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    Summary
    EudraCT Number:2017-001455-32
    Sponsor's Protocol Code Number:WIN001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-01-17
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-001455-32
    A.3Full title of the trial
    A proof of concept study to explore safety and efficacy of tri-therapy approach in advanced/metastatic NSCLC and retrospectively assess the ability of integrated genomics and transcriptomics to match patients to the combination
    Prueba de concepto para evaluar la seguridad y eficacia de la triple terapia en el CPNM avanzado o metastásico y análisis retrospectivo de la eficacia del uso conjunto de la genómica y la transcriptómica para seleccionar la mejor terapia combinada para cada paciente.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Survival Prolongation by Rationale Innovative Genomics
    Prolongación de la supervivencia a través de los Fundamentos de la Genómica Innovadora
    A.3.2Name or abbreviated title of the trial where available
    SPRING
    A.4.1Sponsor's protocol code numberWIN001
    A.5.4Other Identifiers
    Name:IND numberNumber:131601
    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 SponsorWorldwide Innovative Network Association
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportARC foundation
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWorldwide Innovative Network Association
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street Address9 rue Guy Môquet
    B.5.3.2Town/ cityVillejuif
    B.5.3.3Post code94800
    B.5.3.4CountryFrance
    B.5.4Telephone number330604090029
    B.5.5Fax number330184108397
    B.5.6E-mailfanny.wunder@winconsortium.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 nameavelumab
    D.3.4Pharmaceutical form Concentrate for 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 INNAVELUMAB
    D.3.9.2Current sponsor codeavelumab
    D.3.9.3Other descriptive namebavencio
    D.3.9.4EV Substance CodeSUB180078
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Inlyta
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    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 nameaxitinib
    D.3.4Pharmaceutical form 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 INNAXITINIB
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeaxitinib
    D.3.9.3Other descriptive nameInlyta
    D.3.9.4EV Substance CodeSUB25427
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAXITINIB
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeaxitinib
    D.3.9.3Other descriptive nameInlyta
    D.3.9.4EV Substance CodeSUB25427
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 Ibrance
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    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 namepalbociclib
    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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.2Current sponsor codepalbociclib
    D.3.9.3Other descriptive nameIbrance
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ibrance
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    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 namepalbociclib
    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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.2Current sponsor codepalbociclib
    D.3.9.3Other descriptive nameIbrance
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    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 Ibrance
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    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 namepalbociclib
    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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.2Current sponsor codepalbociclib
    D.3.9.3Other descriptive nameIbrance
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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: 6
    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 Inlyta
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    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 nameaxitinib
    D.3.4Pharmaceutical form 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 INNAXITINIB
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeaxitinib
    D.3.9.3Other descriptive nameInlyta
    D.3.9.4EV Substance CodeSUB25427
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Patients with advanced/metastatic non-small cell lung cancer (NSCLC) with no documented targetable alterations (EGFR mutation, ALK translocation, ROS1 mutation if available or MET exon 14 skipping mutation if available)
    Pacientes con carcinoma pulmonar no microcítico (NSCLC) avanzado o metastásico sin alteraciones diana documentadas (mutación EGFR, translocación ALK, mutación ROS1 si está disponible o mutación por omisión del exón 14 de MET si está disponible)
    E.1.1.1Medical condition in easily understood language
    Lung cancer
    cancer de pulmón
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •To determine the safety of the tested 3-drug combination therapy based on NCI CTCAE v4.03 June 14, 2010,
    •To assess activity parameters, including response rate (RR) by RECIST 1.1, duration of response, progression-free survival (PFS), overall survival (OS),
    •To correlate clinical outcome with the predicted SIMS matching through a retrospective study.
    •Determinar la seguridad de la triple terapia combinada de acuerdo con los criterios CTCAE del NCI v4.03 del 14 de junio de 2010.
    •Evaluar los parámetros de actividad, incluida la tasa de respuesta (RR) según los criterios RECIST 1.1, la duración de la respuesta, la supervivencia libre de progresión (PFS), así como la supervivencia global (OS).
    •Determinar la correlación entre el resultado clínico y la asociación SIMS estimada mediante un estudio retrospectivo.
    E.2.2Secondary objectives of the trial
    •Describe any safety issues related to biopsy acquisition or tri-therapy,
    •Describe genomic/transcriptomic aberrations seen in NSCLC.
    •Describir aspectos de seguridad relacionados con la realización de biopsias o la triple terapia,
    •Describir las aberraciones genómicas/transcriptómicas halladas en el NSCLC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Age: Men and women aged >18 years,
    2.Signed written informed consent,
    3.Any histologic type of locally advanced or metastatic NSCLC,
    4.Life expectancy of ≥ 12 weeks,
    5.Measurable or evaluable (cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions which do not fulfill RECIST 1.1 criteria for measurable disease) lesions according to RECIST v1.1 criteria for phase 1 portion. For phase 2, all patients must have RECIST 1.1 measurable disease,
    6.Physiologic function:
    -Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused),
    -Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN,
    -Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
    7.Pregnancy and contraception:
    -Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential,
    -Contraception: Highly effective contraception for both male and female subjects throughout the study and for at least 90 days after avelumab treatment administration if the risk of conception exists.
    8.Ability to comply with protocol requirements,
    9.Willingness to consent and ability to undergo a trucut biopsy to obtain tumor tissue from metastasis or primary tumor in case no adequate tumor tissue is available, and to undergo a bronchoscopy in order to obtain normal bronchial mucosa,
    10.No serious or medically uncontrolled concomitant conditions that are likely to make the patient unfit for SPRING combination therapy, as per investigator assessment,
    11.ECOG performance status of 0 to 1.
    •Edad: Hombres y mujeres mayores de 18 años
    •Firma del formulario de consentimiento informado
    •Cualquier tipo histológico de NSCLC localmente avanzado o metastásico,
    •Esperanza de vida de ≥ 12 semanas,
    •Lesiones medibles o evaluables (enfermedad detectable citológica o radiológicamente tales como ascitis, depósitos peritoneales o lesiones que no cumplan los criterios RECIST 1.1 para enfermedad medible) mediante los criterios RECIST v1.1 para la fase 1. Para la fase 2, todos los pacientes deberán presentar enfermedad medible con los criterios RECIST 1.1,
    •Función fisiológica:
     Hematológica: Número absoluto de neutrófilos ≥ 1.5 × 109 / L, recuento de plaquetas ≥ 100 × 109 / L y hemoglobina ≥ 9 g / dL (podrán haber recibido transfusión),
     Función hepática: Nivel total de bilirrubina ≤ 1.5 veces el límite superior del rango normal (LSN) y niveles de AST y ALT ≤ 2.5 veces el LSN,
     Función renal: Aclaramiento de creatinina estimada ≥ 30 ml / min según la fórmula de Cockcroft-Gault (o método estándar empleado en cada centro)
    •Embarazo y contracepción
    Prueba de embarazo: Prueba de embarazo en suero u orina negativa en el cribado de mujeres en edad fértil,
    Contracepción: Uso de métodos anticonceptivos altamente eficaces tanto en hombres como en mujeres a lo largo del estudio y durante al menos los 90 días posteriores a la última administración de avelumab, en caso de existir riesgo de concepción.
    •Capacidad para cumplir las condiciones del protocolo.
    •Dar el consentimiento para someterse a una biopsia trucut dirigida a obtener tejido tumoral de la metástasis o del tumor primario en caso de que no se disponga de tejido tumoral suficiente, así como someterse a una broncoscopia para obtener muestras de mucosa bronquial.
    •No padecer otras enfermedades concomitantes no controladas médicamente que, a juicio del investigador, hagan al paciente no apto para recibir la terapia combinada SPRING,
    •Estado funcional ECOG de 0 a 1.
    E.4Principal exclusion criteria
    -Patients with documented oncogenic aberrations at enrollment: EGFR, ALK, ROS1 when available, MET exon 14 skipping when available.
    Note: For Phase 1 portion, all patients with adenocarcinoma histology must have documentation of results for druggable oncogenic aberrations (EGFR mutations, ALK rearrangements, and ROS1 when available) prior to enrollment on the study.

    -For Phase 1 portion, >2 lines of prior therapy in the metastatic setting.

    -For the dose escalation phase of the study or until the MTD for the combination regimen has been determined, patients with moderate hepatic impairment defined as AST, ALT, ALP >5 times ULN, which would be grade 3 or higher. However patients with liver metastases with AST/ALT ≤ 5 x ULN can be included in the study.

    -For Phase 2 portion, any prior therapy in the metastatic setting.

    Clinical exclusion criteria for Phase 1 and Phase 2 studies:
    1.Documented untreated central nervous system metastases (indicated by clinical symptoms, cerebral edema, steroid requirement, or progressive disease in the prior four weeks),
    2.Participants with a history of myocardial infarction within the last 2 years or with significant cardiac arrhythmias uncontrolled by medication or pacemaker,
    3.Participants with any history of interstitial lung disease,
    4.Prior clinically significant toxicities from anticancer agents or radiotherapy which have not regressed to Grade ≤ 1 severity (NCI-CTCAE version 4.03) apart from peripheral neuropathy and alopecia,
    5.History of any second malignancy in the last two years; patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease-free for at least two years,
    6.Autoimmune condition requiring medical intervention,
    7.Uncontrolled concomitant illness, active infection requiring i.v. antibiotics,
    8.Participants who are at risk for, or who have a history of arterial thromboembolic events within the past 12 months and/or venous thromboembolic events within the past 6 months, or have had any recent active gastrointestinal bleeding,
    9.Prior > G3 hemoptysis, major blood vessel involvement, and/or central cavitations,
    10.Known or suspected drug hypersensitivity to any drug used in the combination,
    11.Difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the oral drugs,
    12.Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the investigator may affect the patient’s ability to sign the informed consent and undergo study procedures,
    13.Taking another experimental drugs within 28 days prior to day 1 of the protocol medications in this study,
    14.Pregnant or breast-feeding women,
    15.Both male and female patients of reproductive potential must agree to use a reliable method of birth control, during the study and for 3 months following the last dose of study drug,
    16.Patients currently taking strong CYP3A4 inducers and inhibitors.
    17.Patients currently taking proton pump inhibitors due to their impact on the disposition of palbociclib during the dose escalation phase,
    18.Other anticancer agents and anticoagulants are excluded (except for low doses of anticoagulants used for access lines),
    19.A time period of at least three weeks or five drug half-lives, whichever is shorter must have elapsed from last non-investigational therapy before 1 day of treatment on this study,
    Specific exclusion criteria for administration of avelumab, in combination:
    -IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, with exceptions detailed in protocol.
    -AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent, with exceptions detailed in protocol.
    -ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell transplantation.
    -INFECTIONS: Active infection requiring systemic therapy.
    -HIV/AIDS: Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
    -HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening.
    -VACCINATION: Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
    -HYPERSENSITIVITY TO STUDY DRUG.
    -CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular disease.
    -OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1) with exceptions detailed in protocol.
    -Other severe acute or chronic medical conditions or psychiatric conditions or laboratory abnormalities.
    •Pacientes con aberraciones oncogénicas documentadas en el momento de inclusión: EGFR, ALK, ROS1 cuando está disponible, MET exón 14 omisión cuando está disponible.
    •Para la fase 1 del estudio, >2 líneas previas de terapia en el contexto metastásico,
    •Para la fase del estudio de escalado de dosis o hasta que se haya determinado la MTD para el régimen de combinación, los pacientes con insuficiencia hepática moderada
    •Para la cohorte del estudio en fase 2, cualquier terapia previa en el contexto metastásico.
    Criterios clínicos de exclusión para las cohortes en fase 1 y 2:
    •Metástasis documentadas no tratadas del sistema nervioso central
    •Los participantes con antecedentes de infarto de miocardio en los últimos 2 años o con arritmias cardíacas significativas no controladas con medicación o marcapasos,
    •Los participantes con antecedentes de enfermedad pulmonar intersticial,
    •Toxicidades clínicas significativas previas por agentes anticancerosos o radioterapia que no hayan retrocedido a un grado de gravedad ≤ 1 (CTCAE del NCI versión 4.0) aparte de neuropatía periférica y alopecia,
    •Antecedentes de otro tumor maligno en los dos últimos años; con excepciones descritas en el protocolo.
    •Enfermedad autoinmune que requiera intervención médica,
    •Enfermedad concomitante no controlada, infección activa que requiera antibióticos por vía intravenosa,
    •Los participantes que estén en riesgo o que tengan antecedentes de eventos tromboembólicos arteriales en los últimos 12 meses y / o acontecimientos tromboembólicos venosos en los últimos 6 meses, o que hayan tenido alguna hemorragia gastrointestinal activa reciente,
    •Antecedentes de Hemoptisis> G3, afectación importante de los vasos sanguíneos y / o cavitaciones centrales
    •Hipersensibilidad conocida o sospechada a alguno de los fármacos incluidos en la terapia combinada,
    •Dificultad para tragar, malabsorción u otra enfermedad gastrointestinal crónica, o afecciones que puedan obstaculizar el cumplimiento y / o la absorción de los fármacos orales,
    •Cualquier circunstancia (p.ej. conocimiento o sospecha de un mal cumplimiento del tratamiento, inestabilidad psicológica, localización geográfica, etc.) que, a juicio del investigador, pudiera limitar la capacidad del pacientes para firmar el consentimiento informado y someterse a los procedimientos del estudio,
    •Toma de cualquier otro fármaco experimental en los 28 días previos al día 1 del tratamiento en estudio.
    •Mujeres embarazadas o en periodo de lactancia,
    •Tanto los hombres como las mujeres en edad fértil deberán comprometerse a emplear un método anticonceptivo fiables durante el estudio y durante los tres meses posteriores a la última dosis del fármaco en estudio,
    •Pacientes en tratamiento actual con inductores e inhibidores potentes de CYP3A4.
    •Pacientes en tratamiento actual con inhibidores de la bomba de protones debido a su impacto en la eliminación del palbociclib durante la fase de aumento de dosis,
    •Se excluyen otros agentes anticancerosos y anticoagulantes (excepto las dosis bajas usadas en las líneas de acceso),
    •Deberán haber transcurrido al menos tres semanas o cinco vidas medias de los fármacos empleados (lo que sea más corto) desde la última terapia no experimental previa al día 1 del tratamiento en estudio.
    •Criterios específicos de exclusión para la administración de avelumab, en combinación con:
    -INMUNOSUPRESORES: Uso actual de inmunosupresores, con excepciones detalladas en el protocolo 
    -ENFERMEDAD AUTOINMUNE: Enfermedad autoinmune activa que pudiera empeorar al recibir un agente inmunoestimulador. Serán elegibles los pacientes con diabetes tipo I, vitiligo, psoriasis o hipo o hipertiroidismo que no requieran tratamiento inmunosupresor.
    -TRASPLANTE DE ÓRGANOS: Receptor de órgano trasplantado incluyendo el trasplante alogénico de células madre.
    - INFECCIONES: Infección activa que requiera terapia sistémica.
    - VIH/SIDA: Antecedentes conocidos de resultado positivo en la prueba del HIV o conocimiento de presencia de síndrome de inmunodeficiencia adquirido.
    - HEPATITIS: Infección por virus de la hepatitis B (VHB) o virus de la hepatitis C (VHC) en el cribado (antígeno de superficie positivo para VHB o ARN del VHC si la prueba de detección del anticuerpo contra el VHC es positiva).
    - VACUNA: Se prohíbe toda vacunación en las cuatro semanas previas a la primera dosis de avelumab y durante el ensayo a excepción de las vacunas inactivadas.
    - HIPERSENSIBILIDAD AL FÁRMACO EN ESTUDIO: Hipersensibilidad grave conocida al producto experimental o a cualquiera de los componentes de su fórmula.
    - ENFERMEDAD CARDIOVASCULAR: Enfermedad cardiovascular clínicamente significativa.
    - OTRAS TOXICIDADES PERSISTENTES: Toxicidad persistente relacionada con una terapia anterior 
    -Serán excluidos los pacientes que presenten otras enfermedades médicas graves, agudas o crónicas o anomalías analíticas.
    E.5 End points
    E.5.1Primary end point(s)
    •To determine the safety of the tested 3-drug combination therapy based on NCI CTCAE v4.03 June 14, 2010, patients with advanced/metastatic NSCLC with no documented targetable alterations (EGFR, ROS1, MET exon 14 skipping mutation or ALK translocation) will receive a tri-therapy associating avelumab, axitinib and palbociclib. During the Phase 1, the tri-therapy will be tested at different doses following a specific dose-escalation scheme in order to establish the safety and identify the recommended dose (RP2D) for the Phase 2. The phase 2 will confirm the safety and will assess the efficacy of the tri-therapy approach in the treatment of advanced/metastatic NSCLC. Endpoints related to safety include an evaluation of Dose-Limiting Toxicities (DLTs), overall safety and parameters related to the optimal biological dose with RP2D. The Maximal Tolerated Dose (MTD) evaluation will be based on the DLT evaluable population. The optimal biological dose will be determined based upon analysis of all subject data, including safety and response data Endpoints for safety profile include assessments of AEs, SAEs, laboratory evaluations, vital signs, and physical examinations. Toxicities will be carefully monitored following the investigator brochure of each drug and the recommendations detailed in the protocol for dose modification or discontinuation. A data safety monitoring board will review the overall patient safety during the trial, starting from the phase 2.
    The occurrence of AEs, abnormal laboratory values, and SAEs reported from the signing of an informed consent through 90 days after the last administration of the treatment will be summarized for all subjects who received at least one dose of the study treatment (safety population).
    To determine the drug levels in blood and their interaction in combination, blood collections will be performed on Day 15’s visit (corresponding to the second injection of avelumab) of each cycle during phase 1, for each dose level and every two cycles during the phase 2. The apparition of auto-antibodies against avelumab will be monitored during the phase 2 at day 15 every two cycles.

    •To assess the efficacy, evaluation will be based on following assessments according to RECIST 1.1 criteria: Best Overall Response, 6-month Response, Progression-Free Survival and Overall Survival (date of death of the patient will be collected). Patients will be considered evaluable if they received at least one cycle of treatment and had their baseline scan within 28 days of the start of therapy and follow-up scans about every 8 weeks (+/- 7 days) thereafter.

    •To correlate clinical outcome with the predicted SIMS matching a retrospective study will be conducted.
    The trial will be considered as meeting its primary endpoint if a 6-month response rate (% of patients achieving RECIST 1.1 complete or partial response within 6 months of treatment start) of 50% is achieved for patients who are fully matched according to the SIMS retrospective analysis and is superior to the partially matched arms. With a type I error of 10% and a power of 94%, 20 patients fully matched will be enough to demonstrate the usefulness of the approach assuming a null response rate of 20% based on the one-sided Fisher’s exact test. This would require a cohort of 200 patients treated. Nevertheless, we intend to treat an initial cohort of 100 patients as an exploratory observational study. Pending clinical activity, the study could be extended to an additional 100 patients treated in order to attain sufficient statistical power to support the validity of the approach.
    SIMS will show clinical utility: If the proportion of patients fully matched to the combination versus partially matched estimated using SIMS (20/80) is similar to the observed proportion in the SPRING cohort (maximum coefficient variability allowed 20%) and if fully matched patients show significantly better clinical outcomes than the partially matched ones and the fully or partially matched ones show significantly better clinical outcomes than the non-matched ones.
    •Para determinar la seguridad de la triple terapia en estudio según los criterios CTCAE del NCI v4.03 del 14 de junio de 2010, los pacientes con carcinoma pulmonar no microcítico (CPNM) avanzado o metastásico sin alteraciones tratables documentadas (mutación de salto en el exón 14 de MET, EGFR, o ROS1, o translocación en ALK) recibirán una triple terapia de avelumab más axitinib más palbociclib. Durante la fase 1, la triple terapia se probará a diferentes dosis tras un régimen de aumento progresivo de dosis, con el fin de determinar la seguridad e identificar la dosis recomendada (RP2D) para la fase 2. En la fase 2 se confirmará la seguridad y evaluará la utilidad clínica de la triple terapia en el tratamiento del CPNM avanzado o metastásico.
    Entre los criterios de valoración relacionados con la seguridad se incluye una evaluación de las toxicidades limitantes de dosis (TLD), la seguridad global y los parámetros relacionados con la dosis biológica óptima con RP2D. La dosis máxima tolerada se basará en la población con una TLD evaluable. La dosis biológica óptima se determinará según el análisis de los datos procedentes de todos los sujetos, incluyendo los datos de respuesta y seguridad. Entre los criterios de evaluación del perfil de seguridad se encuentran las evaluaciones de eventos adversos, eventos adversos graves, análisis de laboratorio, signos vitales y exámenes físicos. Se llevará a cabo un estrecho seguimiento de las toxicidades de cada fármaco siguiendo las instrucciones para la modificación o interrupción de dosis detalladas en el protocolo y en el folleto del investigador. A partir de la fase 2, un comité independiente de vigilancia de datos y seguridad (DSMB) supervisará la seguridad general de los pacientes durante el ensayo. Aplicable a todos los sujetos que recibieron al menos una dosis del tratamiento en estudio (población de seguridad), y tras la firma del consentimiento informado correspondiente, se registrará la incidencia de eventos adversos, resultados analíticos alterados, y eventos adversos graves mediante en los 90 días posteriores a la última dosis del tratamiento.
    Para determinar los niveles de cada fármaco en sangre, su interacción cuando se combinan y la aparición de anticuerpos, se tomarán muestras de sangre en la visita del Día 15 (coincidente con la segunda inyección de avelumab) de cada ciclo durante la fase 1, para cada nivel de dosis, y cada dos ciclos durante la fase 2.
    En la fase 2, en el día 15 cada dos ciclos, se vigilará la aparición de autoanticuerpos contra avelumab.
    •La eficacia del tratamiento se determinará mediante la evaluación de los siguientes parámetros conforme a los criterios RECIST 1.1: Mejor respuesta global, respuesta a los seis meses, supervivencia libre de enfermedad y supervivencia global (se registrará la fecha de fallecimiento del paciente). Se considerará que los pacientes son evaluables si han recibido al menos un ciclo de tratamiento y se les realizó la tomografía computarizada basal en los 28 días previos al inicio de la terapia y a continuación cada 8 semanas (+/- 7 días).
    •Para determinar la correlación entre el resultado clínico y la asociación SIMS estimada, se realizará un estudio retrospectivo. Se considerará que el ensayo ha cumplido su objetivo principal si se alcanza una tasa de respuesta a los seis meses (porcentaje de pacientes que logran una respuesta completa o parcial según los criterios RECIST 1.1 en los seis meses posteriores al inicio del tratamiento) del 50% en los pacientes para los que se encontró una correspondencia terapéutica completa en el análisis retrospectivo con el SIMS, y dicha tasa es superior a la de los pacientes con correspondencia parcial. Con un error tipo I del 10% y una potencia estadística del 94%, bastará con 20 pacientes con correspondencia completa para demostrar la utilidad de la técnica, asumiendo una tasa de respuesta nula del 20% medida mediante la prueba exacta de Fisher unilateral. Para ello, será necesaria una cohorte de 200 pacientes tratados. No obstante, pretendemos tratar una cohorte inicial de 100 pacientes como estudio observacional exploratorio. A la espera de actividad clínica, se podría ampliar el estudio en unos 100 pacientes tratados adicionales con el fin de alcanzar suficiente potencia estadística que sustente la validez de la técnica. Se considerará que SIMS tiene utilidad clínica: Si la proporción de pacientes para los que se encontró una correspondencia terapéutica completa frente a aquellos con correspondencia parcial hallada empleando el sistema SIMS (20/80) es similar a la observada en la cohorte SPRING (con un coeficiente máximo de variabilidad permitido del 20%) y si los pacientes con correspondencia completa muestran resultados significativamente mejores que los pacientes con correspondencia parcial y los pacientes con correspondencia completa o parcial muestras resultados clínicos significativamente mejores que aquellos para los que no se encontró correspondencia.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety endpoints related to the phase 1 part will be analyzed through the study until the end of the phase 1. Analysis will continue during the phase 2 until the end.
    Efficacy endpoints will be analyzed according to the stopping rules described in the protocol. An interim analyses will be perform once 50 treated patients has been reached. Final analysis will be done at the end of the study.
    Correlation of the clinical outcome with the SIMS algorithm will be performed at the end of the study.
    Los criterios de valoración relacionados con la seguridad de la parte de fase 1 se analizarán durante el estudio hasta el final de la fase 1. El análisis continuará durante la fase 2 hasta el final.
    Los criterios de valoración de la eficacia se analizarán de acuerdo con las reglas de parada descritas en el protocolo. Se realizará un análisis intermedio una vez que se hayan alcanzado 50 pacientes tratados. El análisis final se realizará al final del estudio.
    La correlación del resultado clínico con el algoritmo SIMS se realizará al final del estudio.
    E.5.2Secondary end point(s)
    •Describe any safety issues related to biopsy acquisition or tri-therapy,
    •Describe genomic/transcriptomic aberrations seen in NSCLC.
    •Describir aspectos de seguridad relacionados con la realización de biopsias o la triple terapia,
    •Describir las aberraciones genómicas/transcriptómicas halladas en el NSCLC.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of the study.
    Al final del estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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
    Test of the Simplified Interventional Mapping System (SIMS) algorithm using genomic and transcriptomic data.
    Testar el algoritmo del Sistema Intervencionista Simplificado de Mapeo (SIMS) utilizando datos de genómica y transcriptómica.
    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
    Safety and efficacy of a treament combination
    Tolerabilidad y eficacia de una combinación de tratamientos
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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
    France
    Israel
    Luxembourg
    Spain
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 last patient 90-day follow-up visit after end of study treatment is defined as the last patient last visit.
    La última visita del último paciente es la visita del última paciente a los 90 días tras la última dosis de tratamiento.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 43
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 87
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 55
    F.4.2.2In the whole clinical trial 130
    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 Decision2018-04-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2022-12-29
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