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    Summary
    EudraCT Number:2018-000345-39
    Sponsor's Protocol Code Number:B9991032
    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:2018-11-05
    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 number2018-000345-39
    A.3Full title of the trial
    A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination with Talazoparib In Patients with BRCA or ATM Mutant Tumors
    ESTUDIO EN FASE II PARA EVALUAR LA SEGURIDAD Y LA ACTIVIDAD ANTITUMORAL DE AVELUMAB EN COMBINACIÓN CON TALAZOPARIB EN PACIENTES CON TUMORES CON MUTACIÓN DE BRCA O ATM
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination with Talazoparib In Patients with BRCA or ATM Mutant Tumors
    ESTUDIO EN FASE II PARA EVALUAR LA SEGURIDAD Y LA ACTIVIDAD ANTITUMORAL DE AVELUMAB EN COMBINACIÓN CON TALAZOPARIB EN PACIENTES CON TUMORES CON MUTACIÓN DE BRCA O ATM
    A.3.2Name or abbreviated title of the trial where available
    JAVELIN BRCA/ATM
    A.4.1Sponsor's protocol code numberB9991032
    A.5.4Other Identifiers
    Name:US INDNumber:133,902
    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 SponsorPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 Yes
    D.2.1.1.1Trade name Bavencio
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Europe Limited
    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 nameAvelumab
    D.3.2Product code MSB0010718C
    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 INNAvelumab
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeMSB0010718C
    D.3.9.3Other descriptive nameAnti PD-L1
    D.3.9.4EV Substance CodeSUB176547
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 nameTalazoparib
    D.3.2Product code PF-06944076 (MDV3800; BMN 673)
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalazoparib
    D.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive nameMDV3800; BMN 673
    D.3.9.4EV Substance CodeSUB122393
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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 nameTalazoparib
    D.3.2Product code PF-06944076 (MDV3800; BMN 673)
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalazoparib
    D.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive nameMDV3800; BMN 673
    D.3.9.4EV Substance CodeSUB122393
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 (primary or recurrent) or metastatic solid tumors with a pathogenic or likely pathogenic germline or loss-of-function somatic BRCA1, or BRCA2, or ATM gene defect
    Tumores sólidos localmente avanzados (primarios o recurrentes) o metastásicos con una estirpe germinal patógena o probablemente patógena o con defecto somático en los genes BRCA1, BRCA2 o ATM
    E.1.1.1Medical condition in easily understood language
    Solid tumors
    Tumores Sólidos
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    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
    To evaluate ORR of avelumab in combination with talazoparib, in patients with locally advanced or metastatic solid tumors harboring BRCA1, BRCA2 or ATM defect.
    Evaluar la TRO de avelumab combinado con talazoparib en pacientes con tumores sólidos localmente avanzados o metastásicos con defectos en BRCA1, BRCA2 o ATM.
    E.2.2Secondary objectives of the trial
    - To assess the overall safety and tolerability of avelumab in combination with talazoparib.
    - To characterize the PK of avelumab and talazoparib when given in combination.
    - To evaluate the immunogenicity of avelumab when given in combination with talazoparib.
    - To assess other measures of the anti-tumor activity of avelumab in combination with talazoparib.
    - To assess the correlation of anti-tumor activity of avelumab in combination with talazoparib with PD-L1 expression in baseline tumor tissue.
    - To assess the correlation of anti-tumor activity and emergence of resistance with defects in a panel of key oncogenes, including BRCA 1/2 and ATM, and TMB in circulating tumor DNA (ctDNA) and tumor tissue at baseline, during treatment and at the end of treatment.
    -Evaluar la seguridad y la tolerabilidad globales de avelumab en combinación con talazoparib.
    -Caracterizar la FC de avelumab y talazoparib cuando se administran en combinación.
    -Evaluar la inmunogenicidad de avelumab cuando se administra en combinación con talazoparib.
    -Evaluar otras medidas de la actividad antitumoral de avelumab en combinación con talazoparib.
    -Evaluar la correlación entre la actividad antitumoral de avelumab en combinación con talazoparib y la expresión de PD-L1 en el tejido tumoral inicial.
    -Evaluar la correlación de la actividad antitumoral y la aparición de resistencias con los defectos en un grupo de oncogenes clave, como los genes BRCA 1/2 y ATM, y la carga mutacional tumoral (CMT) en el ADN tumoral circulante (ADNtc) y en el tejido tumoral al inicio, durante el tratamiento y al final del tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Pathogenic or likely pathogenic germline or somatic gene defect as determined by local assessment and classification:
    - One or more BRCA1 or BRCA2 gene defect (Cohort 1);
    - ATM gene defect in the absence of concurrent BRCA 1/2 defect (Cohort 2).
    2. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent, as follows:
    a. Recurrent Epithelial Ovarian Cancer;
    b. TNBC (defined as ER- and PgR-negative [IHC nuclear staining <5%] and HER2-negative [IHC 0, 1+, or 2+ and/or ISH non-amplified with ratio less than 2.0]) or hormone-receptor-positive (HR+), HER2-negative breast cancer;
    c. Metastatic castration-resistant prostate cancer (mCRPC) without small cell features;
    d. Metastatic ductal adenocarcinoma of the pancreas;
    e. Any other advanced solid tumor.
    3. Availability of a fresh or recent tumor tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy; the sample must have been obtained within 24 months prior to study enrollment. When only bone disease is present, an archival tumor tissue sample obtained within 5 years prior to study enrollment may be accepted for non-prostate cancer patients and a fresh bone biopsy may be accepted for prostate cancer patients only).
    4. Have progressive disease at study enrollment as defined by RECIST v1.1 (except for mCRPC, who must meet criterion 2c above).
    5. Must have measurable disease by RECIST v1.1 with at least 1 measurable lesion that has not been previously irradiated (patients with mCRPC may have only non-measurable disease).
    6. Age ≥18 years (except in Japan, where patients must be ≥ 20 years old).
    7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
    8. Adequate bone marrow function (without hematopoietic growth factor or transfusion support within 14 days prior to study enrollment), including:
    a. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥ 1.5 x 109/L.
    b. Platelets ≥ 100,000/mm3 or ≥100 x 109/L.
    c. Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L).
    9. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula as:
    - CLCR={[(140–age) × weight)]/(72 x SCR)} × 0.85 (if female), where CLCR (creatinine clearance) is measured in mL/min, age is expressed in years, weight inkilograms (kg), and SCR (serum creatinine) in mg/dL;
    - Or as measured by 24h urine assessment.
    10. Adequate liver function, including:
    a. Total serum bilirubin ≤ 1.5 × the upper limit of normal range (ULN);
    b. Aspartate and Alanine aminotransferase (AST and ALT) ≤ 2.5 x ULN.
    11. Female patients of childbearing potential must have negative serum pregnancy or urine pregnancy test at screening. Female patients of nonchildbearing potential must meet at least 1 of the following criteria:
    - Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
    - Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    - Have medically confirmed ovarian failure.
    All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
    12. Evidence of a personally signed and dated informed consent document, within >28 days prior to enrollment, indicating that the patient has been informed of all pertinent aspects of the study.
    13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    1. Estirpe germinal patógena o probablemente patógena o defecto génico somático según la evaluación y la clasificación locales:
    -Uno o más defectos en los genes BRCA1 o BRCA2 (cohorte 1);
    -Defecto en el gen ATM en ausencia de defecto simultáneo en los genes BRCA 1/2 (cohorte 2).
    2. Diagnóstico histológico de tumores sólidos localmente avanzados (primarios o recurrentes) o metastásicos no susceptibles de tratamiento con intención curativa, según lo siguiente: a. Cáncer epitelial de ovario recurrente:
    b. Cáncer de mama triple negativo (CMTN) (definido como negativo para RE y RPg [tinción nuclear IHQ <5 %] y negativo para HER2 [IHQ 0, 1+ o 2+ y/o HIS sin amplificación con una proporción inferior a 2,0]) o cáncer de mama positivo para receptores hormonales (RH+) negativo para HER2
    c. Cáncer de próstata resistente a la castración metastásico (CPRCm) sin rasgos microcíticos
    d. Adenocarcinoma ductal metastásico de páncreas
    e. Cualquier otro tumor sólido avanzado
    3. Disponibilidad de una muestra de tejido tumoral fresca o reciente de una intervención quirúrgica/biopsia diagnóstica o de una biopsia de tumor metastásico; la muestra debe haberse obtenido dentro de los 24 meses anteriores a la inclusión en el estudio. Si solo existe metástasis ósea, se podrá aceptar una muestra de tejido tumoral de archivo obtenida dentro de los 5 años anteriores a la inclusión en el estudio en los pacientes con cáncer no de próstata y se podrá aceptar una biopsia ósea fresca de los pacientes con cáncer de próstata solamente. (Para obtener más detalles, véase la sección 7.4.1).
    4. Mostrar progresión de la enfermedad en el momento de la inclusión en el estudio, tal como se define en los criterios RECIST v1.1 (excepto para el CPRCm, que debe cumplir el criterio 2c anterior).
    5. Deben tener enfermedad medible según los criterios RECIST v1.1 con al menos 1 lesión medible que no haya sido irradiada previamente (los pacientes con CPRCm solo pueden tener enfermedad no medible).
    6. Edad 18 años (salvo en Japón, donde los pacientes deben tener 20 años).
    7. Estado funcional (EF) de 0 o 1 según el Grupo Oncológico Cooperativo del Este (Eastern Cooperative Oncology Group, ECOG).
    8. Funcionamiento adecuado de la médula ósea (sin factor de crecimiento hematopoyético ni apoyo transfusional dentro de los 14 días anteriores a la inclusión en el estudio), lo que engloba:
    a. Recuento absoluto de neutrófilos (RAN) 1500/mm3 o 1,5 × 109/l.
    b. Trombocitos 100 000/mm3 o 100 × 109/l.
    c. Hemoglobina 9 g/dl (5,6 mmol/l).
    9. Funcionamiento renal adecuado, definido por un aclaramiento de creatinina estimado 30 ml/min según la fórmula de Cockcroft-Gault del modo siguiente:
    •AclCr={[(140-edad) × peso)]/(72 × CrS)} × 0,85 (si es mujer), donde el AclCr (aclaramiento de creatinina) se mide en ml/min, la edad se expresa en años, el peso en kilogramos (kg) y la CrS (creatinina sérica) en mg/dl;
    •O medido por una evaluación de la orina de 24 h.
    10. Funcionamiento hepático adecuado, lo que incluye:
    a. Bilirrubina sérica total 1,5 × el límite superior de la normalidad (LSN);
    b. Aspartato y alanina aminotransferasa (AST y ALT) 2,5 × LSN.
    11. Las pacientes con capacidad de concebir deben dar un resultado negativo en la prueba de embarazo en suero o en orina de la selección. Las pacientes sin capacidad de concebir deben cumplir al menos 1 de los siguientes criterios:
    -Haber alcanzado el estado posmenopáusico, definido como: cese de las menstruaciones regulares durante al menos 12 meses seguidos sin una causa patológica o fisiológica alternativa y tener una concentración de hormona foliculoestimulante (FSH) en suero que confirme el estado posmenopáusico;
    -Haberse sometido a una histerectomía y/u ovariectomía bilateral documentadas.
    -Tener una insuficiencia ovárica médicamente confirmada.
    Todas las demás pacientes (incluidas las que tengan ligadura de trompas) se consideran con capacidad de concebir.
    12. Constancia de un documento de consentimiento informado firmado y fechado personalmente, dentro de los >28 días previos a la inclusión, que indique que se ha informado al paciente de todos los aspectos pertinentes del estudio.
    13. Voluntad y disponibilidad para cumplir las visitas programadas, el plan de tratamiento, las pruebas analíticas y otros procedimientos de estudio.
    E.4Principal exclusion criteria
    1. Prior treatment with a PARP inhibitor.
    2. Prior immunotherapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody.
    3. Prior anti-cancer therapy within 2 weeks prior to study enrollment or prior radiation therapy within 2 weeks prior to study enrollment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed at least 2 days prior to study enrollment and no clinically significant toxicities are expected (eg, mucositis, esophagitis).
    4. Major surgery within 4 weeks prior to study enrollment.
    5. Current use of immunosuppressive medication at the time of study enrollment, EXCEPT for the following permitted steroids: see Section 4.2.
    6. Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies ([NCI CTCAE] v4.03 Grade ≥ 3).
    7. Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.
    8. Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid disease not requiring immunosuppressive treatment are eligible.
    9. Prior organ transplantation including allogenic stem-cell transplantation.
    10. Administration of live attenuated vaccines within 4 weeks of study enrollment.
    11. Diagnosis of myelodysplastic syndrome (MDS).
    12. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
    13. Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation.
    14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, alopecia and sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 AEs not constituting a safety risk, based on investigator's judgment, are acceptable.
    15. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    16. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
    17. Active infection requiring systemic therapy. Minor infections, eg, periodontal or urinary tract infection (UTI) infection, which may be treated with short term oral antibiotics are allowed.
    18. Clinically significant (ie, active) cardiovascular disease: cerebral vascular
    accident/stroke (<6 months prior to study enrollment), myocardial infarction
    (<6 months prior to study enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or a serious cardiac arrhythmia requiring medication.
    19. Current or anticipated use of a P-glycoprotein (P-gp) inhibitor (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir , itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and verapamil), P-gp inducer (avasimibe, carbamazepine, phenytoin, rifampin, and St. John’s wort), or inhibitor of breast cancer resistance protein (BCRP) (curcumin, cyclosporine, elacridar [GF120918], and eltrombopag).
    20. Inability to swallow capsules, known intolerance to talazoparib or its excipients, known malabsorption syndrome, or other condition that may impair absorption of talazoparib.
    21. Bisphosphonate or denosumab dosage that was not stable (ie, not the same) for at least 2 weeks before study enrollment for patients receiving these therapies.
    22. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    23. Diagnosis of any other malignancy within 2 years prior to study enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast, bladder, or cervix, or low-grade (Gleason ≤ 6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration), or other early-stage low-risk cancers.
    1. Tratamiento previo con un inhibidor de PARP.
    2. Inmunoterapia anterior con anticuerpos anti-PD-1, anti-PD-L1, anti-PD-L2 anti-CTLA-4.
    3. Tratamiento antineoplásico previo dentro de las 2 semanas anteriores a la inclusión en el estudio o radioterapia previa dentro de las 2 semanas anteriores a la inclusión en el estudio. Se permite la radioterapia paliativa previa para las lesiones metastásicas, siempre que haya terminado al menos 2 días antes de la inclusión en el estudio y no se esperen toxicidades clínicamente significativas (p. ej., mucositis, esofagitis).
    4. Cirugía mayor dentro de las 4 semanas anteriores a la inclusión en el estudio.
    5. Uso en curso de medicación inmunodepresora en el momento de la inclusión en el estudio, A EXCEPCIÓN de los siguientes corticoesteroides permitidos:
    a. Corticoesteroides intranasales, inhalados, tópicos, en colirio o inyección local de corticoesteroides (p. ej., inyección intraarticular);
    b. Corticoesteroides sistémicos a dosis fisiológicas 10 mg/día de prednisona o equivalente;
    c. Corticoesteroides como premedicación para las reacciones de hipersensibilidad (p. ej., premedicación para exploraciones de tomografía axial computarizada [TAC]).
    6. Hipersensibilidad grave conocida a los productos en investigación o a cualquier componente de sus formulaciones, incluidas las reacciones de hipersensibilidad grave conocida a anticuerpos monoclonales (criterios terminológicos comunes para acontecimientos adversos definidos por el Instituto Nacional del Cáncer de los Estados Unidos [NCI CTCAE] v.4.03 de grado 3).
    7. Antecedentes conocidos de colitis inmunomediada, enfermedad inflamatoria intestinal, neumonitis o fibrosis pulmonar.
    8. Enfermedad autoinmunitaria activa o anterior que pueda empeorar al recibir inmunoestimulantes. Son aptos los pacientes con diabetes de tipo 1, vitíligo, psoriasis, hipotiroidismo o hipertiroidismo que no necesiten tratamiento inmunodepresor.
    9. Trasplante de órganos anterior, incluyendo el trasplante alogénico de células madre.
    10. Administración de vacunas vivas atenuadas dentro de las 4 semanas anteriores a la inclusión en el estudio.
    11. Diagnóstico de síndrome mielodisplásico (SMD).
    12. Metástasis cerebrales sintomáticas conocidas que requieran corticoesteroides. Los pacientes con metástasis cerebrales diagnosticadas anteriormente son aptos si han terminado su tratamiento y se han recuperado de los efectos agudos de la radioterapia o de la cirugía antes de la inclusión en el estudio, si han interrumpido el tratamiento con corticoesteroides para tratar dichas metástasis durante un mínimo de 4 semanas y si están estables desde el punto de vista neurológico.
    13. Participación en otros estudios con productos experimentales dentro de las 4 semanas anteriores a la entrada en el estudio y/o durante la participación en el estudio.
    14. Toxicidad persistente relacionada con un tratamiento anterior (NCI CTCAE v4.03 de grado >1); sin embargo, son aceptables la alopecia y la neuropatía sensitiva de grado 2 u otros AA de grado 2 que no constituyan un riesgo para la seguridad a juicio del investigador.
    15. Antecedentes conocidos de resultado positivo para el virus de la inmunodeficiencia humana (VIH) o síndrome de inmunodeficiencia adquirida (SIDA) conocido.
    16. Infección por el virus de la hepatitis B (VHB) o el virus de la hepatitis C (HVC) en la selección (resultado positivo para el antígeno de superficie del VHB o ARN del VHC si la prueba del antianticuerpo del VHC de la selección ha dado resultado positivo).
    17. Infección activa con necesidad de tratamiento sistémico. Se permiten las infecciones menores, p. ej., infección periodontal o infección del tracto urinario (ITU), que se puedan tratar con antibióticos orales a corto plazo.
    18. Enfermedad cardiovascular clínicamente significativa (es decir, activa): accidente cerebrovascular/derrame cerebral (<6 meses antes de la inclusión en el estudio), infarto de miocardio (<6 meses antes de la inclusión en el estudio), angina de pecho inestable, insuficiencia cardíaca congestiva (clase II según la clasificación de la Asociación Neoyorquina de Cardiología [New York Heart Association]) o arritmia cardíaca grave que requiera medicación.
    19. Uso actual o previsto de un inhibidor de la glucoproteína P (P-gp) (amiodarona, carvedilol, claritromicina, cobicistat, darunavir, dronedarona, eritromicina, indinavir, itraconazol, ketoconazol, lapatinib, lopinavir, propafenona, quinidina, ranolazina, ritonavir, saquinavir, telaprevir, tipranavir, valspodar y verapamilo), inductor de la P-gp (avasimiba, carbamazepina, fenitoína, rifampicina e hipérico) o inhibidor de la proteína de resistencia al cáncer de mama (BCRP) (curcumina, ciclosporina, elacridar [GF120918] y eltrombopag).
    Para más criterios refierase al Protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Confirmed OR in patients with locally advanced or metastatic solid tumors with BRCA 1/2 or ATM defect, as assessed by Blinded Independent Central Review (BICR), using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1 and PCWG3 (bone).
    RO confirmada en pacientes con tumores sólidos localmente avanzados o metastásicos con defecto en BRCA 1/2 o en ATM, evaluada mediante revisión central independiente con enmascaramiento (RCIE) usando los criterios RECIST v1.1 y, en los pacientes con CPRCm, los criterios RECIST v1.1 y del Grupo de trabajo 3 sobre el cáncer de próstata (PCWG3) (huesos)
    E.5.1.1Timepoint(s) of evaluation of this end point
    For patients with solid tumors, except mCRPC: Objective response (OR) is defined as a CR or PR per RECIST v1.1 from the first dose of study treatment until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met.
    For patients with mCRPC: Objective response (OR) is defined as the proportion of patients with a best overall soft tissue response of CR or PR per RECIST v1.1 from the first dose of study treatment until disease progression or death due to any cause. Soft tissue responses will be confirmed by a follow-up radiographic assessment at least 4 weeks later with a repeated CT or MRI with no evidence of confirmed bone disease progression per PCWG3 criteria.
    Para pacientes con tumores sólidos, excepto CPRCm: la respuesta objetiva (RO) se define como una RC o RP según RECIST v1.1 desde la primera dosis del tratamiento del estudio hasta la progresión de la enfermedad o la muerte por cualquier causa. Tanto la RC como la RP deben confirmarse mediante evaluaciones repetidas realizadas en no menos de 4 semanas después de que se cumplan los criterios de respuesta.
    Para pacientes con CPRCm: la respuesta objetiva (RO) se define como la proporción de pacientes con una mejor respuesta general de RC o RP en tejidos blandos según RECIST v1.1 desde la primera dosis de tratamiento hasta la progresión de la enfermedad o la muerte por cualquier causa.
    Para más detalles refierase al Protocolo.
    E.5.2Secondary end point(s)
    - Adverse Events as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.4.03), timing, seriousness, and relationship to study therapy.
    - Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v.4.03) and timing.
    - PK parameters including: pre-dose/trough concentrations (Ctrough) for avelumab and talazoparib and post-dose concentrations (for talazoparib) and
    maximum concentrations (Cmax) for avelumab.
    - Avelumab Anti-drug antibody (ADA) levels and neutralizing antibodies (Nab) against avelumab.
    - Confirmed OR as assessed by the investigator, using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1 and PCWG3.
    - Time to event endpoints: Endpoints as assessed by BICR and as assessed by the investigator, using RECIST v1.1 and in patients with mCRPC, RECIST v1.1 and PCWG3, including time to tumor response (TTR), duration of response (DR), and progression free survival (PFS). Additional time-to-event endpoints include overall survival (OS) for all patients and time to prostate-specific antigen (PSA) progression (≥ 25% increase) for mCRPC patients.
    - PSA response ≥ 50% decrease and CTC count conversion for patients with mCRPC.
    - Cancer antigen (CA)-125 response ≥ 50% decrease for patients with ovarian cancer.
    - PD-L1 expression level in baseline tumor tissue
    - Presence of defects in a panel of key oncogenes, including BRCA1/2 and ATM, and TMB in ctDNA and tumor tissue at baseline, during treatment, and at the end of treatment.
    -Acontecimientos adversos (AA) caracterizados por tipo, intensidad (según la clasificación de los Criterios terminológicos comunes para acontecimientos adversos del Instituto Nacional del Cáncer de EE. UU. [CTCAE del NCI], v.4.03), momento de aparición, gravedad y relación con el tratamiento del estudio.
    -Anomalías en los análisis caracterizadas por tipo, intensidad (según la clasificación de los CTCAE del NCI, v.4.03) y momento de aparición.
    -Parámetros FC, lo que incluye: concentraciones predosis/mínimas (Cmínima) de avelumab y talazoparib y concentraciones posdosis (de talazoparib) y concentraciones máximas (Cmáx) de avelumab.
    -Concentraciones de anticuerpos antifármaco (AAF) contra avelumab y de anticuerpos neutralizantes
    (AcN) contra avelumab.
    -RO confirmada evaluada por el investigador, según RECIST v1.1 (Apéndice 3) y, en los pacientes con CPRCm, RECIST v1.1 y PCWG3 (Apéndice 5).
    -Criterios de valoración del tiempo hasta el acontecimiento: Criterios de valoración evaluados mediante RCIE y por el investigador, utilizando los criterios RECIST v1.1 (Apéndice 3) y, en pacientes con CPRCm, los criterios RECIST v1.1 y PCWG3 (Apéndice 5), incluidos el tiempo hasta la respuesta del tumor (TRT), la duración de la respuesta (DR) y la supervivencia sin progresión (SSP). Los criterios de valoración adicionales de tiempo transcurrido hasta el acontecimiento incluyen la supervivencia general (SG) de todos los pacientes y el tiempo hasta la progresión según el antígeno prostático específico (PSA) (incremento >/=25 %) en los pacientes con CPRCm.
    -Respuesta en el PSA con un descenso >/=50 % y conversión de la cifra de células tumorales circulantes (CTC) en los pacientes con CPRCm.
    -Respuesta en el antígeno de cáncer (CA)-125 con una disminución del >/=50 % en las pacientes con cáncer de ovario.
    -Grado de expresión de PD-L1 en el tejido tumoral inicial.
    -Presencia de defectos en un grupo de oncogenes clave, como BRCA 1/2 y ATM, y CMT en el ADNtc y en el tejido tumoral al inicio, durante el tratamiento y al final del tratamiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    multiple timepoints as per protocol
    Según 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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability, Immunogenicity
    Tolerabilidad, inmunogenética
    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 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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Argentina
    Belgium
    Denmark
    France
    Israel
    Italy
    Netherlands
    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
    End of trial in a Member State of the European Union (EU) is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State.
    End of trial in all other participating countries is defined as last subject last visit (LSLV).
    El fin de estudio en un estado miembo de la Unión Europea (UE) está definido como el momento en que se considera que se ha reclutado a un número suficiente de pacientes y completado el estudio como se indica en la solicitud de ética y reglamentación en el Estado miembro .
    El final del ensayo en todos los demás países participantes se define como la última visita del último sujeto (LSLV).
    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 months11
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days10
    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: 216
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 325
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 196
    F.4.2.2In the whole clinical trial 541
    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 Decision2019-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-26
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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