24, AUC0??, t1/2 y RAC.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - AEs/SAEs, vital signs, ECOG status, physical examinations: weekly
    - ECG: on Day 1 of each cycle
    - Hematology, blood chemistry: weekly
    - Urinalysis: on Day 1 of each cycle
    - Additional Clinical Efficacy: every 6 weeks for the first 24 weeks, then every 9 weeks
    - Pharmacokinetics (PK): Day 1, 8, 15 of cycle 1 and Day 1 of subsequent cycles
    - AA/AAG, constantes vitales, estado ECOG, exploraciones físicas: semanalmente
    - ECG: dia 1 de cada ciclo
    - Hematología, análisis bioquímico de sangre: semanalmente
    - Análisis de orina: dia 1 de cada ciclo
    - Eficacia clínica adicional: cada 6 semanas para los 24 primeras semanas, y después cada 9 semanas
    - Farmacocinética (PK): Dias 1, 8, 15 del ciclo 1 y Dia 1 de los ciclos ulteriores
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    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
    Dosage determination
    Determinación 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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Último paciente úlima visita
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 31
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 31
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 31
    F.4.2.2In the whole clinical trial 31
    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)
    None
    Ninguno
    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 Decision2016-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-18
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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