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    Summary
    EudraCT Number:2015-002525-19
    Sponsor's Protocol Code Number:D5660C00004
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    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 number2015-002525-19
    A.3Full title of the trial
    A Phase 1b/2, Open-Label, Multicentre Study Assessing the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumour Activity of MEDI4736 in Combination With AZD9150 or AZD5069 in Patients With Advanced Solid Malignancies and Subsequently Comparing AZD9150 and AZD5069 Both as Monotherapy and in Combination With MEDI4736 as Second Line Treatment in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck
    Estudio en fase Ib/II, abierto y multicéntrico para evaluar la seguridad, la tolerabilidad, la farmacocinética y la actividad antineoplásica preliminar de MEDI4736 en combinación con AZD9150 o AZD5069 en pacientes con tumores sólidos avanzados, en el que posteriormente se compararán AZD9150 y AZD5069 en monoterapia y en combinación con MEDI4736 como tratamiento de segunda línea en pacientes con carcinoma epidermoide de cabeza y cuello recidivante y/o metastásico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and tolerability of MEDI4736 in Combination With AZD9150 or AZD5069 in solid tumors and subsequently evaluating AZD9150 or AZD5069 as single agent or in combinations with MEDI4736 in Patients with recurrance or spread of Squamous Cell Carcinoma of the Head and Neck
    Seguridad y tolerabilidad de MEDI4736 en combinación con AZD9150 y AZD5069 en tumores sólidos y posteriormente evaluar AZD9150 y AZD5069 como agente único o en combinación con MEDI4736 en pacientes con recurrencia o propagación de carcinoma epidermoide de cabeza y cuello
    A.4.1Sponsor's protocol code numberD5660C00004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02499328
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca Farmacéutica Spain, S.A.
    B.5.2Functional name of contact pointUnidad de Investigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressSerrano Galvache, 56
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28033
    B.5.3.4CountrySpain
    B.5.4Telephone number900200444
    B.5.6E-mailinformacionEECC-Spain@astrazeneca.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 nameMedi4736 50mg/ml solution for infusion
    D.3.2Product code Medi4736
    D.3.4Pharmaceutical form Solution for 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 INNdurvalumab
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 nameAZD9150 50mg/ml concentrate for solution for infusion
    D.3.2Product code AZD9150
    D.3.4Pharmaceutical form Concentrate for solution for 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 INNAZD9150
    D.3.9.1CAS number 1402100-56-4
    D.3.9.2Current sponsor codeAZD9150
    D.3.9.3Other descriptive nameISIS481464
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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: 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 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 nameAZD5069 10mg film-coated tablet
    D.3.2Product code AZD5069
    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 INNAZD5069
    D.3.9.1CAS number 878385-84-3
    D.3.9.2Current sponsor codeAZD5069
    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.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 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 nameAZD5069 40mg film-coated tablet
    D.3.2Product code AZD5069
    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 INNAZD5069
    D.3.9.1CAS number 878385-84-3
    D.3.9.2Current sponsor codeAZD5069
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    Part A (US ONLY): advanced solid malignancies
    Part B (NA, EU): Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck
    Parte A (sólo EE.UU.): tumores malignos sólidos avanzados
    Parte B (NA, EU): con recurrencia o propagación de carcinoma epidermoide de cabeza y cuello
    E.1.1.1Medical condition in easily understood language
    Part A (US ONLY): advanced solid tumor
    Part B (NA, EU): Recurrent and/or spreading tumor of Head and Neck
    Parte A (sólo EE.UU.): tumores malignos sólidos avanzados
    Parte B (NA, EU): con recurrencia o propagación de carcinoma epidermoide de cabeza y cuello
    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 10065147
    E.1.2Term Malignant solid tumor
    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 18.1
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    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
    Part A (dose escalation-US ONLY)
    To determine the MTDs or recommended doses for dose-expansion and to determine the safety profiles of either AZD9150 or AZD5069 in combination with MEDI4736 in patients with advanced solid malignancies refractory to standard therapy or for which no standard of care regimen currently exists.
    Part B (dose expansion-NA, EU)
    to evaluate the ORR of AZD9150 and AZD5069 both as monotherapy and in combination with MEDI4736 in the second-line treatment of patients with RM-SCCHN.
    Parte A de búsqueda de dosis (sólo EE.UU.)
    Determinar las DMT o las dosis recomendadas para la fase de ampliación y determinar los perfiles de seguridad de AZD9150 y AZD5069 en combinación con MEDI4736 en pacientes con tumores sólidos avanzados resistentes al tratamiento de referencia o para los que actualmente no existe un tratamiento de referencia.
    Parte B de ampliación (NA, EE.UU.)
    Evaluar la tasa de respuesta objetiva de AZD9150 y AZD5069 tanto en monoterapia como administrados en combinación con MEDI4736 en tratamiento de segunda línea en pacientes con CECC recidivante y/o metastásico.
    E.2.2Secondary objectives of the trial
    Part A: To assess: Pharmacokinetics (PK) of AZD9150, AZD5069, & MEDI4736, immunogenicity (IM) of MEDI4736 with AZD9150 or AZD5069, IM of AZD9150 with MEDI4736, blood pharmacodynamic (PD) response for AZD9150 & MEDI4736, baseline circulating myeloid-derived suppressor cells (MDSC) & effect of treatment on them, anti-tumor activity of AZD9150 or AZD5069 with MEDI4736
    Part B: To assess: safety & tolerability of AZD9150 & AZD5069 alone & with MEDI4736, secondary efficacy measures (disease control rate; overall response duration; progression-free survival; overall survival; proportion of patients alive at 12 months), PK of AZD9150 & AZD5069 alone & with MEDI4736, effect of food on AZD5069 monotherapy PK, urinary PK of AZD9150, PK of MEDI4736 with AZD9150 or AZD5069, IM of MEDI4736 with AZD9150 or AZD5069, IM of AZD9150 alone or with MEDI4736, blood PD response for AZD9150 & MEDI4736, tumor cell PD, baseline circulating MDSC and effect of treatment on them, baseline tumor PD-L1 expression
    Parte A: farmacocinética de AZD9150, AZD5069 y MEDI4736, nmunogenicidad (IM) de MEDI4736 con AZD9150 o AZD5069, IM de AZD9150 con MEDI4736, respuesta farmacodinámica en sangre a AZD9150 y MEDI4736, células mieloides supresoras derivadas de la circulación en el momento basal y el efecto del tratamiento sobre la MDSC en circulación, actividad antineoplásica de AZD9150 o AZD5069 en combinación con MEDI4736.
    Parte B: Evaluar: la seguridad y la tolerabilidad de AZD9150 y AZD5069 en monoterapia y administrados en combinación con MEDI4736, las variables secundarias de la eficacia (tasa de beneficio clínico a los 2, 4, 6 y 12 meses; duración de la respuesta global, supervivencia sin progresión (SSP), supervivencia global (SG), y proporción de pacientes vivos a los 12 meses), FC de AZD9150 y AZD5069 en monoterapia y administrados en combinación con MEDI4736, efecto de la alimentación en la FC de AZD5069 administrado en monoterapia, FC en orina de AZD9150, VÉASE CONTINUACION EN EL PROTOCOLO
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Eastern Cooperative Oncology Group performance status score of 0 or 1
    -Measurable disease
    -Male and female above 18 years
    - Undergone ?3 previous regimens of cytoreductive therapies including, but not limited to, platinum-based compounds, taxanes, or 5-fluorouracil.
    -Adequate organ and marrow function
    -Women of childbearing potential and men who are sexually active with a female partner of childbearing potential must prevent pregnancy and women may not be breast feeding

    Additional inclusion criteria for Part A:
    -Histological confirmation of a solid malignancy (other than HCC) refractory to standard therapy or for which no standard of care regimen currently exists.

    Additional inclusion criteria for Part B:
    -Histologically and/or cytologically confirmed SCCHN that is RM and not amendable to curative therapy by surgery or radiation. Squamous cell carcinoma of the head and neck originating from the following sites is eligible: oral cavity, oropharynx, larynx, or hypopharynx.
    -Has at least 1 SCCHN tumour lesion (TL) amenable to biopsy and must be medically fit and willing to undergo a biopsy during screening and, unless clinically contraindicated, at the end of Cycle 1.
    -Must have failed, refused, or has been found to be ineligible for least 1 prior platinum-based chemotherapy for RM-SCCHN

    Additional inclusion criteria for Part B, arms B1 & B2
    Has had prior exposure to any anti PD (L)1 antibody
    -Puntuación de 0 a 1 en el estado funcional del Grupo Oncológico Cooperativo de la Costa Este.
    -tumor mensurable
    -mujeres y hombres, deberán tener 18 años o más
    -Haberse sometido a ?3 tratamientos citorreductores previos con derivados del platino, taxanos o 5-fluorouracilo, entre otros.
    -Funcionamiento orgánico y de la médula ósea adecuado
    -Las mujeres fértiles y los hombres sexualmente activos que tengan una pareja fértil debe prevenir el embarazo y las mujeres pueden no estar dando el pecho

    Otros criterios de inclusión para la parte A
    -Confirmación histológica de un tumor sólido (distinto al CHC) resistente al tratamiento de referencia o para el que no existe un tratamiento de referencia actualmente

    Otros criterios de inclusión para la parte B
    -CECC confirmado histológica o citológicamente R/M, que no sea operable ni pueda tratarse con radioterapia. Carcinoma epidermoide de cabeza y cuello en las siguientes localizaciones: cavidad bucal, orofaringe, laringe o hipofaringe.
    -Presentar al menos una lesión tumoral (LT) del CECC en la que pueda practicarse una biopsia y estar dispuestos a someterse a una biopsia durante la selección y, a menos que esté clínicamente contraindicado, al final del ciclo 1
    -Deberá no haber presentado respuesta, haber rechazado o haber sido considerado no idóneo a al menos 1 tratamiento previo con quimioterapia de derivados del platino

    Otros criterios de inclusión para los grupos de tratamiento B1 y B2 de la parte B de ampliación
    -Exposición previa a algún anticuerpo anti PD (L)1
    E.4Principal exclusion criteria
    -Symptomatic spinal cord compression
    -Second malignancy
    -Concurrent chemotherapy, radiotherapy, immunotherapy, or biologic or hormonal therapy for cancer
    -Ongoing toxicity related to prior treatment and assessed as grade >1 Immune-related adverse events (AEs) while receiving prior immunotherapy (including anti-cytoxic T-lymphocyte-associated protein 4 treatment) and assessed as grade ?3
    -Has active or prior documented autoimmune disease within the past 2 years with the exception of vitiligo, Grave?s disease, and/or psoriasis not requiring systemic treatment
    -Active or prior documented inflammatory bowel disease
    -History of primary immunodeficiency
    -Prior organ transplant that requires use of immunosuppressive treatment
    -Cardiac conditions that render the patient unsuitable for participation in the study
    -Inability to take oral medications and/or has a clinical or radiological diagnosis of bowel obstruction
    -History of allergic reactions attributed to the study treatments (AZD9150, AZD5069, or MEDI4736), their compounds, or agents of similar chemical or biologic composition
    -Suffers from a comorbidity that in the opinion of the Investigator renders the patient unsuitable for participation in the study
    -As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases such as active bleeding diatheses, or is positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)
    -History of tuberculosis
    -Condition that, in the opinion of the Investigator, would interfere with the evaluation of the study drugs or the interpretation of patient safety or study results
    -Live attenuated vaccine within 28 days before the first dose of study drug
    -Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
    -Patients with brain metastases considered stable may be enrolled into Part A of the study; they are excluded form Part B of the study
    -Patients must not be included in the optional genetic research if they have previously received an allogeneic bone marrow transplant or have received non-leukocyte depleted whole blood transfusion(s) within 120 days before the date of the genetic sample collection

    Additional exclusion criteria for Part A:
    -Patients with clinically active brain metastases (known or suspected) are excluded
    unless the brain metastases have been previously treated and are considered stable.
    Stable brain metastases are defined as no change on CT scan or magnetic resonance
    imaging (MRI) scan for a minimum of 2 months AND no change in steroid dose for
    a minimum of 4 weeks, unless change due to intercurrent infection or other acute
    event.
    - Has had prior exposure to AZD9150, AZD5069, MEDI4736, or any other anti PD (L)1 antibody.


    Additional exclusion criteria for Part B:
    Patients with brain metastases (known or suspected) are excluded

    Additional exclusion criteria Part B: treatment arms B3, B4, B5, and B6
    Has had prior exposure to AZD9150, AZD5069, MEDI4736, or any other anti PD (L)1 antibody.
    -Compresión medular a menos que sea asintomática
    -un segundo cáncer primario
    -Toda quimioterapia, radioterapia, inmunoterapia o tratamiento biológico u hormonal para el cáncer
    -Toxicidad en curso relacionada con un tratamiento previo de grado >1
    -AA relacionados con el sistema inmunitario durante un tratamiento anterior con inmunoterapia (incluido el tratamiento con anti-CTLA4) valorado como de grado ?3 según los criterios CTCAE del NCI
    -Enfermedad autoinmunitaria previa o activa documentada en los últimos 2 años, a excepción del vitiligo, la enfermedad de Graves-Basedow y/o la psoriasis que no precisen de tratamiento sistémico
    -Enfermedad intestinal inflamatoria previa o activa documentada
    -Antecedentes de inmunodeficiencias primarias
    -Trasplante previo de un órgano que precise un tratamiento con inmunodepresores
    -Condiciones cardíacas que hacen que el paciente no sea apto para participar en el estudio
    -Imposibilidad de tomar fármacos orales y/o diagnóstico radiológico de obstrucción intestinal
    -Antecedentes de reacciones alérgicas atribuidas a los tratamientos del estudio (AZD9150, AZD5069 o MEDI4736), a sus excipientes o a fármacos de composición química o biológica similar
    -Cualquier otra enfermedad o trastorno concomitante que, en opinión del investigador, impida al paciente participar en el estudio
    -A juicio del investigador, cualquier indicio de que el paciente sufra una enfermedad grave o que no se haya curado como una diátesis hemorrágica o que presente una infección activa por el virus de la inmunodeficiencia humana (VIH), el virus de la hepatitis B (VHB) y/o el virus de la hepatitis C (VHC)
    -Antecedentes de tuberculosis
    -Cualquier otra enfermedad o trastorno que, en opinión del investigador, pudiera interferir con la evaluación de los fármacos en estudio o con la interpretación de los datos sobre la seguridad del paciente o los resultados del estudio
    -Haber recibido vacunas elaboradas con microbios vivos atenuados en los 28 días anteriores a la primera dosis del fármaco en estudio
    -Si el investigador juzga que el paciente no debería participar en el estudio porque es probable que no cumpla los procedimientos, restricciones y requisitos del estudio
    -Los pacientes con metástasis cerebrales estables podrán incluirse en la parte A del estudio, pero quedarán excluidos de la parte B
    -Los pacientes no podrán ser incluidos en la investigación genética opcional si se han sometido anteriormente a un alotrasplante de médula ósea o a una transfusión de sangre desleucocitada en un plazo de 120 días antes de la fecha de la recogida de muestras genéticas

    Otros criterios de exclusión para la parte A de aumento escalonado de la dosis
    -Los pacientes con metástasis cerebrales clínicamente activas (conocidas o sospechadas) quedan excluidos a menos que las metástasis cerebrales hayan sido previamente tratadas y se consideren estables. Las metástasis cerebrales estables se definen como la ausencia de cambios en la TAC o en la RM (resonancia magnética) durante 2 meses Y ASIMISMO la ausencia de cambios en la dosis de corticoides durante un mínimo de 4 semanas, a menos que el cambio se deba a una infección intercurrente o a otro acontecimiento agudo
    -Exposición previa a AZD9150, AZD5069, MEDI4736 o a algún otro anticuerpo anti PD (L)1
    Otros criterios de exclusión para la parte B de ampliación
    -Los pacientes con metástasis cerebrales (conocidas o sospechadas) quedan excluidos
    Otros criterios de exclusión para los grupos de tratamiento B3, B4, B5 y B6 de la parte B de ampliación
    -Exposición previa a AZD9150, AZD5069, MEDI4736 o a algún otro anticuerpo anti PD (L)1
    E.5 End points
    E.5.1Primary end point(s)
    Part A:
    -MTD or recommended dose for dose expansion
    -AEs, SAEs, laboratory evaluations, vital signs, and physical examinations
    -Treatment-emergent AEs (TEAEs), SAEs and death(s), graded in accordance with NCI CTCAE v4.03

    Part B
    -Objective response - defined as a CR or PR according to RECIST version 1.1
    Parte A:
    -DMT o dosis recomendada para la expansión de dosis
    -AA, AAG, evaluaciones analíticas, constantes vitales y exploraciones físicas
    -AA surgidos durante el tratamiento (AAST), AAG y muerte(s), gradificadas conforme a los CTCAE del NCI v4.03

    Parte B:
    Respuesta objetiva, definida como RC o RP conforme a los RECIST versión 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A:
    -MTD or recommended dose for dose expansion: based on patients completing DLT evaluation period as defined in protocol for each arm.
    - Patients are to be followed up for 28 (+7) days after the last dose of study treatment for any new reports of AEs, SAEs. Safety follow-up for IM will continue for all patients treated with MEDI4736 for 90 days after the last dose of MEDI4736 or until the initiation of subsequent anticancer therapy.

    Part B:
    Tumour assessments to be performed using RECIST 1.1 at screening, Day 15 of Cycle 2, beginning of each subsequent even numbered cycle, and at end of treatment visit. Patients discontuning treatment for reasons other than progressive disease (PD) will continue to undergo assessment every 2 months until PD is noted.
    Parte A:
    -DMT o dosis recomendada para la expansión de dosis: basadas en los pacientes que realizaron la evaluación de TLD como se define en el protocolo para cada brazo.
    -Los pacientes serán objeto de seguimiento durante 28 (+7) días después de la última dosis del tratamiento del estudio para recoger las nuevas notificaciones de AA, AAG y medicamentos concomitantes. El seguimiento de la seguridad para IM continuará en todos los pacientes que reciban MEDI4736 durante 90 días después de la última dosis de MEDI4736 o hasta el inicio de un tratamiento antineoplásico posterior
    Parte B:
    -Las evaluaciones del tumor se llevarán a cabo en la selección, el día 15 del ciclo 2 (es decir, al inicio de la semana 7), al inicio de cada ciclo par posterior y en la visita de FT. VÉASE PROTOCOLO
    E.5.2Secondary end point(s)
    Part A & B:
    Tumor response by RECIST, Pharmacokinetics, Pharmacodynamics and safety.
    Parte A y B:
    Respuesta tumoral por RECIST, farmacocinetica, farmacodinamica y seguridad.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response- Scr, C2D15, even cycles, & EOT. Assessment every 2 months until PD. OS: time from the date of C1D1 until death. AEs- Scr, all clinic visits until 28 days after the last dose. PK (blood)- AZD9150 & AZD5069: lead in, C1D1, C2D1 & Day 1 of all cycles. MEDI4736: C1D1, C2D15, Cycle 4 & all even cycles. 90 days after last dose of MEDI4736 for patients stopping drug. IM for MEDI4736 & AZD9150: C1D1, Cycle 2, & Day 1 of even-numbered cycle & 90 days after last dose of MEDI4736 for patients stopping drug. PD (blood)- STAT3 knockdown: Scr, Day -7; C1D1&8; C2, 2, 4, 5 D1, & EOT. sPD-L1 protein: C1D1; C2D15; & Day 1 of even cycles & 90 days after last dose of MEDI4736 for patients stopping drug. MDSC1&2: Scr, Day -7, C1, 2, 3, 5 D1 & EOT. Tumor STAT3: Baseline & on-treatment biopsies.
    Respuesta- Scr, C2D15, incluso los ciclos, y FT. Evaluación cada 2 meses hasta la PT. SG: el tiempo desde la fecha de C1D1 hasta la muerte. AAs-Scr, todas las visitas hasta 28 días después de la última dosis. PC (sangre) - AZD9150 y AZD5069: conducir en, C1D1, C2D1 & Day 1 de todos los ciclos. MEDI4736: C1D1, C2D15, ciclo 4 y todos los ciclos pares. 90 días después de la última dosis de MEDI4736 para los pacientes que detienen el tratamiento. IM para MEDI4736 y AZD9150: C1D1, Ciclo 2, y el día 1 del ciclo de número par y 90 días después de la última dosis de MEDI4736 para los pacientes que detienen el tratamiento. PT (sangre) - caída STAT3: Scr, Día -7; C1D1 y 8; C2, 2, 4, 5 D1, y FT. proteína SPD-L1: C1D1; C2D15; & Day 1 incluso de ciclos
    VÉASE PROTOCOLO
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    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 Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Information not present in EudraCT
    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 trial6
    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 EEA25
    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
    Belgium
    Canada
    Germany
    Italy
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The trial will end when all patients have been successfully followed up for survival endpoint with the exception of patients who withdraw and go on alternate anti cancer therapy or patients who are lost to follow up.
    El ensayo terminará cuando todos los pacientes se hayan seguido con éxito hasta el criterio de valoración de supervivencia a excepción de los pacientes que se hayan retirado y seguido una terapia alternativa contra el cáncer alternativo o pacientes que se perdieron durante el seguimiento
    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
    E.8.9.2In all countries concerned by the trial months5
    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: 147
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 37
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 184
    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 Decision2016-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-04
    P. End of Trial
    P.End of Trial StatusRestarted
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