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    Summary
    EudraCT Number:2018-003012-51
    Sponsor's Protocol Code Number:D5084C00007
    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:2019-04-12
    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 number2018-003012-51
    A.3Full title of the trial
    A Phase II, Single Arm Study Assessing the Efficacy of Osimertinib in Combination with Savolitinib in Patients with EGFRm+ and MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer who have Progressed Following Treatment with Osimertinib
    Ensayo fase II, de un solo brazo, para evaluar la eficacia de Osimertinib en combinación con Savolitinib en pacientes con cáncer de pulmón no microcítico localmente avanzado o metastásico, con mutación EGFRm positivo y MET positivo, que hayan progresado después de un tratamiento con Osimertinib (ensayo SAVANNAH).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Osimertinib plus savolitinib in patients with EGFRm+/MET+ non small cell lung cancer following prior osimertinib
    Osimertinib en combinación con Savolitinib en pacientes con cáncer de pulmón no microcítico localmente avanzado o metastásico, con mutación EGFRm positivo y MET positivo después de un tratamiento con Osimertinib.
    A.3.2Name or abbreviated title of the trial where available
    SAVANNAH
    A.4.1Sponsor's protocol code numberD5084C00007
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03778229
    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
    B.5.2Functional name of contact pointInformation Centre
    B.5.3 Address:
    B.5.3.1Street AddressNot applicable
    B.5.3.2Town/ cityNot applicable
    B.5.3.3Post code19803
    B.5.3.4CountryUnited States
    B.5.6E-mailinformationcentre@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 Yes
    D.2.1.1.1Trade name TAGRISSO
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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 nameosimertinib
    D.3.2Product code AZD9291
    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 INNOsimertinib
    D.3.9.1CAS number 1421373-65-0
    D.3.9.2Current sponsor codeAZD9291
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 TAGRISSO
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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 nameosimertinib
    D.3.2Product code AZD9291
    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 INNOsimertinib
    D.3.9.1CAS number AZD9291
    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.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 nameSavolitinib
    D.3.2Product code AZD6094
    D.3.4Pharmaceutical form 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 INNSavolitinib
    D.3.9.1CAS number 1313725-88-0
    D.3.9.3Other descriptive nameSAVOLITINIB
    D.3.9.4EV Substance CodeSUB181945
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 nameSavolitinib
    D.3.2Product code AZD6094
    D.3.4Pharmaceutical form 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 INNSavolitinib
    D.3.9.3Other descriptive nameSAVOLITINIB
    D.3.9.4EV Substance CodeSUB181945
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    EGFRm+ and MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer
    Cáncer de pulmón no microcítico localmente avanzado o metastásico, con mutación EGFRm positivo y MET positivo
    E.1.1.1Medical condition in easily understood language
    Non-Small Cell Lung Cancer
    Cáncer de pulmón no microcítico
    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 efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+ (determined centrally by FISH), locally advanced or metastatic NSCLC who have progressed on osimertinib.
    Determinar la eficacia de savolitinib en combinación con osimertinib en pacientes con cáncer de pulmón no microcítico localmente avanzado o metastásico, con mutación EGFRm positivo y MET positivo (determinado centralmente mediante FISH), que hayan progresado con osimertinib.
    E.2.2Secondary objectives of the trial
    - To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+ (determined centrally by FISH and centrally confirmed by IHC and in all patients) locally advanced or metastatic NSCLC who have progressed on osimertinib.

    - To assess the impact of savolitinib and osimertinib on disease related symptoms and HRQoL in this patient population (in patients MET+ by FISH, MET+ by IHC and in all patients).

    - To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population (all patients).

    - To determine the rate of ctDNA clearance after osimertinib and savolitinib treatment in this patient population (in patients MET+ by FISH, MET+ by IHC and in all patients).

    - To evaluate the safety and tolerability of savolitinib in combination with osimertinib.
    Determinar la eficacia de savolitinib en combinación con osimertinib en pacientes con CPNM localmente avanzado o metastásico, con EGFRm+ y MET+ (evaluados centralmente mediante FISH y confirmados por immunohistoquímica en todos los pacientes), que hayan progresado con osimertinib
    -Valorar el impacto de savolitinib y osimertinib en los síntomas relacionados con la enfermedad y la calidad de vida relativa a la salud en esta población (en pacientes con mutación MET+ según FISH, con mutación MET+ según immunohistoquímica, y en todos los ptes)
    -Evaluar la farmacocinética de osimertinib y savolitinib en esta población de pacientes (todos los pacientes)
    -Evaluar el ratio de aclaramiento del ADN circulante tumoral después de un tto con osimertinib y savolitinib en esta población de pacientes (en pacientes con mutación MET+ según FISH, con mutación MET+ según immunohistoquímica, y en todos los pacientes).
    -Evaluar la seguridad y tolerabilidad de savolitinib en combinación con osimertinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients must be ≥18 years of age (≥20 years of age in Japan). All genders are permitted.

    - Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity (including either exon 19 deletion and/or L858R) which is not amenable to curative therapy.

    - Documented radiologic disease progression following treatment with osimertinib (osimertinib does not need to be the most recent therapy).

    - MET amplification/high expression as determined by FISH (central), IHC (central) or NGS (local) testing on tumour tissue collected following progression on prior osimertinib treatment.

    - Available tissue from a biopsy for MET analysis or willingness to collect additional tissue for central testing which fulfils the following requirements: obtained within 2 years of submission for MET analysis; sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory Manual.

    - At least 1 lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is suitable for accurate repeated measurements.

    - Received at least 1 but no more than 3 prior lines of therapy (may include investigational therapy) in the locally advanced/metastatic setting.
    - No more than one prior line of chemotherapy regimen
    - A chemotherapy regimen including a programmed cell death-1 (PD1) or a PD1 ligand 1 (PD L1) agent is acceptable, provided it was not the most recent line of therapy.
    - No more than 2 prior lines of therapy containing EGFR TKI are acceptable

    - Adequate haematological function defined as:
    - Absolute neutrophil count ≥1500/μL
    - Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks)
    - Platelets ≥100,000/μL (no transfusion in the past 10 days)

    - Adequate liver function
    - ALT, AST ≤2.5 x ULN with total bilirubin ≤ ULN
    OR
    - Total bilirubin >ULN to ≤1.5x ULN with ALT and AST ≤ ULN

    - Adequate renal function - creatinine <1.5 times the institutional ULN OR a glomerular filtration rate ≥50 mL/min. Confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.

    - Adequate coagulation parameters - INR <1.5 x ULN and activated partial thromboplastin time <1.5 x ULN unless patients are receiving therapeutic anti coagulation which affects these parameters.

    - Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for ≥2 weeks.

    - ECOG/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.

    - Females of childbearing potential must be using highly effective contraceptive measures and have a negative pregnancy test.

    - Males with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug.
    -Pacientes de 18 años o más de cualquier género
    -CPNM localmente avanzado o metastásico con mutación EGFR+ confirmado histológicamente o citológicamente albergando una mutación EGFR conocida asociada con la sensibilidad al inhibidor de la tirosina kinasa del receptor del factor de crecimiento epidérmico.
    -Progresión de la enfermedad documentada radiológicamente tras el tratamiento con osimertinib (no es necesario que osimertinib sea el tratamiento más reciente)
    -Amplificación/elevada expression de MET determinda por FISH (central), Immunohistoquímica (central) o NGS (local), testados en muestras obtenidas de tejido tumoral después de una progresión con tratamiento previo de osimertinib
    -La muestra de tejido biopsiado disponible para el análisis de MET o la muestra adicional de tejido opcional recogida para el análisis central tiene que cumplir los siguientes requisitos: obtenida durante los 2 años desde el envío para el análisis de MET, suficiente tejido para alcanzar el mínimo requerimiento tisular definido en el manual de laboratorio en vigor.
    -Al menos 1 lesión, no irradiada previamente, no biopsiada durate el periodo de selección, que pueda ser medida apropiadamente en el momento basal como > o = 10 mm en el diámetro mayor (excepto nódulos linfáticos, que deben tener un eje corto > ó = 15mm) con TC o RM que son los métodos preferidos para valoraciones precisas repetidas.
    -Haber recibido al menos 1 y no más de 3 líneas de tratamiento previas (puede incluir tratamiento experimental) en la lesión localmente avanzada / metastásica.
    - No más de una línea de régimen de tratamiento previo de quimioterapia
    - Es aceptable un régimen de tratamiento de quimioterapia incluyendo muerte celular programada -1 (PD1) o un agente asociado 1 a la muerte celular programada (PDL1), siempre que no sea la línea de tratamiento más reciente.
    - No se aceptan más de 2 líneas de tratamiento previas que contengan EGFR-TKI
    -Función hematológica adecuada, definida como:
    -Recuento absoluto de neutrófilos > o = 1500 μL
    - Hemoglobina >/= 9 g/dL (sin transfusiones las 2 semanas anteriores)
    - Plaquetas >/=100.000/ μL (sin transfusión los 10 días anteriores)
    - Función hepática adecuada:
    - ALT, AST</=2,5 LSN (Límite superior de la normalidad) con una bilirrubina total </= LSN
    Ó
    -Bilirrubina total > LSN a </= 1,5 x LSN con ALT y AST </= LSN
    - Función renal adecuada – creatinine < 1,5 veces el LSN institucional o una tasa de filtración glomerular >/= 50 mL/min. Solo se requerirá confirmación del aclaramiento de la creatinina cuando la creatinina sea > 1,5 veces el LSN.
    - Parámetros de coagulación adecuados – INR < 1,5 x LSN y tiempo de activación de la tromboplastina parcial < 1,5 x LSN a no ser que los pacientes estén recibiendo tratamiento anticoagulante que afecte a estos parámetros.
    - Son elegibles los pacientes con trombo tumoral conocido o trombosis venosa profunda si son clínicamente estables o han recibido heparina de bajo peso molecular durante 2 semanas o más.
    - Estado funcional según ECOG/WHO de 0 ó 1 sin deterioro durante las 2 semanas previas y una esperanza de vida mínima de 12 semanas.
    - Mujeres potencialmente fértiles deberán usar métodos anticonceptivos de alta eficacia y tener un test de embarazo negativo.
    - Hombres con parejas que sean mujeres potencialmente fértiles deberán estar dispuestos a usar métodos anticonceptivos de barrera durante el ensayo y los 6 meses siguientes a la finalización del tratamiento del ensayo.
    E.4Principal exclusion criteria
    - Unresolved toxicities from any prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum therapy related neuropathy.

    - As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection).

    - Any of the following cardiac diseases currently or within the last 6 months:
    Unstable angina pectoris
    Congestive heart failure (New York Heart Association [NYHA] ≥Grade 2)
    Acute myocardial infarction
    Stroke or transient ischemic attack
    Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy).
    Mean resting correct QT interval (QTcF) >470 msec for women and >450 msec for men at

    Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value.
    Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events such as heart failure, chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
    Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval >250 msec.
    Acute coronary syndrome

    - Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy.

    - Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days

    - Evidence of severe or uncontrolled systemic diseases, including renal transplant, active bleeding diatheses or uncontrolled hypertension, which in the investigator’s opinion makes it undesirable for the patient to participate

    - Active hepatitis B or C

    - Known serious active infection e.g. tuberculosis or human immunodeficiency virus

    - Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.

    - Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study treatment.

    - Past medical history of interstitial lung disease(ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

    -Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values
    Absolute neutrophil count <1.5 x 109/L
    Platelet count <100 x 109/L
    Haemoglobin <90 g/L

    - Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib.

    - Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).

    - Patients who have received ≥4 lines of systemic therapy for NSCLC.

    - Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days prior to the first dose of study treatment with the exception of monotherapy osimertinib which may continue uninterrupted during screening.

    - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers or strong inhibitors of CYP3A4, strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks of the first dose of study treatment (3 weeks for St John’s Wort).

    - Warfarin is not permitted (low molecular weight heparin is allowed).

    - Participation in another clinical study with a cytotoxic, investigational product (IP), or other anticancer drug for the treatment of advanced NSCLC if received IP from that study within 14 days of the first dose of study treatment.

    - Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.
    Toxicidades no resueltas de algún tto previo <grado 1 CTCAE al inicio del tto del ensayo excepto alopecia, y neuropatía relacionada con tto de platino previo de grado 2
    A criterio del investigador, enfermedad gastrointestinal activa u otra condición que pueda interferir significativamente con la absorción, distribución, metabolismo, o excreción de tto oral (p. ej. Úlcera, nauseas incontroladas, vómitos, diarrea de grado >/=2, absorción intestinal insuficiente o resección de intestino significativa previa
    Cualquiera de las sig enfermedades cardiacas actuales o en los últimos 6 meses:
    -Angina de pecho inestable
    -Fallo cardiaco congestivo (NYHA Grado ≥ 2)
    -Infarto agudo de miocardio
    -Apoplejía o ataque isquémico transitorio
    Hipertensión no controlada (BP ≥150/95 mmHg a pesar de terapia médica)
    Intervalo medio QT en reposo correcto (QTcF) >470 msec para mujeres y >450 msec para hombres en la selección, obtenidos en 3 ECGs utilizando el valor QTcF derivado mediante equipo de ECG clínico para selección
    Cualquier factor que pueda incrementar el riesgo de prolongación de la QTcF o el riesgo de acontecimientos de arritmias como fallo cardiaco, hipocaliemia crónica no corregible con suplementos, síndrome de QT largo congénito o familiar, antecedentes familiares de muerte súbita de causa desconocida antes de los 40 años de edad en familiares de 1er grado o cualquier medicación concomitante que se conozca prolonga el intervalo de QT y cause taquicardia ventricular
    -Cualquier trastorno importante en el ritmo, conducción o morfología en el ECG en reposo, ej. bloqueo fascicular anterior y fascicular posterior, bloqueo cardiaco de 3er grado, bloqueo cardiaco de 2do grado, intervalo P-R >250 mseg.
    -Síndrome coronario agudo
    -Radioterapia de campo amplio (incluiyendo radiosótopos terapéuticos como el strontium 89) administrado >/= 28 días, o radiación de campo limitado para la paliación >/= 7 días antes del inicio del tto del ensayo, o no haberse recuperado de los efectos secundarios de esta terapia
    -Cirugía mayor en los 28 días o menor en los 7 días desde el comienzo del tto del ensayo
    -Evidencia de enfermedades sistémicas graves o no controladas, incluyendo trasplante renal, diatesis de sangrado activo o hipertensión no controlada, que a juicio del investigador hacen que no sea recomendable que el pte participe
    -Hepatitis B o C activa
    -Infección activa grave conocida ej. Tuberculosis o virus de inmunodeficiencia humana
    -Presencia de otros canceres activos, o antecedentes de tto para cáncer invasivo en los últimos 5 años. Son elegibles los ptes con cáncer de estadío I que hayan recibido tto local definitivo al menos en los 3 años previos, y se considera poco probable que se repita. Son elegibles todos los ptes con carcinoma previamente tratados in situ (ej, no invasivo), como son los ptes con antecedentes de cáncer de piel no melanoma
    -Compresión de la médula espinal o metástasis cerebral menos asintomáticos, estables y que no requieran esteroides al menos en las 2 semanas previas al inicio del tto del ensayo
    -Antecedentes de ILD, ILD inducida por medicamentos, neumonitis por radiación que haya requerido tto con esteroides, o cualquier evidencia de ILD activa clínicamente
    -Reserva inadecuada de la médula ósea o función de los órganos diagnosticada por cualquiera de los siguientes valores de laboratorio:
    Recuento absoluto de neutrófilos <1,5 x 109/l
    Recuento de plaquetas < 100 x 109/l
    Hemoglobina <90 g/l
    -Tto previo o actual con inhibidor de la tirosina kinasa EGFR de 3ª generación distinto a osimertinib.
    -Tto previo o actual con savolitinib u otro inhibidor de MET (ej. foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib)
    -Ptes que hayan recibido tto >/= 4 líneas de tto sistémico para CPNM
    -Cualquier quimioterapia citotóxica, agentes de investigación u otros medicamentos para el cáncer para el tto del CPNM avanzado de un régimen de tto o ensayo clínico previo en los 14 días anteriores a la 1ra dosis del tto del ensayo, con la excepción de osimertinib en monoterapia que podría continuar ininterrumpidamente durante la selección
    -Ptes que estén recibiendo en la actualidad (o que no puedan dejar de recibir antes de la primera dosis del tto del ensayo) medicamentos o complementos herbarios conocidos como inductores fuertes o inhibidores fuertes de CYP3A4, inhibidores fuertes de CYP1A2, o sustratos CYP3A4 que tengan un rango terapéutico estrecho, durante las 2 semanas de la primera dosis del tto del ensayo (3 semanas para hierba de San Juan)
    -No está permitida la Warfarina (si está permitida la heparina de bajo peso molecular)
    -Participación en otro ensayo clínico con un citotóxico, producto en investigación (PI), u otro tto contra el CPNM si se ha recibido algún PI de ese ensayo en los 14 días antes de la primera dosis del tto del ensayo
    -Hipersensibilidad conocida a los excipientes activos o inactivos de osimertinib o savolitinib o a medicamentos con estructura o clase química similar
    E.5 End points
    E.5.1Primary end point(s)
    Overall Response Rate (ORR) by investigator assessment in accordance with RECIST 1.1
    Tasa de respuestas objetivas basada en la valoración del investigador conforme a los criterios RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of ORR will occur when all patients have had the opportunity to be treated for 6 months. The final analysis of ORR will occur when 70% of patients have progressive disease or have died or 18 months after the last patient in (which ever occurs first).
    El análisis principal de la tasa de respuestas objetivas se realizará cuando todos los pacientes hayan tenido la oportunidad de recibir tratamiento durante 6 meses. El análisis final de la tasa de respuestas objetivas se realizará cuando el 70% de los pacientes hayan progresado o fallecido, o 18 meses después de la inclusión del último paciente (lo que ocurra antes).
    E.5.2Secondary end point(s)
    - ORR by investigator assessment in accordance with RECIST 1.1.

    - PFS by investigator assessment in accordance with RECIST 1.1.
    OS
    DoR
    Percentage change in tumour size by investigator assessment in accordance with RECIST 1.1.

    - Mean change from baseline in EORTC QLQ-C30 and QLQ-LC13.

    - Plasma concentrations of osimertinib, savolitinib and their metabolites.

    - Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).

    - AEs, SAEs and discontinuation rate due to AEs.
    Clinical chemistry/haematology including LFTs.
    ECHOs, ECGs and vital signs including blood pressure and heart rate.
    Tasa de respuestas objetivas valorada por el investigador conforme a los criterios RECIST 1.1
    Supervivencia libre de progresión (SLP) valorada por el investigador conforme a los criterios RECIST 1.1
    Supervivencia global
    Duración de la respuesta
    Cambio porcentual en el tamaño del tumor valorada por el investigador conforme a los criterios RECIST 1.1
    Cambio significativo desde el momento basal en EORTC QLQ-C30 y QLQ-LC13.
    Concentración en plasma de osimertinib, savolitinib y sus metabolitos.
    Tolerancia total en mutaciones EGFR y 6 semanas después del inicio del tratamiento (porcentanje y cambio absoluto desde el momento basal en frecuencia alélica de la mutación EGFR).
    - AAs, AAGs y tasa de retirada debido a Aas.
    Química clínica / hematología incluyendo test de función hepática.
    Ecocardiogramas, ECGs y signos vitales incluyendo presión sanguínea y frecuencia cardiaca.
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR & PFS: baseline; every 6 weeks after treatment start until Cycle 7 (C7), then every 8 weeks until disease progression. Survival follow-up every 12 weeks.

    EORTC QLQ-C30 and QLQ-LC13: baseline; QLQ-C30 every 4 weeks after treatment start, QLQ-LC13 weekly after treatment start in C1 and C2, then every 4 weeks from C3 onwards; 7 days after treatment discontinuation.

    Plasma concentrations: C1 and C2 on Day 1 pre-dose, 1 hour and 3 hours post-dose; Day 1 of C3, 6, and 11; discontinuation visit.

    EGFR: Pre-dose on C1 Day 1; C1 Days 8, 15, 22; C2 Day 1; then at the time of every RECIST 1.1 scan

    AEs, vital signs, ECGs, safety labs at every clinic visit (every 7 during C1, every 28 during treatment (MUGA/ECHO every 12 weeks), 7 days after final dose, 28 day follow-up).
    Tasa de respuestas objetivas y SLP, cada 6 sem después del inicio del tto hasta C7, después cada 8 sem hasta progresión de enfermedad
    Seguimiento de supervivencia cada 12 sem
    EORTC QLQ-C30 y QLQ-LC13: basal, QLQ-C30 cada 4 sem después de inicio del tto, QLQ-LC13 semanal después de inicio de tto en C1 y C2, después cada 4 sem desde C3, y 7 días después de retirada
    Concentraciones de plasma: C1 y C2 en día 1 antes de dosis, 1 y 3 h después de dosis, día 1-C3, 6 y 11, v de retirada
    EGFR: Antes de dosis día 1-C1, C1 días 8, 15, 22; C2 día 1, después en momento de cada scaner RECIST 1.1.
    AAs, signos vitales, ECGs, análisis de seguridad de lab en cada visita (cada 7 durante C1, cada 28 durante tto (MUGA/Ecocardiograma cada 12 sem), 7 días después de última dosis, el día 28 de seguimiento)
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Health-related quality of life (HRQoL)
    Calidad de vida relativa a la salud
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the 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
    Brazil
    Canada
    Chile
    Denmark
    France
    India
    Israel
    Italy
    Japan
    Korea, Republic of
    Taiwan
    United States
    Vietnam
    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 end of study is defined as the last expected visit/contact of the last patient undergoing the
    study.
    El final del ensayo se define como la última visita prevista o contacto del último paciente participante en el ensayo.
    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 months5
    E.8.9.1In the Member State concerned days27
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days24
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 58
    F.4.2.2In the whole clinical trial 172
    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)
    Patients may continue to receive treatment with Osimertinib in combination with savolitinib despite disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator, and in the absence of discontinuation criteria.Treatment beyond progression with monotherapy Osimertinib is also available.
    Los pacientes podrán seguir recibiendo tratamiento con osimertinib en combinación con savolitinib aunque haya progresión de la enfermedad, si a criterio del investigador continúan mostrando beneficio clínico, y en ausencia de criterios de retirada. También estará disponible el tratamiento con osimertinib en monoterapia como tratamiento tras la progresión.
    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 Decision2019-05-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-10
    P. End of Trial
    P.End of Trial StatusOngoing
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