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    Summary
    EudraCT Number:2019-000212-28
    Sponsor's Protocol Code Number:LOXO-RET-18036
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-01-21
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-000212-28
    A.3Full title of the trial
    A Phase 1/2 Study of the Oral RET Inhibitor LOXO-292 in Pediatric Patients with Advanced RET-Altered Solid or Primary Central Nervous System Tumors
    Studio di fase 1/2 sull’inibitore orale di RET, LOXO 292, in pazienti pediatrici affetti da tumori solidi avanzati o da tumori primitivi del sistema nervoso centrale con alterazione di RET
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study on the effects of the LOXO-292 (study drug) in Pediatric Patients with Advanced Solid or Primary Central Nervous System Tumors
    Studio di fase 1/2sugli effetti di LOXO 292 (farmaco in studio) in pazienti pediatrici affetti da tumori solidi avanzati o da tumori primitivi del sistema nervoso centrale
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberLOXO-RET-18036
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03899792
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/369/2019
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLOXO ONCOLOGY INCORPORATED
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLoxo Oncology, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Addressul. Ilzecka 24
    B.5.3.2Town/ cityWarsaw
    B.5.3.3Post code02-135
    B.5.3.4CountryPoland
    B.5.4Telephone number000000
    B.5.5Fax number000000
    B.5.6E-mailregsubmissions@medpace.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameSelpercatinib
    D.3.2Product code [LOXO-292]
    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 INNSelpercatinib
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameLOXO-292
    D.3.9.4EV Substance CodeSUB186998
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameSelpercatinib
    D.3.2Product code [LOXO-292]
    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 INNSelpercatinib
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameSelpercatinib
    D.3.9.4EV Substance CodeSUB186998
    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 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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameSelpercatinib
    D.3.2Product code [LOXO-292]
    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 INNSelpercatinib
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameLOXO-292
    D.3.9.4EV Substance CodeSUB186998
    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 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: 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameSelpercatinib
    D.3.2Product code [LOXO-292]
    D.3.4Pharmaceutical form Powder for oral suspension
    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 INNSelpercatinib
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameLOXO-292
    D.3.9.4EV Substance CodeSUB186998
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pediatric Patients with Advanced RET-Altered Solid or Primary Central Nervous System Tumors
    Pazienti pediatrici affetti da tumori solidi avanzati o da tumori primitivi del sistema nervoso centrale con alterazione di RET
    E.1.1.1Medical condition in easily understood language
    Pediatric patients with an activating RET alteration and an advanced solid or primary Central Nervous System (CNS) Tumors
    Pazienti pediatrici affetti da tumori solidi avanzati o da tumori primitivi del sistema nervoso centrale con alterazione di RET
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10007958
    E.1.2Term Central nervous system neoplasm
    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 LLT
    E.1.2Classification code 10007959
    E.1.2Term Central nervous system neoplasm 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 LLT
    E.1.2Classification code 10049516
    E.1.2Term Malignant tumor
    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 20.1
    E.1.2Level HLT
    E.1.2Classification code 10007960
    E.1.2Term Central nervous system neoplasms malignant NEC
    E.1.2System Organ Class 100000004852
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10027105
    E.1.2Term Medullary thyroid 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
    FASE 1
    The primary objective is to determine the safety profile, including dose-limiting toxicities (DLTs), of the oral RET inhibitor Selpercatinib.

    FASE 2
    To determine the objective response rate (ORR) as determined by an Independent Review Committee (IRC) and measured by the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors, version 1.1(RECIST v1.1), or Response Assessment in Neuro- Oncology (RANO) criteria, as appropriate, following treatment with Selpercatinib.
    FASE 1
    Determinare il profilo di sicurezza, incluse le tossicità dose-limitanti, dell’inibitore orale del proto-oncogene riarrangiato durante la trasfezione Selpercatinib.

    FASE 2
    Determinare tasso di risposta obiettiva secondo la valutazione di un Comitato di revisione indipendente e misurato sulla base della percentuale di pazienti con migliore risposta globale confermata di risposta completa (RC) o risposta parziale (RP) secondo i Criteri di valutazione della risposta nei tumori solidi, versione 1.1 (Response Evaluation Criteria in Solid Tumors, RECIST v1.1), oppure i Criteri di valutazione della risposta in neuro-oncologia (Response Assessment in Neuro-Oncology, RANO), a seconda del caso, dopo il trattamento con Selpercatinib.
    E.2.2Secondary objectives of the trial
    PHASE 1
    •characterize SelpercatinibPKproperties
    •identify MTD and/or RP2D appropriate Selpercatinib dose
    •describe Selpercatinib antitumor activity
    •evaluate changes from baseline in pain and HRQoL measures assessed by Wong-BakerFacesScale and PedsQL
    PHASE 2
    •determine:
    -ORR using RECIST1.1orRANO criteria
    -DOR in pts with best overall response of CRorPR
    -PFS duration following Selpercatinib initiation
    -OS following Selpercatinib initiation
    -CBR based on proportion of pts with best overall response of CR,PR or stable disease lasting 16or more weeks
    •assess Selpercatinib safety profile and tolerability
    •characterize SelpercatinibPKproperties
    •evaluate concordance of prior molecular profiling that detected an activating RETalteration within the tumor
    •characterize post-operative staging and surgical margin status in pts who have definitive surgery following Selpercatinib
    •describe putative pretreatment surgical plan and capture post treatment actual approach
    Refer to ProtocolSynopsis
    FASE 1
    •Caratt proprietà Fcinetiche Selpercatinib
    •Dose max tollerata e/o appropriata Selpercatinib
    •Attività antitumorale Selpercatinib
    •Variazioni rispetto al basale nelle misure di dolore e qualità di vita
    FASE 2
    •Det.:
    oORR in base RECIST1.1oRANO
    oDurata risp in pz con migliore risposta complessiva RCoRP
    oDurata sopravv senza progressione di Selpercatinib
    oSopravvivenza complessiva dopo inizio Selpercatinib
    oBenefici clinici in base della percentuale di pz con migliore risposta complessiva di RC, RP o malattia stabile persistente per 16 o più settimane dopo inizio di tp
    •Sicurezza e tollerabilità Selpercatinib
    •PK Selpercatinib
    •Concordanza del precedente profilo molecolare che aveva evidenziato presenza di alterazione attivante RET nel tumore
    •Stadiazione postoperatoria e stato dei margini nei pz sottoposti a chirurgia definitiva secondariamente a Selpercatinib
    •Piano chirurgico pre-trattamento putativo e fissare effettivo approccio post-trattamento
    Riferisi anche a Sinossi
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Pediatric patients major= 12 years of age and minor= 21 years of age at Cycle 1 Day 1 (C1D1) with a locally advanced or metastatic solid or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and/or for which no standard or available systemic curative therapy exists.
    a) Patients with locally advanced disease who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection are also eligible.
    2. Evidence of an activating RET gene alteration in tumor and/or blood as identified through molecular assays, as performed for clinical evaluation.
    3. Patients with primary CNS tumors or cerebral metastasis:
    a) Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment
    b) Must have not required increasing doses of steroids within the 7 days prior to enrollment to manage CNS symptoms
    4. Imaging study must be performed within 28 days of C1D1 while on stable dose steroid medication (if needed) for at least 7 days immediately before the imaging study.
    5. Histologic verification of malignancy at original diagnosis or relapse, except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebral spinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or betahuman chorionic gonadotropin (HCG).
    6. Must have measurable or evaluable disease.
    7. Karnofsky (patients 16 years and older) or Lansky (patients younger than 16 years) performance score of at least 50.
    8. Must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy to CTCAE (v5.0) Grade minor= 2.
    9. An archival (FFPE or fresh frozen) or fresh tumor tissue sample must be available (refer to Section 7.5 of the protocol)
    10. Adequate hematologic status, defined as:
    a) Absolute neutrophil count (ANC) major =1.0× 10^9/L not requiring growth factor support for at least 7 days prior to treatment
    b) Platelet count major= 75 × 10^9/L not requiring transfusion support for at least 7 days prior to treatment
    c) Hemoglobin (Hb) major= 8 mg/dL not requiring transfusion support or erythropoietin for at least 7 days prior to treatment
    11. Adequate hepatic/pancreatic function, defined as:
    a) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) minor= 2.5 × the upper limit of normal (ULN) or minor= 5 × ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor),
    and
    b) Total bilirubin minor= 1.5 × ULN or minor=3×ULN with documented liver involvement or Gilbert's Disease (patients with Gilbert's Disease may be enrolled with prior Sponsor approval) and
    c) Pancreatic lipase minor=1.5 × ULN (or Sponsor's approval).
    12. Adequate renal function, defined as:
    a) Estimated glomerular filtration rate major= 30 mL/min/1.73 m2 based on local institutional practice for determination, or a maximum serum creatinine by age and gender as presented in Synopsis Table 3.
    13. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
    14. Willingness of male and female patients with reproductive potential to utilize double effective birth control methods
    15. Ability to swallow capsules, liquid suspension, or gastric access via a naso- or gastric tube.
    16. Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study Informed Consent Form (ICF) and applicable Pediatric Assent Form before initiation of any protocol related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.
    17. Life expectancy of at least 3 months.
    Please refer also to Protocol
    1.Paz pediatrici di età maggiore 12 anni e minore=21 anni, il Giorno 1 del Ciclo 1 (C1G1) con tumore solido localmente avanzato o metastatico oppure tumore primitivo del SNC recidivato, progredito o non responsivo alle terapie disponibili e/o per il quale non esiste alcuna terapia curativa sistemica standard o disponibile
    a)Pazienti con malattia localmente avanzata che richiederebbe, secondo opinione dello sperimentatore, una chirurgia mutilante o l’amputazione di un arto per ottenere una resezione chirurgica completa
    2.Evidenza di un’alterazione genica attivante di RET nel tumore e/o nel sangue, identificata tramite saggi molecolari eseguiti ai fini della valutazione clinica
    3.Pazienti con tumore primitivo del SNC o metastasi cerebrali:
    a) neurologicamente stabili, secondo quanto accertato dalla visita neurologica, per 7 gg prima dell’arruolamento
    b)non devono aver richiesto la somministrazione di dosi crescenti di steroidi nei 7 gg precedenti l’inserimento nello studio per il trattamento dei sintomi a livello del SNC
    4.Scansione eseguita entro 28 gg da C1G1 mentre il paziente è in terapia con corticosteroidi in dose stabile (se richiesta) da almeno 7 gg subito prima della scansione
    5.Conferma istologica della neoplasia in occasione della prima diagnosi o della recidiva, tranne i pazienti con tumori intrinseci del tronco cerebrale, gliomi delle vie ottiche, oppure nei pazienti con tumori della regione pineale e aumento dei livelli di marcatori tumorali nel liquido cerebrospinale (LCS) o nel siero, inclusa l’alfa-fetoproteina o la beta-gonadotropina corionica umana
    6.Presentare malattia misurabile o valutabile
    7.Punteggio della scala di valutazione di Karnofsky o di Lansky pari ad almeno 50
    8. Guarigione dagli effetti tossici acuti di tutte le precedenti chemioterapie anticancro al Grado CTCAE (v5.0) minore= 2
    9.Deve essere disponibile un campione di tessuto tumorale d’archivio (fissato in formalina e incluso in paraffina [Formalin Fixed Paraffin Embedded, FFPE] o congelato fresco) o fresco
    10.Adeguato stato ematologico definito come:
    a)Conta neutrofilica assoluta (Absolute Neutrophil Count, ANC)maggiore=1.0x 10^9/l senza dover ricorrere al supporto con fattori di crescita per almeno 7 giorni prima del trattamento;
    b)Conta piastrinica maggiore=75 x 10^9/l senza dover ricorrere a supporto trasfusionale per almeno 7 giorni prima del trattamento
    c)Emoglobina (Hb) maggiore=8 mg/ml senza dover ricorrere a supporto trasfusionale o terapia con eritropoietina per almeno 7 giorni prima del trattamento
    11.Adeguata funzione epatica/pancreatica definita come:
    a)Alanina aminotransferasi (ALT) o aspartato aminotransferasi (AST)minore =2,5 x limite superiore dell’intervallo normale (Upper Limit of Normal, ULN) o minore=5 x ULN con documentato coinvolgimento epatico (come metastasi del fegato o tumore biliare primario), e
    b)bilirubina totale minore=1,5 x ULN o minore=3 x ULN con documentato coinvolgimento epatico o malattia di Gilbert e
    c) Lipasi pancreatica minore=1,5×ULN (o approvazione Sponsor)
    12.Adeguata funzione renale, definita come:
    a)V di filtrazione glomerulare stimata maggiore=30 ml/min/1,73 m2 in linea con la prassi locale per la misurazione oppure un livello massimo di creatinina sierica in base all’età e al sesso
    13.Capacità di attenersi al trattamento ambulatoriale, monitoraggio dei parametri di laboratorio e visite presso il centro richieste per la durata della partecipazione allo studio
    14.Disponibilità dei pz ambosesso in età fertile a utilizzare metodi contraccettivi efficaci doppi
    Per gli altri si prega di Riferirsi al Protocollo
    E.4Principal exclusion criteria
    1. Major surgery within 4 weeks prior to C1D1.
    2. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to C1D1; ongoing cardiomyopathy; or current prolonged QT interval corrected for heart rate (QTc) interval major 440 milliseconds for patients minor= 15 years old and major 470 milliseconds for patients major 15 years old. For patients minor= 15 years old, Bazett's Formula will be utilized to determine QTc. For patients major 15 years old, either method, Fridericia or Bazett's Formula may be applied.
    3. Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the Investigator makes the risk: benefit ratio for the patient to participate in the trial unfavorable.
    4. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
    5. Pregnancy or lactation.
    6. Uncontrolled hypotension or hypertension major= Grade 3 CTCAE (v 5.0).
    7. Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the patient required a modification to current thyroid medication in the 7 days before start of selpercatinib).
    8. Uncontrolled symptomatic hypercalcemia or hypocalcemia.
    9. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (refer to Appendix D of the main protocol for examples).
    10. Known hypersensitivity to any of the components of the investigational agent, selpercatinib or Ora-Sweet® SF and OraPlus®, for patients who will receive selpercatinib suspension.
    11. Current treatment with proton pump inhibitors (PPIs).
    12. Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s]).
    Note: Patients who discontinue another selective RET inhibitor(s) due to intolerance may be eligible with prior Sponsor approval.
    1. Intervento di chirurgia maggiore nei 14 giorni (2 settimane) precedenti il C1G1.
    2. Patologia cardiovascolare clinicamente significativa in atto o pregresso infarto miocardico nei 6 mesi precedenti il C1G1, cardiomiopatia cronica oppure attuale prolungamento dell’intervallo QT corretto per la frequenza cardiaca (QTc) maggiore 440 millisecondi
    per pazienti di età minore=15 anni e maggiore 470 millisecondi per pazienti di età >15 anni. Per i pazienti di età minore=15 anni, sarà utilizzata la formula di Bazett per determinare il QTc. Per i pazienti di età maggiori 15 anni, può essere utilizzato uno dei due metodi, la formula di Fridericia o di Bazett.
    3. Infezione sistemica attiva di natura batterica, virale o micotica non controllata che, secondo l’opinione dello sperimentatore, renderebbe sfavorevole il rapporto benefici/rischi per la partecipazione del paziente alla sperimentazione. Non è richiesto lo screening delle condizioni croniche.
    4. Sindrome da malassorbimento attiva clinicamente significativa o altra condizione che possa alterare l’assorbimento gastrointestinale del farmaco dello studio.
    5. Gravidanza o allattamento.
    6. Ipotensione o ipertensione non controllata di grado maggiore=3 CTCAE (v5.0)
    7. Ipertiroidismo o ipotiroidismo sintomatico non controllato (ovvero, il paziente ha richiesto una modifica dell’attuale terapia tiroidea nei 7 giorni precedenti l’inizio di selpercatinib)
    8. Ipercalcemia o ipocalcemia sintomatica non controllata.
    9. Trattamento in corso con potenti inibitori o induttori del citocromo P450 3A4 (CYP3A4)
    10. Nota ipersensibilità a qualsiasi componente dell’agente sperimentale, selpercatinib o Ora-Sweet® SF e OraPlus®, per i pazienti che riceveranno la sospensione di selpercatinib
    11. Trattamento in corso con inibitori della pompa protonica (IPP).
    12. Pregresso trattamento con uno o più inibitori RET selettivi (inclusi uno o più inibitori RET selettivi sperimentali).
    Nota: i pazienti che interrompono un altro inibitore RET selettivo possono essere idonei previa approvazione dello Sponsor.
    E.5 End points
    E.5.1Primary end point(s)
    PHASE 1
    Frequency, severity and relatedness of TEAEs and SAEs, including DLTs in pediatric patients receiving Selpercatinib

    PHASE 2
    ORR based on RECIST v1.1 or RANO as appropriate to tumor type as determined by an IRC
    FASE 1
    Frequenza, gravità e correlazione di TEAE ed eventi avversi seri (Serious Adverse Event, SAE), comprese le DLT, nei pazienti pediatrici che ricevono Selpercatinib

    FASE 2
    ORR in base ai criteri RECIST v1.1 o RANO, a seconda del tipo di tumore, determinato da un IRC
    E.5.1.1Timepoint(s) of evaluation of this end point
    PHASE 1:
    From the time of informed consent, for approx.24 months (or earlier if the patient discontinues from the study), and through Safety FU (28 days after the last dose). DLTs during the first 28-day cycle of Selpercatinib treatment

    PHASE 2:
    Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed.
    FASE 1
    Dal momento del consenso informato, per circa 24 mesi (o prima se il paziente discontinua dallo studio), e attraverso Safety FU (28 giorni dopo l'ultima dose). DLTs durante il primo ciclo di 28 giorni di trattamento con Selpercatinib

    FASE 2
    Approssimativamente ogni 8 settimane per un anno, poi ogni 12 settimane, 7 giorni dopo l'ultima dose (fino a 2 anni) in pazienti che non hanno progredito.
    E.5.2Secondary end point(s)
    PHASE 1:
    1. Plasma concentrations of Selpercatinib and PK parameters, including, but not limited to area under the concentration versus time curve from time 0 to 24 hours (AUC0-24), maximum drug concentration (Cmax), time to maximum plasma concentration (Tmax), degree of accumulation, and other characterizations
    2. To identify the MTD and/or the RP2D of Selpercatinib in pediatric patients
    3. To describe the antitumor activity of Selpercatinib in pediatric patients with tumors harboring an activating RET alteration
    4. Changes from baseline in pain scales and PedsQL-Core scores
    PHASE 2
    1. ORR based on RECIST v1.1 or RANO as appropriate to tumor type per the treating Investigator's response assessment
    2. DOR (IRC and treating Investigator)
    3. PFS (IRC and treating Investigator)
    4. OS
    5. CBR (IRC and treating Investigator)
    6. Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, and assessments of physical examinations, vital signs, and ECGs
    7. Concordance rate of prior molecular profiling that detected a RET alteration within the patient's tumor with diagnostic tests being evaluated by the Sponsor
    8.. Post-operative staging and surgical margin status in patients who have definitive surgery following treatment with Selpercatinib
    9. Number of patients with putative pretreatment surgical plan and the actual post treatment approach with an emphasis on the functional and cosmetic outcome
    FASE 1
    • Concentrazioni plasmatiche di Selpercatinib e parametri PK inclusi, a titolo puramente esemplificativo, area sotto la curva (Area Under the Curve, AUC) concentrazione-tempo dal tempo 0 a 24 ore (AUC0-24), concentrazione massima del farmaco (Cmax), tempo al raggiungimento della concentrazione plasmatica massima (Tmax), grado di accumulo e altre caratterizzazioni
    • Identificare la MTD e/o RP2D di Selpercatinib in pazienti pediatrici
    • Descrivere l’attività antitumorale di Selpercatinib in pazienti pediatrici con tumori portatori di un’alterazione attivante di RET
    • Variazioni rispetto al basale nelle scale del dolore e nei punteggi del PedsQL-Core
    FASE 2
    1. ORR in base ai criteri RECIST v1.1 o RANO, a seconda del tipo di tumore, sulla base della valutazione della risposta a discrezione dello sperimentatore curante
    2. DOR (valutata dall’IRC e dallo sperimentatore curante)
    3. PFS (valutata dall’IRC e dallo sperimentatore curante)
    4. OS
    5. CBR (valutato dall’IRC e dallo sperimentatore curante)
    6. Frequenza, gravità e correlazione di TEAE e SAE, variazioni nei valori di ematologia ed ematochimica e valutazioni di esami obiettivi, segni vitali ed ECG
    7. Tasso di concordanza del precedente profilo molecolare che aveva evidenziato la presenza di un’alterazione di RET all’interno del tumore del paziente rispetto ai test diagnostici oggetto di valutazione da parte dello Sponsor
    8. Stadiazione postoperatoria e stato dei margini chirurgici nei pazienti sottoposti a chirurgia definitiva secondariamente alla terapia con Selpercatinib
    9 Numero di pazienti con piano chirurgico pre-trattamento putativo ed effettivo approccio post-trattamento, con particolare riferimento all’esito funzionale ed estetico
    E.5.2.1Timepoint(s) of evaluation of this end point
    PHASE 1:
    1.Day 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation
    2.MTD: Day 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intrapatient Dose Escalation
    2.RP2D: first 28 days of treatment (Cycle 1) and every cycle for approx.12 months
    3.Approx.every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed
    4.Up to 24 months
    PHASE 2:
    1-5.Approx. every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed.
    6.From the time of informed consent, for approx.24 months (or earlier if the patient discontinues from the study), and through Safety FU (28 days after the last dose)
    7. 6months
    8. 6months
    9. 6months
    FASE 1:
    1. giorno 1 & 8 del ciclo 1, giorno 1 del ciclo 3 e del giorno 8 dopo l'escalation della dose intra-paziente
    2. MTD: giorno 1 & 8 del ciclo 1, giorno 1 del ciclo 3 e del giorno 8 dopo l'escalation della dose Intrapatient
    2. RP2D: primi 28 giorni di trattamento (ciclo 1) e ogni ciclo per circa 12 mesi
    3. circa ogni 8 settimane per un anno, poi ogni 12 settimane, 7 giorni dopo l'ultima dose in pazienti che non hanno progredito
    4. fino a 24 mesi
    FASE 2:
    1-5. circa ogni 8 settimane per un anno, poi ogni 12 settimane, e 7 giorni dopo l'ultima dose (fino a 2 anni) in pazienti che non hanno progredito.
    6. dal momento del consenso informato, per circa 24 mesi (o prima se il paziente discontinua dallo studio), e attraverso Safety FU (28 giorni dopo l'ultima dose)
    7. 6mesi
    8. 6mesi
    9. 6mesi
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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
    Dose escalation
    Aumento della dose
    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 Yes
    E.8.1.7.1Other trial design description
    In aperto
    Open
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA 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
    Japan
    United States
    Denmark
    France
    Germany
    Italy
    Spain
    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
    Individual patients will continue dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. It is anticipated that a patient on this study will receive treatment with open-label selpercatinib until the patient is able to obtain commercially available
    selpercatinib in their respective country, the patient does not meet criteria requiring discontinuation of treatment, and the patient's participation in the study has not ended.
    I singoli pazienti continueranno a somministrazioni fino a PD, tossicità inaccettabile o altri motivi per l'interruzione del trattamento. Si prevede che un paziente in questo studio riceverà il trattamento con selpercatinib in aperto fino a quando il paziente non è in grado di ottenere selpercatinib disponibile in commercio nel rispettivo paese, il paziente non soddisfa i criteri che richiedono l'interruzione del trattamento e la partecipazione del paziente allo studio non è terminata.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    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 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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 42
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 25
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 17
    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 25
    F.4.2.2In the whole clinical trial 90
    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)
    After treatment discontinuation, Long-Term Follow-up (LTFU) assessments and procedures will be conducted in accordance with the Schedule of Assessments (Protocol, Table 11-1). LTFU will occur approximately every 3 months (±1 month) until the patient experiences PD, withdraws consent for further participation, is lost to follow-up, has died, or close of the study.
    Dopo l'interruzione del trattamento, le valutazioni e le procedure di follow-up a lungo termine (LTFU) saranno condotte in conformità con lo Schedule of Assessments (Protocollo, Tabella 11-1). L'LTFU si verificherà approssimativamente ogni 3 mesi (± 1 mese) fino a quando il paziente non ha una PD, ritira il consenso per ulteriore partecipazione, è perso al follow-up, è deceduto o si chiude lo studio.
    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 Decision2019-09-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-26
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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