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    Summary
    EudraCT Number:2016-003352-67
    Sponsor's Protocol Code Number:E7389-G000-213
    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:2021-01-22
    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 number2016-003352-67
    A.3Full title of the trial
    A Phase 1/2 single-arm study evaluating the safety and efficacy of eribulin mesilate in combination with irinotecan in children with refractory or recurrent solid tumors
    “Studio di Fase 1/2 a braccio singolo per valutare la sicurezza e l’efficacia di eribulina mesilato in combinazione con irinotecan in bambini con tumori solidi ricorrenti o refrattari”
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1 and 2 trial studying how well a combination of eribulin mesilate and irinotecan works in children with different types of cancer that are not responding to treatment or have reappeared following an initial recovery. The aim of the study is to find out how safe and effective the drug combination is in this treating this types of cancer.
    Sperimentazione di Fase 1 e 2 che studia il funzionamento della combinazione di eribulina mesilato e irinotecan in bambini con differenti tipi di tumore che non rispondono al trattamento o si ripresentano dopo iniziale recupero.
    Lo scopo dello studio è scoprire la sicurezza e l’efficacia della combinazione dei farmaci nel trattamento di questi tipi di tumore.
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberE7389-G000-213
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/330/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEISAI LIMITED
    B.1.3.4Country
    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.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 AddressMosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number004408456761400
    B.5.5Fax number004408456761401
    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 Halaven
    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 nameHalaven
    D.3.2Product code [E7389]
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNeribulina mesilato
    D.3.9.2Current sponsor codeE7389
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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.2.1.2Country 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 nameNA
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNirinotecan cloridrato
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB02772MIG
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Phase 1: paediatric subjects with relapsed/refractory solid tumors (excluding CNS)
    Phase 2: paediatric subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS)
    soggetti pediatrici con tumori solidi ricorrenti o refrattari (escluso SNC)
    • Fase II: soggetti pediatrici con rabdomiosarcoma (RMS), sarcoma dei tessuti molli non-rabdomiosarcoma (NRSTS) e sarcoma di Ewing (EWS) recidivante/refrattario
    E.1.1.1Medical condition in easily understood language
    Different types of cancer that are not responding to treatment or have
    reappeared following an initial recovery
    Diversi tipi di tumore che non rispondono al trattamento o che sono ricomparsi dopo un recupero iniziale
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • Phase 1: To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with weekly and daily irinotecan hydrochloride in paediatric subjects with relapsed/refractory solid tumors (excluding CNS)

    • Phase 2: To assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS)
    • Fase 1: Determinare la dose massima tollerata (MTD) e la dose di Fase 2 raccomandata (RP2D) di eribulina mesilato in combinazione con irinotecan cloridrato con somministrazione settimanale e giornaliera in soggetti pediatrici con tumori solidi recidivanti/refrattari (eccetto SNC)
    • Fase 2: Valutare il tasso di risposta obiettiva (ORR) e la durata della risposta (DOR) di eribulina mesilato in combinazione con irinotecan cloridrato in soggetti pediatrici con rabdomiosarcoma (RMS), sarcoma dei tessuti molli non-rabdomiosarcoma (NRSTS) e sarcoma di Ewing (EWS) recidivante/refrattario
    E.2.2Secondary objectives of the trial
    Phase 1:
    • To assess the safety and tolerability of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects
    • To determine the optimal schedule of irinotecan hydrochloride when administered with standard schedule (Days 1 and 8) of eribulin mesilate in paediatric subjects

    Phase 2:
    • To assess Progression Free Survival (PFS) of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects.
    • To assess the Clinical Benefit Rate (CBR) at 12 weeks of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects

    Phase 1&2:
    • To evaluate the pharmacokinetic (PK) profile of eribulin, irinotecan and its active metabolite and (both Phases) and potential for drug-drug interaction of eribulin mesilate and irinotecan hydrochloride and its active metabolite, when coadministered (Phase 1 only).
    Fase 1:
    • Valutare la sicurezza e la tollerabilità di eribulina mesilato in combinazione con irinotecan cloridrato in soggetti pediatrici
    • Determinare lo schema ottimale di irinotecan cloridrato quando somministrato in associazione con lo schema standard (Giorni 1 e 8) di eribulina mesilato in soggetti pediatrici
    Fase 2:
    • Valutare la sopravvivenza libera da progressione (PFS) per eribulina mesilato in combinazione con irinotecan cloridrato in soggetti pediatrici
    • Valutare il tasso di beneficio clinico (CBR) a 12 settimane di eribulina mesilato in combinazione con irinotecan cloridrato in soggetti pediatrici
    Fase 1 e 2:
    • Valutare il profilo farmacocinetico (PK) di eribulina, irinotecan e del relativo metabolita attivo e (entrambe le fasi ) e quello potenziale per interazione farmaco-farmaco di eribulina mesilato e irinotecan cloridrato e suoi metaboliti attivi, quando co-somministrati (solo fase 1).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age: =12 months to <18 years old at the time of ICF. >6 months and <12 months at the times of ICF pts will be enrolled one dose level behind he dose level at which the =12 months to <18 years old group are enrolled.2. Diagnosis: Ph 1: Histologically confirmed solid tumor, excluding CNS tumor, which is relapsed or refractory, and for which there are no currently available therapies. Ph 2: Histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory having received at least 1 prior therapy), including primary treatment.3. Disease status:Ph 1: Pts must have either measurable or evaluable disease as per RECIST 1.1. Ph 2: Pts must have measurable disease as per RECIST 1.1.Measurable disease is defined as meeting the following criteria:a. At least 1 lesion of =1.0 cm in the longest diameter for a non-lymph node or =1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1 CT/MRI. b. Lesions that have had radiotherapy must show subsequent radiographic evidence of increase in size by at least 20% to be deemed a target lesion.4. Therapeutic options: Pt’s current disease state must be one for which there is no known curative therapy.5. Performance level: Performance score =50% KPS or Lansky.6. Pts must have fully recovered from the acute toxic effects of all prior anticancer treatments prior to study drug admin:• Myelosuppressive chemotherapy: Must not have received within 21 days to study drug admin Hematopoietic growth factors: Must not have received a long-acting growth factor within 14 days or a short-acting factor within 7 days. For agents that have known AEs occurring beyond 7 days after admin, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor.• Targeted therapy:Must not have received an antineoplastic targeted therapy within 14 days. For agents that have known AEs occurring beyond 14 days after admin, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor.• Immunotherapy: Must not have received immunotherapy, e.g. tumor vaccines, within 42 days. • Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal Ab.• XRT: Must not have received within 14 days prior to study drug admin or 42 days for craniospinal XRT, or if =50% radiation of pelvis.• Autologous Stem cell infusion: At least 84 days must have elapsed after stem cell infusion prior to study drug admin. • Allogeneic bone marrow transplant, including mini-transplant: No evidence of active Graft vs. Host disease and at least 100 days must have elapsed after transplant or stem cell infusion prior to study drug admin.7. Adequate bone marrow function, defined as:• ANC =1 × 109/L.• Platelet count =100 × 109/L.• Hb at least 8.0 g/dL at baseline As blood transfusions are permitted to meet the hemoglobin criteria, pts must not be known to be refractory to red blood cell or platelet transfusions. 8. Adequate renal function, defined as:• A serum creatinine based on age/gender, derived from the Schwartz formula for estimating GFR. Refer to table in protocol.• GFR =50ml/min/1.73m2, based on a 12 or 24h urine creatinine collection. 9. Adequate liver function, defined as:• Bilirubin (sum of conjugated + unconjugated) =1.5 times the ULN for age.• Alkaline phosphatase, ALT and AST =3 × ULN, unless there are bone metastases, in which case liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase. • Serum albumin =2 g/dL.10. Informed ICF: All pts and/or their parents or legally authorized representatives must sign a written informed ICF. Assent, when appropriate, will be obtained according to institutional guidelines. Pts must be willing to comply with all aspects of the protocol.
    1.Età: a.da =12 m a <18 anni. b. i sogg > 6 m e < 12 m al momento del ICF saranno arruolati al livello di dosaggio immediatamente inferiore rispetto ai sogg = 12 m 2. Diagnosi: Fase 1: tumore solido confermato istologicamente, esclusi i tumori del SNC, che è recidivante o refrattario e per il quale nn esistono attualmente terapie disponibili. Fase 2: RMS, NRSTS ed EWS confermato istologicamente che è recidivante o refrattario dopo aver ricevuto almeno 1 precedente terapia sistemica, incluso il trattamento primario. 3.Fase 1: I sogg devono presentare malattia misurabile o valutabile secondo i RECIST 1.1. Fase 2: I sogg devono presentare malattia misurabile secondo i RECIST 1.1. La malattia misurabile è definita come malattia che soddisfa i seguenti criteri: a.Almeno 1 lesione = 1,0 cm di diametro dell’asse lungo per un nodo nn linfatico o = 1,5 cm di diametro dell’asse breve per un linfonodo che sia misurabile in serie secondo RECIST 1.1 per mezzo di tomografia computerizzata / risonanza magnetica. b.Le lesioni sottoposte a radioterapia devono mostrare successiva evidenza radiografica di incremento della dimensione di almeno il 20% per essere considerate lesioni target. 4. Opzioni terapeutiche: lo stato attuale di malattia del soggetto deve essere uno stato per il quale nn esiste alcuna terapia curativa nota. 5. Livello di performance: punteggio di KPS o Lansky = 50%. 6.I sogg devono essersi completamente ristabiliti dagli effetti tossici acuti di tutti i precedenti trattamenti antitumorali prima della somministrazione del farmaco in studio: •Chemio mielosoppressiva: nn deve essere stata somministrata nei 21 gg precedenti la somministrazione del farmaco in studio. •Fattori di crescita ematopoietica: nn deve essere stato somministrato un fattore di crescita a lunga durata d'azione nei 14 gg precedenti o un fattore di crescita a breve durata d'azione nei 7 gg precedenti. Per gli agenti per cui esistono AE noti che si verificano oltre 7 gg dopo la somministrazione, tale periodo deve essere esteso oltre il lasso di tempo durante il quale è noto che si verificano gli AE. La durata di tale intervallo deve essere discussa con lo Sponsor. •Terapia mirata nn deve essere stata somministrata una terapia antineoplastica mirata nei 14 gg precedenti. Per gli agenti per cui esistono AE noti che si verificano oltre 14 gg dopo la somministrazione, tale periodo deve essere esteso oltre il lasso di tempo durante il quale è noto che si verificano gli AE. La durata di tale intervallo deve essere discussa con lo Sponsor. •Immunoterapia: nn deve essere stata somministrata immunoterapia, ad es. vaccini antitumorali, nei 42 gg precedenti.•Ab monoclonali: nn devono essere stati somministrati come minimo entro le 3 emivite dell'anticorpo successive all'ultima dose di un anticorpo monoclonale.•Radiotp: nn deve essere stata eseguita nei 14 gg precedenti la somministrazione del farmaco in studio o nei 42 gg precedenti per XRT cranio-spinale o se l'irradiazione della pelvi è = 50%.•Infus di cellule staminali autologhe: devono essere trascorsi almeno 84 gg dall'infus di cellule staminali prima della somministrazione del farmaco in studio• Trapianto di midollo osseo allogenico, compreso mini-trapianto: nessuna evidenza di malattia del trapianto contro l'ospite attiva e devono essere trascorsi almeno 100 gg dal trapianto o dall'infus di cellule staminali prima della somministrazione del farmaco in studio7.Funzione del midollo osseo adeguata, definita come:• ANC =1,0 × 109/l.• Conta piastrinica = 100 × 109/l •Hb almeno 8,0 g/dL alla baseline.Sono consentite trasfusioni di sangue per soddisfare i criteri relativi all'emoglobina, i sogg che richiedono trasfusioni nn devono presentare refrattarietà nota alle trasfusioni di globuli rossi o piastrine. 8.Funzionalità renale adeguata 9.Funzione epatica adeguata 10. ICF: Tutti i sogg e/o i loro genitori o tutori devono firmare un consenso informato scritto. spazio insufficiente: vedere protocollo
    E.4Principal exclusion criteria
    1. Pregnancy, breastfeeding, contraception: Females who are breastfeeding or pregnant at Screening or Baseline. 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.- Females of childbearing potential* who: Do not agree to use a highly effective method of contraception for the entire study
    period and for 6 months after study drug discontinuation, ie: Total abstinence IUD or IUS, A contraceptive implant, an oral contraceptive**OR Do not have a vasectomized partner with confirmed azoospermia.
    *All post pubertal females will be considered to be of childbearing potential unless they
    have early menopause (amenorrheic for at least 12 consecutive months, in the
    appropriate age group, and without other known or suspected cause) or have been
    sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral
    oophorectomy, all with surgery at least 1 month before dosing).
    **Must be on a stable dose of the same oral hormonal contraceptive product for at least
    4 weeks before dosing with study drug and for the duration of the study and for 6 months after study drug discontinuation.
    2. Concomitant Medications: Corticosteroids: Pt receiving corticosteroids who have not been on a stable dose for at least 7 days prior to study drug administration. Anticancer agents: Pt who are currently receiving other anticancer agents. Anti-GVHD agents post-transplant: Pt who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant. Strong CYP3A4 inducers/inhibitors.
    3. Prior Therapies: Phase 1: Received prior therapy with eribulin mesilate within 6 months prior to study drug administration. Phase 2: Received prior therapies with eribulin mesilate or irinotecan hydrochloride.
    4. Any malignancy that required treatment, within 2 years prior to study drug administration.
    5. Has hypersensitivity to either study drug or any of the excipients.
    6. Has a known prior history* of viral hepatitis (B or C) as demonstrated by positive
    serology (presence of antigens) or have an uncontrolled infection requiring treatment (*
    Pt with a known prior history of hepatitis B or C may be eligible pending
    agreement with the sponsor).
    7. Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor neuropathy graded according to the Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies.
    8. Has cardiac pathology, defined as: Pt with known congestive heart failure, symptomatic or LV ejection fraction <50% or shortening fraction <27% and pt with congenital long QT syndrome, bradyarrhythmias, or QTc >480 msec on at least 2 separate ECGs.
    9. Has CNS disease: Pt with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration. Pt must be clinically stable. It is not the intention of this protocol to treat pt with active brain metastases.
    10. Have had or are planning to have the following invasive procedures: Major surgical procedure or significant traumatic injury within 28 days prior to study drug administration. Laparoscopic procedure or open biopsy within 7 days prior to study drug administration. Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 2 days prior to study drug administration. Core biopsy, including bone marrow biopsy within 2 days prior to study drug administration. Fine needle aspirate within 3 days prior to study drug administration.
    11. Pt with HIV; due to lack of available safety data for eribulin therapy in HIV infected pt.
    12. Has any serious concomitant illness that in the opinion of the investigator(s) could affect the subject’s safety . See protocol
    1. Pt donne che allattano o in gravid allo Screening o alla Baseline È necessaria una valutazione alla baseline separata qualora si riscontri un test di gravidanza neg allo screening oltre 72 ore prima della prima dose di farmaco dello studio. Donne in età fertile che: non accettano di utilizzare un metodo contraccettivo altamente efficace per l'intero periodo dello studio e per 6 mesi dopo l'interruzione del trattamento con il farmaco in studio, ossia: astinenza completa, IUD o IUS un impianto contraccettivo un contraccettivo orale OPPURE non hanno un partner vasectomizzato con azoospermia confermata. 2 Farmaci concomitanti: Corticosteroidi: pt che ricevono corticosteroidi che non sono in terapia a una dose stabile da almeno 7 gg prima della somministrazione del farmaco in studio. Agenti antitumorali: pt che attualmente ricevono altri agenti antitumorali. Agenti anti-GVHD post-trapianto: pt che ricevono ciclosporina, tacrolimus o altri agenti per prevenire la malattia del trapianto contro l'ospite dopo il trapianto di midollo osseo. Forti induttori/inibitori del CYP3A4
    3.Terapie precedenti: Fase 1: precedente terapia con eribulina mesilato nei 6 mesi precedenti la somministrazione del farmaco in studio. Fase 2: precedenti terapie con eribulina mesilato o irinotecan cloridrato.
    4.Qualsiasi tumore maligno che ha richiesto trattamento (eccetto carcinoma cutaneo non melanomatoso o escissione completa di carcinoma in situ confermata istologicamente) nei 2 anni precedenti la somministrazione del farmaco in studio.
    5.Ipersensibilità al farmaco in studio o a eccipienti.
    6.Anamnesi precedente* di epatite virale (B o C) nota come dimostrato da sierologia positiva (presenza di antigeni) o presenza di infezione non controllata che richiede trattamento (*i pt con anamnesi precedente di epatite B o C nota possono essere eleggibili in attesa di un accordo con lo Sponsor).
    7.Neuropatia sensoriale periferica > Grado 1 o neuropatia motoria periferica > Grado 1 classificate secondo la scala pediatrica ("Balis") modificata delle neuropatie periferiche.
    8.Patologia cardiaca, definita come: Pt con insufficienza cardiaca congestizia nota, frazione di eiezione del ventricolo sinistro sintomatica o < 50% o frazione di accorciamento < 27% e pt con sindrome congenita del QT lungo, bradiaritmie o QTc > 480 msec in almeno 2 ECG separati.
    9.Malattia del SNC: i pt con metastasi cerebrali o subdurali non sono eleggibili salvo che le metastasi siano asintomatiche e non richiedano trattamento o siano state adeguatamente trattate con terapia locale e che i pt abbiano interrotto l'uso di corticosteroidi per questa indicazione da almeno 28 gg prima della somministrazione del farmaco in studio. I pt devono essere clinicamente stabili. Non è finalità del presente protocollo trattare i pt con metastasi cerebrali attive.
    10.Esecuzione seguenti proced: Intervento chirurgico importante o lesione traumatica significativa nei 28 gg precedenti la somministrazione del farmaco in studio. Procedura laparoscopica o biopsia “a cielo aperto” nei 7 gg precedenti la somministrazione del farmaco in studio. Il posizionamento di una linea centrale o di una porta sottocutanea non è considerato un intervento importante ma deve avvenire almeno 2 gg prima della somministrazione del farmaco in studio. Agobiopsia, inclusa biopsia del midollo osseo nei 2 gg precedenti la somministrazione del farmaco in studio. Agoaspirato nei 3 gg precedenti la somministrazione del farmaco in studio.
    11. Pt con infezione nota da HIV; a causa della mancanza di dati sulla sicurezza per la terapia con eribulina nei pt infetti da HIV.
    12.Eventuale malattia concomitante seria che a giudizio medico potrebbe influire sulla sicurezza del sogg o interferire con le valutaz dello studio.
    13.Somministrazione di un vaccino con virus vivo nei 30 gg precedenti l'inizio programmato della terapia in studio. Sono consentiti vaccini antinfluenzali che non contengono un virus vivo.
    vedere prot
    E.5 End points
    E.5.1Primary end point(s)
    • Phase 1: The MTD/RP2D of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects with relapsed/refractory extra-cranial solid tumors, excluding CNS tumors. Note: Subjects <12 months will not contribute to the determination of MTD/RP2D and data is for descriptive purposes only.

    • Phase 2: Objective response rate (ORR): defined as the proportion of subjects achieving a best overall response of confirmed partial or complete response, as determined by investigator assessment.
    Fase 1: MTD / RP2D di eribulina mesilato in combinazione con
    irinotecan cloridrato in soggetti pediatrici con tumori solidi extra-cranici recidivi / refrattari, esclusi i tumori del CNS. Nota: soggetti <12
    mesi non contribuiranno alla determinazione di MTD / RP2D e dati
    saranno solo a scopo descrittivo.
    Fase 2: Tasso di risposta obiettiva (ORR): definito come la percentuale di soggetti che raggiungono una migliore risposta globale di risposta parziale o completa confermata, come stabilito in base alla revisione dello sperimentatore.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Phase 1: DLTs to establish the MTD are assessed during the first cycle for each subject on each dose level.

    • Phase 2: Tumour assessments are performed every 6 weeks until Week 24 and then and then the frequency of assessments may decrease to every 9 weeks (or sooner if clinically indicated).
    Fase 1: Le DLT per stabilire la MTD sono valutate durante il primo ciclo per ciascun soggetto a ogni livello di dosaggio.
    Fase 2: Le valutazioni del tumore sono eseguite ogni 6 settimane fino alla Settimana 24 e successivamente la frequenza delle valutazioni potrà essere ridotta a ogni 9 settimane (o prima se clinicamente indicato).
    E.5.2Secondary end point(s)
    Phase 1 & 2 Endpoints:
    • Safety and tolerability: adverse events (AEs), serious adverse events, clinical laboratory values, ECG parameters, vital sign measurements and physical examinations

    Timepoint of evaluation:
    Following provision of informed consent/assent and through out the study until 28 days after the last dose of study drug.

    • The pharmacokinetic profile of eribulin, irinotecan and its active metabolite.

    Timepoint of evaluation:
    Phase 1 (Cycle 1): For subjects > e = 12 months (Irinotecan, its metablite and eribulin will be assayed).
    Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first),
    and at the end of the eribulin infusion, then at 1, 2, 4, 6 and 24 hours post-eribulin
    infusion. Both irinotecan (and its metabolite, SN-38) and eribulin will be assayed. At 48, 72, 96 and 120 hours post eribulin infusion, eribulin only will be assayed.
    For subjects <12 months (Irinotecan, its metablite and eribulin will be assayed).
    Cycle 1, Day 1: Before the irinotecan and eribulin infusion and then immediately
    after the end of the eribulin infusion (ie 10 ± 5 minutes from the start of the eribulin
    infusion).
    Cycle 1, Day 4 or 5: During the collection of the first twice weekly CBC sample.
    Cycle 1, Day 8: Before the eribulin infusion and then immediately after the end of the eribulin infusion (ie 10 ± 5 minutes from the start of the eribulin infusion).

    Phase 2 Endpoints:
    • Progression-free survival (PFS): defined as the time from the first dose date to the date of disease progression as determined by investigator review, or death

    Timepoint of evaluation:
    Progression-free survival, defined as the time from the date of first dose to the date of first documentation of disease progression, or date of death (whichever occurs first).

    • The Clinical Benefit Rate (CBR) at 12 weeks: defined as the proportion of subjects with best overall response (BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD >11 weeks)

    Timepoint of evaluation:
    Clinical Benefit Rate, defined as the proportion of subjects with best overall response (BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD >11 weeks).
    Fase 1 e 2:
    Sicurezza e tollerabilità: eventi avversi (AE), eventi avversi seri, valori clinici di laboratorio, parametri ECG, misurazioni delle funzioni vitali ed esami obiettivi

    Tempo/i di rilevazione di questo end point:
    A seguito del consenso/assenso informato e per tutto il corso dello studio fino a 28 giorni dopo l’ultima dose di farmaco in studio.

    End point secondario
    Fase 1 e 2: Profilo farmacocinetico di eribulina, irinotecan e relativo metabolita attivo
    Tempo/i di rilevazione di questo end point:
    Fase 1 (Ciclo 1): Per i soggetti > e = 12 mesi (saranno analizzati irinotecan, relativo metabolita ed eribulina).
    Ciclo 1, Giorno 1: Alla fine dell'infusione di irinotecan (irinotecan è somministrato per primo) e alla fine dell'infusione di eribulina, quindi 1, 2, 4, 6 e 24 ore dopo l'infusione di eribulina. Saranno analizzati sia irinotecan (e relativo metabolita, SN-38) sia eribulina. 48, 72, 96 e 120 ore dopo l'infusione di eribulina, sarà analizzata solo eribulina.
    Per i soggetti <12 mesi (saranno analizzati irinotecan, relativo metabolita e eribulina).
    Ciclo 1, Giorno 1: Prima dell'infusione di irinotecan ed eribulina e quindi subito dopo la fine dell'infusione di eribulina (ovvero 10 ± 5 minuti dall'inizio dell'infusione di eribulina).
    Ciclo 1, Giorno 4 o 5: Durante la raccolta del primo campione CBC prelevato due volte alla settimana.
    Ciclo 1, Giorno 8: Prima dell'infusione di eribulina e quindi subito dopo la fine dell'infusione di eribulina (ovvero 10 ± 5 minuti dall'inizio dell'infusione di eribulina).

    End point secondario
    Fase 2: Sopravvivenza libera da progressione (PFS): definita come il tempo che intercorre tra la data della prima dose e la data della progressione della malattia, come stabilito in base alla revisione dello sperimentatore, o del decesso
    Tempo/i di rilevazione di questo end point:
    Sopravvivenza libera da progressione, definita come il tempo dalla data della prima dose alla data della prima documentazione di progressione della malattia o alla data di decesso (a seconda dell'evento che si verifica per primo).

    End point secondario
    Fase 2: Tasso di beneficio clinico (CBR) a 12 settimane: definito come la percentuale di soggetti con la migliore risposta globale (BOR) di CR, PR o SD durevole secondo RECIST 1.1 (SD durevole > 11 settimane)
    Tempo/i di rilevazione di questo end point:
    Tasso di beneficio clinico, definito come la percentuale di soggetti con la migliore risposta globale (BOR) di CR, PR o SD durevole secondo RECIST 1.1 (SD durevole > 11 settimane).
    E.5.2.1Timepoint(s) of evaluation of this end point
    As detailed under Secondary endpoint (above). Not possible to detail in full in this field due to limit on number of characters.
    Come dettagliato negli endpoit secondario (sopra). Non è possibile dettagliare ulteriormente in questo campo a causa del limitato numero di caratteri.
    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 No
    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
    Paediatric study
    studio pediatrico
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA48
    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
    Austria
    France
    Germany
    Greece
    Ireland
    Italy
    Poland
    Spain
    Switzerland
    United Kingdom
    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
    LVLS
    ultima visita dell'ultimo paziente LPLV
    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 months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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 Yes
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 7
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 74
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 106
    F.4.2.2In the whole clinical trial 111
    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)
    As long as the subject is still receiving clinical benefit and has not experienced intolerable toxicity, he or she can continue to receive study treatment for up to 1 year, after which any continued treatment would need to be discussed with the Sponsor.
    Finché il soggetto continua a ricevere benefici clinici e non ha subito tossicità intollerabile, può continuare a ricevere il trattamento di studio massimo fino a 1 anno, trascorso il quale la continuazione del trattamento dovrà essere discussa con lo 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 Decision2018-07-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-15
    P. End of Trial
    P.End of Trial StatusCompleted
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