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    Summary
    EudraCT Number:2021-004729-55
    Sponsor's Protocol Code Number:GD2CAR02
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-11-04
    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 number2021-004729-55
    A.3Full title of the trial
    Phase I study of anti-GD2 Chimeric Antigen Receptor-Expressing T cells in pediatric and young adult patients affected by relapsed/refractory central nervous system tumors
    Studio di fase I su cellule T esprimenti un recettore chimerico anti-GD2 in pazienti pediatrici e giovani adulti affetti da tumori al sistema nervoso centrale recidivati/refrattari
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I study of anti-GD2 Chimeric Antigen Receptor-Expressing T cells in pediatric and young adult patients affected by relapsed/refractory central nervous system tumors
    Studio di fase I su cellule T esprimenti un recettore chimerico anti-GD2 in pazienti pediatrici e giovani adulti affetti da tumori al sistema nervoso centrale recidivati/refrattari
    A.3.2Name or abbreviated title of the trial where available
    GD2CAR02
    GD2CAR02
    A.4.1Sponsor's protocol code numberGD2CAR02
    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 SponsorIRCCS, OSPEDALE PEDIATRICO BAMBINO GESÙ DI ROMA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS Ospedale Pediatrico Bambino Gesù
    B.5.2Functional name of contact pointDipartimento oncoematologia
    B.5.3 Address:
    B.5.3.1Street AddressPiazza Sant’Onofrio, 4
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00168
    B.5.3.4CountryItaly
    B.5.4Telephone number0668592678
    B.5.5Fax number0668592392
    B.5.6E-mailfranco.locatelli@opbg.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGD2-CART01
    D.3.2Product code [GD2-CART01]
    D.3.4Pharmaceutical form 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 INNLinfociti T modificati geneticamente con fattore retrovirale SFG-iC9 CAR.GD2.CD28.41BB.zeta
    D.3.9.2Current sponsor codeGD2-CART01
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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.2.5The 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 nameCiclofosfamide monoidrata
    D.3.2Product code [n.a]
    D.3.4Pharmaceutical form Powder and solvent 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 INNCiclofosfamide
    D.3.9.1CAS number 50-18-0
    D.3.9.2Current sponsor coden.a
    D.3.9.3Other descriptive nameCyclophosphamide
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAP1903
    D.3.2Product code [n.a]
    D.3.4Pharmaceutical form 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 INN2-Piperidinecarboxylic acid, 1-[(2S)-1-oxo- 2-(3,4,5-trimethoxyphenyl)butyl]-, 1,2- ethanediylbis[imino(2-oxo-2,1-ethanediyl)oxy-3,1-phenylene[(1R)-3-
    D.3.9.1CAS number 195514-63-7
    D.3.9.2Current sponsor codeAP1903
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 Yes
    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 nameFludarabina Fosfato
    D.3.2Product code [n.a]
    D.3.4Pharmaceutical form Powder and solvent 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 INNFludarabina
    D.3.9.1CAS number 21679-14-1
    D.3.9.2Current sponsor coden.a
    D.3.9.3Other descriptive nameFludarabine
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    Relapsed/refractory malignant central nervous system tumors
    Tumori maligni al sistema nervoso centrale recidivati/refrattari
    E.1.1.1Medical condition in easily understood language
    Relapsed/refractory malignant central nervous system tumors
    Tumori maligni al sistema nervoso centrale recidivati/refrattari
    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 SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate the safety and feasibility and establish the maximum tolerated dose (MTD)/recommended dose (RD) of iC9-GD2-CAR T-cells infused in pediatric and young adult patients affected by relapsed/refractory malignant central nervous system (CNS) tumors.
    L’obiettivo primario di questo studio è valutare la sicurezza e la fattibilità e stabilire la dose massima di tollerabilità (MTD)/dose raccomandata (RD) delle cellule iC9-GD2-CAR T infuse in pazienti pediatrici e giovani adulti affetti da Tumori maligni al Sistema Nervoso Centrale (CNS) recidivati/refrattari.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the protocol will be aimed at characterizing the kinetics of expansion and distribution of the infused iC9-GD2-CAR-T cells, document CRS features and obtain preliminary data on the efficacy of the treatment. The same features will be analyzed in the subgroup of patients receiving AP1903, in order to define the impact of the activation of the safety switch. Intracerebral microdialysate analysis will be performed to monitor cerebral metabolism after GD2-CAR T-cells treatment. Furthermore, microdialysate cerebrospinal fluid (CSF) samples will be used to obtain local cytokines profile after GD2-CAR T-cells treatment and to monitor CRS in the CNS in response to immunotherapy.
    Gli obiettivi secondari dello studio saranno volti a caratterizzare la cinetica dell’espansione e distribuzione dell'infusione di cellule iC9-GD2-CAR-T, documentare le specificità della sindrome da rilascio citochinico (CRS) e ottenere dati preliminari sull’efficacia del trattamento. Le stesse specificità verranno analizzate nel sottogruppo di pazienti che ricevono AP1903, per poter definire l’impatto della sicurezza del passaggio da un trattamento all’altro. Analisi di microdialisi intracerebrale saranno condotte per monitorare il metabolismo cerebrale dopo il trattamento con cellule GD2-CAR T. Inoltre, campioni di liquido cerebrospinale microdializzato (CSF) saranno utilizzati per ottenere il profilo delle citochine locali dopo il trattamento con cellule GD2-CAR T e per monitorare la CRS nel CNS in risposta all’immunoterapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Procurement eligibility
    1. Histological diagnosis of relapsed/refractory CNS tumors, including:
    a. Medulloblastoma (MB)/other embryonal tumor (ARM A)
    b. Hemispheric high-grade glioma (HGG) (ARM B)
    c. Thalamic HGG, diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) and other rare CNS tumors not included in Arm A and B (ARM C)
    2. Eligibility according to GD2 expression:
    - GD2-positivity: the patient will be considered eligible and will be enrolled in the present protocol since there is not any other effective treatment to be explored
    - GD2-negativity: the patient will be considered NOT eligible for the treatment: an alternative treatment of rescue, whenever possible, or palliation will be proposed to the patient in this case
    - Impossibility of obtaining tumor samples: the patient will be considered eligible and will be enrolled in the present protocol since there is not any other effective treatment to be explored
    3. Age: 6 months – 30 years
    4. Adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis
    5. Written and signed informed consent from patients, parents or legal guardians. For subjects < 18 year-old their legal guardian must give informed consent. In addition, pediatric subjects will be included in age-appropriate discussion and written informed assent will be obtained for those greater than or equal to 7 years of age, when appropriate
    6. Karnofsky/Lansky = 60

    Treatment eligibility
    1. Imaging assessments performed within 14 days of start of treatment
    2. Age: 6 months – 30 years
    3. Measurable or evaluable disease on at least 2 dimensions on MRI at the time of treatment enrollment
    4. Karnofsky/Lansky = 60
    5. Recover from the toxic effects of previous radiation and chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade = 2; in presence of chronic complications (i.e. treatment-associated thrombocytopenia), patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria
    6. Positioning of an implantable intraventricular access device (Codman Holter Rickham reservoir, Integra LifeSciences, NJ, U.S.A) and a microdialysis probe (71 high cutoff microdialysis bolt catheter, M Dialysis AB, Stockholm Sweden)
    7. “Written and signed informed consent from patients, parents or legal guardians. For subjects < 18 year-old their legal guardian must give informed consent. In addition, pediatric subjects will be included in age-appropriate discussion and written informed assent will be obtained for those greater than or equal to 7 years of age, when appropriate”
    8. Patients of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen
    9. Females of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus
    Eleggibilità all’aferesi:
    Tutti i pazienti devono soddisfare i seguenti criteri di inclusione di ammissibilità al momento dell'eleggibilità.
    1. Diagnosi istologica di tumori del Sistema Nervoso Centrale recidivati/refrattari, includendo:
    a. Medulloblastoma (MB)/altri tumori embrionali (ARM A)
    b. Glioma emisferico di alto grado (HGG) (ARM B)
    c. Glioma talamico di alto grado, glioma diffuso della linea mediana (DMG) o glioma diffuso intrinseco del ponte (DIPG) e altri tumori rari del CNS non inclusi nei bracci A e B (ARM C)
    2. Eleggibilità secondo l’espressione GD2:
    - Positività GD2: il paziente sarà considerato eleggibile e verrà arruolato nel presente protocollo poiché non vi è alcun altro trattamento efficace da esplorare
    - Negatività GD2: il paziente non sarà considerato idoneo al trattamento: in questo caso, verrà proposto al paziente un trattamento alternativo di recupero, se possibile, o di palliazione
    - Impossibilità di ottenere campioni tumorali: il paziente sarà considerato eleggibile e verrà arruolato nel presente protocollo poiché non vi è alcun altro trattamento efficace da esplorare
    3. Età: 6 mesi – 30 anni
    4. Accesso venoso adeguato per l’aferesi o eleggibile ad un appropriato posizionamento del catetere e assenza di altre controindicazione per la leucoaferesi
    5. Consenso informato firmato da pazienti, genitori e tutori legali. I pazienti pediatrici saranno inclusi se di età appropriata e l’assenso verbale sarà ottenuto per coloro che hanno un’età superiore o uguale a 12 anni, se appropriato
    6. Karnofsky/Lansky = 60

    Eleggibilità al trattamento
    1. Valutazione diagnostica effettuata entro 14 giorni dall’inizio del trattamento
    2. Età: 6 mesi – 30 anni
    3. I pazienti devono avere una malattia misurabile o valutabile con la risonanza magnetica in almeno due dimensioni al momento dell’arruolamento al trattamento
    4. Karnofsky/Lansky = 60
    5. Recuperare dagli effetti tossici indotti da precedenti radiazioni e chemioterapie: le tossicità non ematologiche di grado 3 o 4 devono essere risolte al grado =2; in presenza di complicazioni croniche (ad esempio la trombocitopenia associata al trattamento), il paziente deve essere clinicamente stabile, secondo il parere dei medici curanti, e soddisfare tutti gli altri criteri di eleggibilità
    6. Posizionamento di un accesso intraventricolare impiantabile (Codman Holter Rickham reservoir, Integra LifeSciences, NJ, U.S.A) e di una sonda per microdialisi (71 high cutoff microdialysis bolt catheter, Mdyalisis AB, Stockolm Sweden)
    7. Consenso informato firmato da pazienti, genitori e tutori legali. Per i soggetti < 18 anni il loro tutore legale deve dare il consenso informato. Inoltre, i soggetti pediatrici riceveranno le informazioni dello studio in base all’età di riferimento e l’assenso informato scritto sarà ottenuto per i pazienti che hanno un’età superiore o uguale a 7 anni, se appropriato
    8. Soggetti di sesso maschile e femminile in età fertile devono essere disposti a praticare il controllo delle nascite dal momento dell’arruolamento in questo studio e per 4 mesi dopo aver ricevuto il trattamento.
    9. Soggetti di sesso femminile in età fertile non devono essere in stato di gravidanza a causa degli effetti potenzialmente dannosi sul feto
    E.4Principal exclusion criteria
    1. Severe, uncontrolled active infections
    2. HIV or active HCV and/or HBV infection
    3. Concurrent or recent prior therapies, before apheresis:
    a. If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days prior to apheresis. Recent or current use of inhaled/topical/nonabsorbable steroids is not exclusionary. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis
    b. Systemic chemotherapy in the 3 weeks preceding apheresis collection
    c. Immunosuppressive agents in the 2 weeks preceding apheresis collection
    d. Radiation therapy must have been completed at least 6 weeks prior to apheresis

    Exclusion criteria:
    1. Pregnant or lactating women
    2. Severe, uncontrolled active infections
    3. HIV or active HCV and/or HBV infection
    4. Rapidly progressive disease with life expectancy < 6 weeks
    5. History of grade 3 or 4 hypersensitivity to murine protein-containing products
    6. Hepatic function: inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN based on age and laboratory specific normal ranges
    7. Renal function: serum creatinine > 3x ULN for age
    8. Blood oxygen saturation < 90%
    9. Cardiac function: left ventricular ejection fraction lower than 45% by ECHO
    10.Marrow function: absolute neutrophils count (ANC) lower than 500/mm3 and/or platelets lower than 20.000 (not reached by transfusion)
    11.Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the principal investigator (PI) would pose an unacceptable risk to the subject.
    12.Concurrent or recent prior therapies, before infusion:
    a. If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days prior to infusion. Recent or current use of inhaled/topical/nonabsorbable steroids is not exclusionary. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis
    b. Systemic chemotherapy in the 3 weeks preceding infusion
    c. Immunosuppressive agents less than or equal to 30 days
    d. Radiation therapy must have been completed at least 6 weeks prior to enrollment
    e. Other anti-neoplastic investigational agents currently or within 30 days prior to start of protocol therapy
    13.Patient-derived GD2-CART01 production failure: vitality 20%, RCR positivity, Vector Copy Number >10, non-sterility, endotoxin contamination (> 1 EU/ml)
    1. Infezioni intercorrenti attive non controllate, severe
    2. HIV o infezione attiva da HCV e/o HBV
    3. Precedenti terapie concomitanti o recenti, prima dell’aferesi:
    a. I pazienti in trattamento steroideo dovranno avere un fabbisogno di steroide stabile da almeno 7 giorni o in riduzione, prima dell’aferesi. Non sono quindi eleggibili pazienti che abbiano un incremento del fabbisogno di steroidi nei 7 giorni che precedono l’aferesi. Saranno inclusi i pazienti che ricevono terapia steroidea inalatoria o topica e coloro che ricevono terapia steroidea sostitutiva. In quest’ultimo caso è eleggibile un paziente che non abbia avuto necessità di incrementare il dosaggio della terapia sostitutiva nelle due settimane precedenti l’aferesi
    b. Chemioterapia sistemica nelle 3 settimane precedenti la raccolta aferetica.
    c. Terapia immunosoppressiva nelle 2 settimane precedenti la raccolta aferetica.
    d. La radioterapia deve essere completata almeno 6 settimane prima dell’aferesi.

    Criteri di esclusione:
    1. Soggetto in stato di gravidanza o allattamento
    2. Infezioni intercorrenti attive non controllate, severe
    3. Infezione attiva da HCV e/o HBV
    4. Malattia in progressione rapida con aspettativa di vita < 6 settimane
    5. Storia di ipersensibilità di grado 3 o 4 a prodotti contenenti proteine murine
    6. Funzione epatica: Funzionalità epatica inadeguata definita come bilirubina totale > 4x sopra il limite del normale (LSN) o transaminasi (ALT and AST) > 6 x LSN basati sull’età e sui normal range specifici del laboratorio
    7. Funzione renale: creatinine sierica > 3x LSN per l’età
    8. Saturazione di ossigeno nel sangue < 90%.
    9. Funzione cardiaca: frazione di eiezione del ventricolo sinistro minore del 45% da ECHO.
    10. Funzionalità midollare: conta neutrofila inferiore a 500/mm3 e/o piastrine inferiori a 20.000 (non raggiunte dalla trasfusione).
    11. Insufficienza cardiaca congestizia, aritmia cardiaca, malattie psichiatriche o condizioni sociali che potrebbero limitare la compliance con le richieste dello studio o che secondo il parere del PI potrebbe comportare un rischio inaccettabile per il soggetto.
    12. Precedenti terapie concomitanti o recenti, prima dell’infusione: a. I pazienti in trattamento steroideo dovranno avere un fabbisogno di steroide stabile da almeno 7 giorni o in riduzione, prima dell’aferesi. Non sono quindi eleggibili pazienti che abbiano un incremento del fabbisogno di steroidi nei 7 giorni che precedono l’aferesi. Saranno inclusi i pazienti che ricevono terapia steroidea inalatoria o topica e coloro che ricevono terapia steroidea sostitutiva. In quest’ultimo caso è eleggibile un paziente che non abbia avuto necessità di incrementare il dosaggio della terapia sostitutiva nelle due settimane precedenti l’aferesi. b. Chemioterapia sistemica nelle 3 settimane precedenti l’infusione. c. Agenti immunosoppressi minore o uguale a 30 giorni. d. La radioterapia deve essere completata almeno 6 settimane prima dell’arruolamento. e. La terapia con I131 MIBG deve essere completata almeno 6 settimane prima dell’arruolamento. f. Altri agenti anti-neoplastici di ricerca attualmente somministrati o entro 30 giorni precedenti l’inizio della terapia del protocollo;
    13. Il fallimento della produzione di GD2-CART01 derivato dal paziente si manifesta con i seguenti criteri: vitalità 20%, positività di RCR, numero di copie di vettore >10, non sterilità, contaminazione da endotossine (> 1 EU/ml)
    E.5 End points
    E.5.1Primary end point(s)
    1. To evaluate the safety of the infusion of iC9-GD2-CAR-T cells at different escalating/de-escalating doses and establish the dose limiting toxicity (DLT) of the cellular product. Toxicity, both systemic and neurological, will be evaluated according to the Common Terminology Criteria for Adverse Event scale, version 5.0, and to specific grading scales (i.e. Lee grading for Cytokine Release Syndrome – CRS - and American Society for Transplantation and Cellular Therapy - ASTCT- Immune effector cell-associated neurotoxicity syndrome - ICANS - Consensus Grading). DLT will be defined as any of the following that is not pre-existing, due to infection or to underlying malignancy and that may be considered possibly, probably or most definitely related to the study cellular products: 1) Non-hematologic DLT is any grade 3 or 4 nonhematologic toxicity, non-responsive to AP1903 infusions; 2) Hematologic DLT is defined as any grade 4 hematologic toxicity, non-responsive to AP1903 infusions; 3) Grade 4 reactions related to infusion; 4) Death related to iC9-GD2-CAR-T cells or to AP1903 infusions. The incidence of grade 3-5 toxicities, with a main attention to severe Cytokine Release Syndrome (CRS), will be evaluated.

    2. To determine the optimal dose of iC9-GD2-CAR transduced T cells resulting in the control of the disease without inducing unacceptable levels of toxicity (MTD/RD).
    1. Valutare la sicurezza dell’infusione delle cellule iC9-GD2-CAR T a differenti dosi escalating/de-escalating e stabilire la dose limitante la tossicità (DLT) del prodotto cellulare. La tossicità, sia sistemica che neurologica, verrà valutata in accordo ai Criteri Comuni di Terminologia per la scala degli Eventi Avversi (CTC AE), versione 5.0 e a determinate scale di giudizio (Lee grading for Cytokine Release Syndrome – CRS - and American Society for Transplantation and Cellular Therapy - ASTCT- Immune effector cell-associated neurotoxicity syndrome - ICANS - Consensus Grading). La DLT sarà definita come una delle seguenti che non è pre-esistente, dovuta a infezione o a malignità sottostanti e che può essere considerata possibile, probabile o connessa al prodotto cellulare di studio:
    1) DLT non-ematologica è la tossicità non ematologica di grado 3 o 4, che non risponde all’infusione di AP1903;
    2) DLT ematologica è definita come ogni tossicità di grado 4, che non risponde all’infusione di AP1903;
    3) Reazioni di grado 4 connesse all’infusione;
    4) Morte in relazione alle infusioni delle cellule iC9-GD2-CAR T o di AP1903. L'incidenza delle tossicità di grado 3-5 sarà valutata, con particolare attenzione alla sindrome da rilascio citochinico (CRS).

    2. Determinare la dose ottimale di cellule T iC9-GD2-CAR trasdotte risultante nel controllo della malattia senza indurre livelli inaccettabili di tossicità (MTD/RD).
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 6 months, 1, 3 and 5 years
    a 6 mesi, 1, 3 e 5 anni
    E.5.2Secondary end point(s)
    1. To assess the in vivo persistence and expansion of the infused CAR T-cells in the peripheral blood (PB) and CSF using immunoassays and transgene detection (Droplet PCR), both for the whole population and the specific T cells subsets
    2. To evaluate the tumor infiltration of the infused T cells by immunohistochemistry (IHC), flow cytometry and/or transgene detection (Droplet PCR), whenever the tumor sample is available after the treatment
    3. To assess the kinetic of GD2-CAR T-cells clearance after AP1903 infusion
    4. To define the serum and CSF cytokine profile and its correlation with CRS in order to identify a possible predictive profile:
    • To dose IL-6, IL-2, IL-1, IL-1b, TNF-alpha, Interferon gamma in the microdialysate and in CSF samples to measure the CRS secondary to immunotherapy; to correlate cytokines trends in CSF and in microdialysis samples after GD2-CAR T-cells treatment
    • To dose glucose, lactate, pyruvate, lactate to pyruvate ratio (LPR), glycerol and glutamate to assess cerebral metabolism and oxidative damage and to correlate these with intracranial pressure (ICP) and cerebral perfusion pressure (CPP) after GD2-CAR T-cells infusion
    5. To assess the clinical response and the kinetics of cytokine levels change in patients with CRS treated with AP1903
    6. To assess the long-term antitumor effect of the infused GD2-CAR T-cells at 1, 3 and 5 years, without further therapy
    7. To assess relapse rate, time to progression (TTP) and event free survival (EFS) and overall survival (OS) at 6 months 1, 3- and 5-years post cell infusion
    8. To assess the disease outcome in patients treated with AP1903
    9. To evaluate the ability of the response evaluation provided by the Response assessment in pediatric neuro-oncology (RAPNO) criteria to predict the disease outcome.
    1. Valutare la persistenza e l’espansione in vivo delle cellule CAR T infuse, nel sangue periferico (PB) e nel CFS utilizzando saggi immunologici e Droplet PCR per il rilevamento del transgene, sia per l’intera popolazione che per specifiche sottopopolazioni di cellule T.
    2. Valutare l’infiltrazione tumorale delle cellule T infuse mediante Immunoistochimica (ICH), citometria a flusso e/o utilizzando Droplet PCR per il rilevamento del transgene, ogni volta che il campione tumorale è disponibile dopo il trattamento.
    3. Valutare la cinetica dell’eliminazione delle cellule CAR T dopo l'infusione di AP1903.
    4. Definire il profilo delle citochine nel siero e nel CFS e la correlazione con la sindrome da rilascio citochinico (CRS) al fine di definire un possibile profilo predittivo:
    • Per il dosaggio IL-6, IL-2, IL-1, IL-1b, TNF-alpha, Interferon gamma nei campioni di microdializzato e CSF per misurare la CRS secondaria per l’immunoterapia; per studiare la correlazione tra l’andamento delle citochine nei campioni di CSF e di microdialisi dopo il trattamento con cellule GD2-CAR T.
    • Per il dosaggio di glucosio, lattato, rapporto tra lattato e piruvato (LPR), glicerolo e glutammato per valutare il metabolismo cerebrale e il danno ossidativo e per correlare gli stessi con la pressione intracranica (ICP) e la pressione di perfusione cerebrale (CPP) dopo l’infusione di cellule GD2-CAR T.
    5. Valutare la risposta clinica e la cinetica dei livelli citochinici nei pazienti con CRS che ricevono AP1903.
    6. Per valutare l’effetto antitumorale a lungo termine delle cellule GD2-CAR T infuse a 1, 3 e 5 anni, senza ulteriori terapie
    7. Valutare la frequenza di recidiva, il tempo alla progressione (TTP), la sopravvivenza libera da eventi (EFS) e la sopravvivenza globale (OS) a 6 mesi, 1, 3 e 5 anni dall’infusione delle cellule.
    8. Valutare l'outcome della malattia nei pazienti trattati con AP1903.
    9. Valutare la risposta fornita dai criteri di valutazione RAPNO (Response assessment in pediatric neuro-oncology) per predire l’outcome della malattia
    E.5.2.1Timepoint(s) of evaluation of this end point
    at 6 months, 1, 3 and 5 years
    a 6 mesi, 1, 3 e 5 anni
    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 No
    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
    dose-finding study
    dose-finding study
    E.7.2Therapeutic exploratory (Phase II) No
    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 trial3
    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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will be closed after the completion of the 15 years of follow-up (for gene therapy follow-up).
    15 anni di follow up
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years15
    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 years15
    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: 3
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 3
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Infants and toddlers; Children. Pediatric subjects will be included in age-appropriate discussion and written informed assent will be obtained for those greater than or equal to 7 years of age
    Lattanti e bambini piccoli; Bambini. I soggetti pediatrici riceveranno le informazioni dello studio in base all’età di riferimento e l’assenso informato scritto sarà ottenuto per i pazienti che hanno un’età superiore o uguale a 7 anni
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state27
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 27
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Nessuno
    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 Decision2023-07-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-27
    P. End of Trial
    P.End of Trial StatusOngoing
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