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    Summary
    EudraCT Number:2016-002778-11
    Sponsor's Protocol Code Number:E7080-G000-218
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-02-12
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-002778-11
    A.3Full title of the trial
    A Randomized, Open-label (formerly Double-blind), Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at Two Different Starting Doses (18 mg vs. 14 mg QD) in Combination with Everolimus (5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment
    Sperimentazione di Fase 2, randomizzata, in aperto (precedentemente in doppio cieco), per valutare la sicurezza e l'efficacia di Lenvatinib a due diverse dosi di partenza (18 mg vs 14 mg QD) in combinazione con Everolimus (5 mg QD) nel carcinoma delle cellule renali a seguito di un precedente trattamento mirato al VEGF
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Open-label (formerly Double-blind), Phase 2 Trial to investigate how safe and how efficacious Lenvatinib is at two different starting doses (18 mg vs. 14 mg QD) when it is given in Combination with Everolimus (5 mg once a day ) in patients with Renal cancer that have already had one VEGF-Targeted Treatment
    Sperimentazione di Fase 2, randomizzata,in aperto (precedentemente in doppio cieco), per valutare la sicurezza e l'efficacia di Lenvatinib a due diverse dosi di partenza (18 mg vs 14 mg QD) quando somministrato in combinazione con Everolimus (5 mg una volta al giorno) a pazienti con carcinoma a cellule renali che si sono già sottoposti a un trattamento mirato al VEGF
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberE7080-G000-218
    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 SponsorEISAI LIMITED
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Ltd
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportEisai Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Europe Ltd
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressEMEA Knowledge Centre, Mosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailEUMedInfo@eisai.net
    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 Kisplyx 4 mg
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe 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 nameLenvatinib
    D.3.2Product code [E7080]
    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 INNLenvatinib
    D.3.9.1CAS number 417716-92-8
    D.3.9.2Current sponsor codeE7080
    D.3.9.4EV Substance CodeSUB64419
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Kisplyx 10 mg
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe 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 nameLenvatinib
    D.3.2Product code [E7080]
    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 INNLenvatinib
    D.3.9.1CAS number 417716-92-8
    D.3.9.2Current sponsor codeE7080
    D.3.9.4EV Substance CodeSUB64419
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Afinitor 5 mg
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharma 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 nameAfinitor
    D.3.2Product code [-]
    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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.2Current sponsor code-
    D.3.9.4EV Substance CodeSUB02065MIG
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced renal cell carcinoma
    Carcinoma delle cellule renali avanzato
    E.1.1.1Medical condition in easily understood language
    Kidney cancer that has advanced and tumours are getting bigger
    Tumore renale progredito e tumori che diventano pi¿ grandi
    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 10038409
    E.1.2Term Renal cell carcinoma NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10038389
    E.1.2Term Renal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess whether a starting dose of lenvatinib 14 mg in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate [ORR] at 24 weeks[ORR24W]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment emergent intolerable Grade 2, or any = Grade 3 adverse events (AEs) in the first 24 weeks after
    randomization).
    Valutare se una dose iniziale di lenvatinib 14 mg in combinazione con everolimus 5 mg una volta al giorno (QD) garantisca un'efficacia paragonabile (in base al tasso di risposta obiettiva [ORR] a 24 settimane [ORR24W]) con un profilo di sicurezza migliore rispetto a lenvatinib 18 mg in combinazione con everolimus 5 mg (in base agli eventi avversi [AE] emergenti dal trattamento di Grado 2 intollerabili o = Grado 3 nelle prime 24 settimane dopo la randomizzazione).
    E.2.2Secondary objectives of the trial
    - To assess progression-free survival (PFS).
    - To assess ORR.
    - To determine the tolerability and safety profile of lenvatinib in combination with everolimus.
    - To assess the proportion of subjects who discontinued treatment due to toxicity.
    - To assess time to treatment failure due to toxicity.
    - To assess pharmacokinetic (PK) profiles of lenvatinib and everolimus during combination therapy and to assess PK and pharmacodynamic
    (PD) drug-drug interactions.
    - To evaluate overall survival (OS).
    - To evaluate the impact of disease and treatment on patients' Health Related Quality of Life (HRQoL) as assessed by using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS), the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European Quality of Life (EuroQol) EQ-5D-3L.
    - To evaluate the PFS after next line of treatment (PFS2).
    -Valutare la sopravvivenza libera da progressione (PFS).
    - Valutare l'ORR.
    -Stabilire tollerabilit¿ e profilo di sicurezza di lenvatinib in combinazione con everolimus.
    -Valutare la percentuale di soggetti che hanno interrotto il trattamento a causa di tossicit¿.
    - Valutare il tempo all'insuccesso del trattamento dovuto a tossicit¿.
    - Valutare i profili farmacocinetici (PK) di lenvatinib ed everolimus durante terapia di combinazione e valutare interazioni farmaco-farmaco di natura PK e farmacodinamica (PD).
    - Valutare la sopravvivenza globale (OS).
    - Valutare l'impatto della malattia e del trattamento sulla qualit¿ di vita correlata allo stato di salute (HRQoL) dei pz come stabilito usando la scala Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS), il questionario QLQ-C30 dell'Organizzazione europea EORTC e il questionario europeo sulla qualit¿ di vita (EuroQol) EQ-5D-3L.
    - Valutare la PFS dopo la successiva linea di trattamento (PFS2)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological or cytological confirmation of predominant clear cell RCC (original tissue diagnosis of RCC is acceptable).
    2. Documented evidence of advanced RCC.
    3. One prior disease progression episode on or after VEGF-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) administered for the treatment of RCC. Prior PD-1/PDL1 treatment in addition to 1 prior VEGF-targeted treatment is allowed.
    4. At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria:
    Lymph node (LN) lesion that measures at least 1 dimension as =1.5 cm in the short axis Non-nodal lesion that measures =1.0 cm in the longest diameter
    The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion.
    5. Male or female subjects age =18 years (or any age >18 years if that age is considered to be an adult per the local jurisdiction) at the time of informed consent.
    6. Karnofsky Performance Status (KPS) of =70.
    7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP =150/90 mmHg at Screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1.
    8. Adequate renal function defined as calculated creatinine clearance = 30 mL/min per the Cockcroft and Gault formula (Appendix 1).
    9. Adequate bone marrow function defined by:
    Absolute neutrophil count (ANC) =1500/mm3 (=1.5 x 109/L) Platelets = 100,000/mm3(=100 x 109/L) Hemoglobin =9 g/dL.
    10. Adequate blood coagulation function defined by International Normalized Ratio (INR) =1.5 (except for subjects on warfarin therapy where INR must be =3.0 prior to randomization).
    11. Adequate liver function defined by:
    Total bilirubin =1.5 times the ULN except for unconjugated hyperbilirubinemia of Gilbert's syndrome.
    Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) =3×ULN (in the case of liver metastases =5×ULN). Subjects with bone metastases with ALP values greater than 3 times can be included.
    12. Subject must voluntarily agree to provide written informed consent.
    13. Subject must be willing and able to comply with all aspects of the protocol.
    1. Conferma istologica o citologica di RCC con predominanza di cellule chiare (è accettabile la diagnosi tissutale di RCC originale).
    2. Evidenza documentata di RCC avanzato.
    3. Un precedente episodio di progressione di malattia al momento o successivamente al trattamento mirato al VEGF (a titolo di esempio, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) somministrato per il trattamento del RCC. È consentito il precedente trattamento PD-1/PDL1 oltre a 1 precedente trattamento mirato al VEGF.
    4. Almeno 1 lesione target misurabile secondo RECIST 1.1 che soddisfi i seguenti criteri:
    Lesione linfonodale (LN) che misuri in almeno 1 dimensione = 1,5 cm sull'asse corto Lesione non linfonodale che misuri = 1,0 cm nel diametro più lungo La lesione è adatta a essere misurata ripetutamente mediante tomografia computerizzata/risonanza magnetica per immagini (TAC/RMI). Per essere considerate lesioni target, le lesioni trattate in precedenza con radioterapia esterna (EBRT) o terapia locoregionale devono mostrare evidenza radiografica di progressione di malattia in base a RECIST 1.1.
    5. Soggetti di sesso maschile o femminile di età = 18 anni (o di qualsiasi età > 18 anni se a tale età il soggetto è considerato adulto in base alle leggi locali) al momento del consenso informato.
    6. Stato di performance Karnofsky (KPS) =70.
    7. Pressione sanguigna adeguatamente controllata (PS) con o senza farmaci antipertensivi, definita come PS = 150/90 mmHg allo screening e assenza di variazione dei farmaci antipertensivi entro 1 settimana prima del Giorno1/Ciclo1.
    8. Funzione renale adeguata definita come clearance della creatinina calcolata = 30 ml/min secondo la formula di Cockroft e Gault (Appendice 1).
    9. Funzione del midollo osseo adeguata, definita da:
    Conta assoluta dei neutrofili (ANC) =1500/mm3 (=1,5 x 109/l) Piastrine = 100.000/mm3(=100 x 109/l) Emoglobina =9 g/dl.
    10. Funzione di coagulazione del sangue adeguata definita in base al rapporto normalizzato internazionale (INR) = 1,5 (tranne per i soggetti in terapia con warfarin dove l'INR deve essere = 3,0 prima della randomizzazione).
    11. Funzione epatica adeguata, definita da:
    Bilirubina totale = 1,5 volte l'ULN eccetto in soggetti con iperbilirubinemia non coniugata dovuta alla sindrome di Gilbert.
    Fosfatasi alcalina (ALP), alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) = 3 x ULN (in caso di metastasi epatiche = 5 x ULN). Possono essere inclusi i soggetti con metastasi ossee con valori di ALP superiori a 3 volte.
    12. Il soggetto deve fornire volontariamente il consenso informato scritto.
    13. Il soggetto deve essere disposto e in grado di attenersi a tutti gli aspetti del protocollo.
    E.4Principal exclusion criteria
    For the complete list please refer to the protocol
    1. More than 1 prior VEGF-targeted treatment for advanced RCC.
    2. Subjects with Central Nervous System (CNS) metastases are not eligible, unless they have completed local therapy for at least 4 weeks and have discontinued the use of corticosteroids for this indication or are on a tapering regimen of corticosteroids (defined as =10 mg prednisolone equivalent) before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.
    3. Active malignancy (except for RCC or definitively treated basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months.
    4. Any anti-cancer treatment (except for radiation therapy, see exclusion #5) within 21 days, or any investigational agent within 30 days prior to the first dose of study drug; subjects should have recovered from any toxicity related to previous anti-cancer treatment to CTC grade 0 or 1.
    5. Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start.
    6. Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity to rapamycins (eg, sirolimus, everolimus, temsirolimus) or any of the excipients.
    7. Subjects with proteinuria >1+ on urinalysis will undergo 24-h urine collection for quantitative assessment of proteinuria. Subjects with urine protein =1 g/24 h will be ineligible.
    8. Fasting total cholesterol > 300 mg/dL (or > 7.75 mmol/L) and/or fasting triglycerides level > 2.5 x ULN. NOTE: these subjects can be included after initiation or adjustment of lipid-lowering medication.
    9. Uncontrolled diabetes as defined by fasting glucose > 1.5 times the ULN. NOTE: these subjects can be included after initiation or adjustment of glucose-lowering medication.
    10. Prolongation of QTc interval to >480 ms.
    11. Subjects who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
    12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib or everolimus.
    13. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (eg, carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
    14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
    15. Significant cardiovascular impairment within 6 months prior to the first dose of study drug; history of congestive heart failure greater than New York Heart Association (NYHA) Class II,unstable angina, myocardial infarction or stroke, or cardiac arrhythmia associated with significant cardiovascular impairment. Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by screening multigated acquisition (MUGA) scan or echocardiogram.
    16. Active infection.
    17.Any medical or other condition that in the opinion of the investigator(s) would preclude the subject's participation in a clinical study.
    18. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ßhCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
    19. Females of childbearing potential* who do not agree to use a highly effective method of contraception for the entire study period and for up to 8 weeks after study drug discontinuation
    Per la lista completa fare riferimento al protocollo
    1. Più di 1 precedente trattamento mirato al VEGF per RCC avanzato.
    2. I pz con metastasi del SNC non sono eleggibili, salvo che abbiano completato la terapia locale da almeno 4 sett. e abbiano interrotto l'uso di corticosteroidi per questa indicazione o siano in terapia con un regime di riduzione graduale della dose di corticosteroidi (definito come = 10 mg di equivalente del prednisolone) prima dell'inizio del trattamento in questo studio. Eventuali segni (ad es. radiologici) o sintomi di metastasi cerebrali devono essere stabili da almeno 4 sett. prima dell'inizio del trattamento in studio.
    3. Tumore maligno attivo (eccetto RCC o carcinoma della pelle a cellule basali o cellule squamose trattato in via definitiva oppure carcinoma in situ della cervice o della vescica) negli ultimi 24 mesi.
    4. Qualsiasi trattamento antitumorale (eccetto radioterapia, si veda criterio di esclusione n. 5) nei 21 giorni o qualsiasi agente sperimentale nei 30 giorni antecedenti la prima dose di farmaco in studio; i pz devono essersi ristabiliti da un'eventuale tossicità correlata a un precedente trattamento antitumorale a Grado CTC 0 o 1.
    5. Precedente radioterapia nei 21 giorni antecedenti l'inizio del trattamento in studio, fatta eccezione per la radioterapia palliativa delle lesioni ossee, che è consentita se completata 2 sett. prima dell'inizio del trattamento in studio.
    6. Intolleranza nota al F in studio (o a uno qualsiasi degli eccipienti) e/o ipersensibilità nota alle rapamicine (ad es. sirolimus, everolimus, temsirolimus) o a uno qualsiasi degli eccipienti.
    7. I pz che presentano proteinuria > 1+ alle analisi delle urine saranno sottoposti a raccolta di urine nelle 24h per una valutazione quantitativa della proteinuria. I pz con proteine nelle urine = 1 g/24 h non saranno eleggibili.
    8. Colesterolo totale a digiuno > 300 mg/dl (o > 7,75 mmol/l) e/o livello di trigliceridi a digiuno > 2,5 x ULN. NOTA: tali pz possono essere inclusi dopo l'inizio o l'aggiustamento della terapia con farmaco ipolipemizzante.
    9. Diabete non controllato come definito da livello di glucosio a digiuno > 1,5 volte l'ULN.
    10. Prolungamento dell’intervallo QTc a > 480 ms.
    11. Pz che non si sono adeguatamente ristabiliti da eventuali tossicità e/o complicazioni successive a interventi chirurgici importanti prima dell'inizio della terapia.
    12. Malassorbimento gastrointestinale, anastomosi gastrointestinale o qualsiasi altra condizione che possa influenzare l'assorbimento di lenvatinib o everolimus.
    13. Disturbi emorragici o trombotici o pz a rischio di emorragia grave. Deve essere considerato il grado di invasione/infiltrazione del tumore nei grandi vasi sanguigni a causa del potenziale rischio di emorragia grave associata alla riduzione/necrosi del tumore successivamente alla terapia con lenvatinib.
    14. Emottisi o sanguinamento tumorale clinicamente significativo nelle 2 sett. precedenti la 1a dose di farmaco in studio.
    15. Significativa alterazione della funzionalità cardiovascolare nei 6 mesi precedenti la 1a dose di farmaco in studio; anamnesi di insufficienza cardiaca congestizia superiore alla Classe II secondo la NYHA, angina instabile, infarto miocardico o ictus o aritmia cardiaca associata a significativa alterazione della funzionalità cardiovascolare. LVEF al di sotto del normale intervallo istituzionale.
    16. Infezione attiva.
    17. Eventuali condizioni mediche o di altro tipo che, a giudizio dello sperimentatore, precluderebbero la partecipazione del pz a uno studio clinico.
    18. Pz di sesso femminile che allattano o sono in stato di gravidanza allo Screening o alla Baseline
    19. Pz di sesso femminile in età fertile che non accettano di utilizzare un metodo contraccettivo altamente efficace per l'intero periodo dello studio e fino a 8 sett. dopo l'interruzione del trattamento con il farmaco in studio
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate at Week 24 (ORR24W) as assessed by the investigator according to RECIST 1.1 . ORR24W is defined as the proportion of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) at the Week-24 (after randomization) time point or earlier. To be considered a BOR, all responses must be confirmed no less than 4 weeks after the initial assessment of response.
    Proportion of subjects with intolerable Grade 2 or any = Grade 3 TEAEs within 24 weeks after randomization (as of the Week-24 time point).
    Tasso di risposta obiettiva (ORR) alla Settimana 24 (ORR24W) valutato dallo sperimentatore secondo i criteri RECIST 1.1. L'ORR24W è definito come la percentuale di soggetti la cui risposta globale migliore (BOR) è la risposta completa (CR) o la risposta parziale (PR) alla Settimana -24 (dopo la randomizzazione) o prima. Per essere considerate una BOR, tutte le risposte devono essere confermate non meno di 4 settimane dopo l'indicazione iniziale della risposta.
    Percentuale di soggetti con TEAE di Grado 2 intollerabile e = Grado 3 nelle 24 settimane successive alla randomizzazione (dalla Settimana -24).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Objective response rate (ORR24W) will be assessed at week-24 (after randomization) time point or earlier and at interim and final analysis.
    The safety end point for the primary analyses will be assessed within 24 weeks after randomisation.
    Il Tasso di risposta obiettiva (ORR24W) sarà valutato alla settimana 24 (dopo la randomizzazione) o prima e in occasione dell’analisi ad interim e finale.
    L’endpoint di sicurezza per le analisi primarie sarà valutato entro 24 settimane dopo la randomizzazione.
    E.5.2Secondary end point(s)
    Progression-free survival (PFS), defined as the time from the date of randomization to the date of first documentation of disease progression or date of death, whichever occurs first. PFS censoring rules will be defined in the statistical analysis plan (SAP) .
    ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment.
    ORR is defined as the proportion of subjects with BOR of CR or PR at the end of treatment. To be considered BOR, all responses must be confirmed no less than 4 weeks after the initial assessment of response.
    Overall safety profile and tolerability of lenvatinib in combination with everolimus.
    Proportion of subjects who discontinue treatment due to toxicity, defined as the proportion of subjects who discontinue study treatment due to TEAEs.
    Time to treatment failure due to toxicity, defined as the time from the date of randomization to the date that a subject discontinues study treatment due to TEAEs.
    Lenvatinib and everolimus exposure parameters and PK and PD drug-drug interactions.
    Overall survival (OS), measured from the date of randomization until date of death from any cause. In the absence of confirmation of death, subjects will be censored either at the date that the subject was last known to be alive or the date of data cutoff, whichever comes earlier.
    Health-Related Quality of Life (HRQoL) will be assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom IndexDisease
    Related Symptoms (FKSI-DRS), the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European
    Quality of Life (EuroQol) EQ-5D-3L instruments.
    PFS2, defined as the time from randomization to the date of disease progression after next line of therapy or death from any cause, whichever occurs first. PFS2 censoring rules will be defined in the SAP

    Sopravvivenza libera da progressione (PFS), definita come il periodo di tempo tra la data di randomizzazione e la data della prima documentazione di progressione di malattia o la data del decesso, a seconda di quale evento si verifichi per primo. Le regole di censorizzazione per la PFS saranno definite nel piano di analisi statistica (SAP).
    ORR come valutato dallo sperimentatore secondo RECIST 1.1 alla fine del trattamento.
    L'ORR ¿ definito come la proporzione di soggetti con BOR di CR o PR alla fine del trattamento. Per essere considerate BOR, tutte le risposte devono essere confermate non meno di 4 settimane dopo l'indicazione iniziale della risposta.
    Profilo di sicurezza globale e tollerabilit¿ di lenvatinib in combinazione con everolimus.
    Proporzione di soggetti che interrompono il trattamento a causa di tossicit¿, definita come proporzione di soggetti che interrompono il trattamento in studio a causa di TEAE.
    Tempo all'insuccesso del trattamento dovuto a tossicit¿, definito come il tempo trascorso dalla data di randomizzazione alla data in cui un soggetto interrompe il trattamento in studio a causa di TEAE.
    Parametri di esposizione a lenvatinib ed everolimus e interazioni farmaco-farmaco PK e PD.
    Sopravvivenza globale (OS), misurata a partire dalla data della randomizzazione fino alla data del decesso per una causa qualsiasi. In assenza di conferma del decesso, i soggetti saranno censurati all'ultima data in cui il soggetto risultava in vita o alla data dell'interruzione della raccolta dei dati, a seconda dell'evento che si verifica per primo.
    La qualit¿ di vita correlata allo stato di salute (HRQoL) sar¿ valutata usando gli strumenti Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS), QLQ-C30 dell'Organizzazione europea per la ricerca e il trattamento del cancro (EORTC) e questionario europeo sulla qualit¿ di vita (EuroQol) EQ-5D-3L.
    PFS2, definita come il tempo trascorso dalla randomizzazione alla data della progressione di malattia dopo la successiva linea di terapia o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo. Le regole di censorizzazione per la PFS2 saranno definite nel SAP
    E.5.2.1Timepoint(s) of evaluation of this end point
    The median survival time and the survival rates at 12 , 18 and 24 months will be assessed.
    HRQoL will be assessed at Baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle, at time of early withdrawal, and at the Off-Treatment Visit.
    Saranno valutati il tempo di sopravvivenza mediano e i tassi di sopravvivenza a 12, 18 e 24 mesi.
    L'HRQoL sar¿ valutata alla Baseline (prima della prima dose di farmaco in studio), il Giorno 1 di ogni ciclo successivo, al momento del ritiro anticipato e alla Visita di interruzione del trattamento.
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group 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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Korea, Republic of
    Russian Federation
    Taiwan
    United States
    Bulgaria
    Finland
    Greece
    Italy
    Netherlands
    Poland
    Portugal
    Romania
    Spain
    United Kingdom
    Czechia
    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 subject's last assessment (Off-treatment visit) will be the End of Study. Subjects on treatment at the time of data cutoff for the primary analysis will continue to receive investigational product until they complete the Off-treatment visit prior to their transition to commercial lenvatinib and everolimus (if commercially available for that individual subject) or through an access program administered by the sponsor.
    L’ultima valutazione dell’ultimo soggetto (Visita di interruzione del trattamento) costituirà la Fine dello studio. I soggetti in trattamento al momento del cut-off dei dati per l’analisi primaria continueranno a ricevere il prodotto sperimentale fino a quando non avranno completato la visita di interruzione del trattamento prima della loro
    transizione a lenvatinib ed everolimus commerciali o mediante un programma di accesso gestito dallo sponsor.
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 149
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 189
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 338
    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)
    Subjects on treatment at the time of data cutoff for the primary analysis will continue to receive investigational product until they complete the Off-treatment visit prior to their transition to commercial lenvatinib and everolimus (if commercially available for that individual subject) or through an access program administered by the sponsor.
    I soggetti in trattamento al momento del cut-off dei dati per l’analisi primaria continueranno a ricevere il prodotto sperimentale fino a quando non avranno completato la visita di interruzione del trattamento prima della loro transizione a lenvatinib ed everolimus commerciali (se disponibili in commercio per quel singolo soggetto) o mediante un programma di accesso gestito dallo sponsor
    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 Decision2018-06-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-06
    P. End of Trial
    P.End of Trial StatusCompleted
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