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    Summary
    EudraCT Number:2018-001404-11
    Sponsor's Protocol Code Number:TEM-GBM_001
    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:2019-06-12
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-001404-11
    A.3Full title of the trial
    A phase I/IIa dose escalation study evaluating the safety and efficacy of autologous CD34+-enriched hematopoietic progenitor cells genetically modified with a lentiviral vector encoding for the human interferon-α2 in patients with glioblastoma multiforme who have an unmethylated O-6- methylguanine-DNA methyltransferase gene promoter
    Sperimentazione Clinica di fase I/II atta a valutare la sicurezza e l’efficacia di dosi crescenti di cellule staminali ematopoietiche autologhe CD34+ geneticamente modificate con un vettore lentivirale codificante per il gene umano dell’interferone-alfa2 in pazienti affetti da Glioblastoma Multiforme con promotore del gene MGMT non metilato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical gene therapy study with hematopoietic stem cells for the treatment of patients suffering from a malignant neoplasm of the central nervous system
    Studio clinico di terapia genica con cellule staminali ematopoietiche per il trattamento di pazienti affetti da un tumore maligno del sistema nervoso centrale
    A.3.2Name or abbreviated title of the trial where available
    TEM-GBM
    TEM-GBM
    A.4.1Sponsor's protocol code numberTEM-GBM_001
    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 SponsorGENENTA SCIENCE SRL
    B.1.3.4CountryItaly
    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 supportGenenta Science S.r.l.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenenta Science
    B.5.2Functional name of contact pointSportello Informazioni Sperimentazi
    B.5.3 Address:
    B.5.3.1Street AddressVia Olgettina 58
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20132
    B.5.3.4CountryItaly
    B.5.4Telephone number0226433982
    B.5.5Fax number0226434621
    B.5.6E-mailinfo-trial@genenta.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTemferon
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNgene codificante l'interferone-alfa2
    D.3.9.2Current sponsor codeTemferon
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.2 to 2
    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 No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MOZOBIL - 20 MG/ML - SOLUZIONE INIETTABILE - USO SOTTOCUTANEO - FLACONCINO (VETRO) - 24 MG/1.2 ML 1 FLACONCINO
    D.2.1.1.2Name of the Marketing Authorisation holderGENZYME EUROPE B.V.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namePLERIXAFOR
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPLERIXAFOR
    D.3.9.1CAS number 155148-31-5
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive namePLERIXAFOR
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MYELOSTIM - 13 1 FLAC LIOF 13.4 MIU + SIR SOLV 1 ML
    D.2.1.1.2Name of the Marketing Authorisation holderCHUGAI SANOFI AVENTIS
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameLENOGRASTIM
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENOGRASTIM
    D.3.9.1CAS number 135968-09-1
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameLENOGRASTIM
    D.3.10 Strength
    D.3.10.1Concentration unit million IU million international units
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number34
    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) Yes
    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 Yes
    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.2.1.1.1Trade name Carmustine
    D.2.1.1.2Name of the Marketing Authorisation holderEmcure Pharma UK
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameCARMUSTINA
    D.3.4Pharmaceutical form Powder and solvent for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCARMUSTINA
    D.3.9.1CAS number 154-93-8
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameCARMUSTINA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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: 5
    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 TEPADINA - 100 MG - POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO(VETRO) - 10MG/ML 1 FLACONCINO DA 100 MG
    D.2.1.1.2Name of the Marketing Authorisation holderADIENNE S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameTEPADINA
    D.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTIOTEPA
    D.3.9.1CAS number 52-24-4
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameTIOTEPA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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
    Glioblastoma Multiforme
    Glioblastoma Multiforme
    E.1.1.1Medical condition in easily understood language
    Malignant brain cancer
    Cancro Maligno al cervello
    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 PT
    E.1.2Classification code 10018337
    E.1.2Term Glioblastoma multiforme
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10018337
    E.1.2Term Glioblastoma multiforme
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10018336
    E.1.2Term Glioblastoma
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10018336
    E.1.2Term Glioblastoma
    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
    In Part A, the primary objective is to evaluate the safety and tolerability of 3 escalating doses of Temferon in up to 9 patients with GBM who have an unmethylated MGMT promoter, following first line radiotherapy and temozolomide treatment. In Part B, the primary objective is to evaluate the safety and tolerability of a single dose, as identified from Part A, of Temferon in 12 patients with GBM and unmethylated MGMT, following first line radiotherapy and temozolomide treatment.
    Parte A: valutare la sicurezza e la tollerabilità di 3 dosi crescenti di Temferon in un massimo di 9 pazienti affetti da glioblastoma multiforme (GBM) con promotore del gene della metiltransferasi O-6-metilguanina-DNA non metilato (MGMT), dopo chirurgia, diagnosi e trattamento di prima linea con radioterapia e temozolomide.
    Parte B: valutare la sicurezza e la tollerabilità di una singola dose di Temferon in 12 pazienti affetti da GBM e con promotore del gene MGMT non metilato, dopo trattamento di prima linea con radioterapia e temozolomide.
    E.2.2Secondary objectives of the trial
    The secondary objective of this study is to evaluate biological activity and efficacy of Temferon in patients with GBM and unmethylated MGMT when used following standard of care first line therapeutic approaches.
    L’obiettivo secondario dello studio è quello di valutare l'attività biologica e l'efficacia di Temferon in pazienti con GBM e con promotore del gene MGMT non metilato in seguito ad approcci terapeutici standard di prima linea.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria at Screening:
    • Patients aged between 18 and ≤70.
    • Histologically confirmed, newly diagnosed supratentorial
    glioblastoma with unmethylated MGMT gene promoter.
    • Patients have undergone complete or partial tumor resection.
    • Able and willing to provide written informed consent and comply with the study protocol and procedures. • Eligible for radiotherapy.
    • Life expectancy of 6 months or more at Screening.
    • Women of child-bearing potential enrolled in the study must
    have a negative pregnancy test at screening and agree to use
    acceptable methods of contraception during the trial.
    • Men enrolled in the study with partners who are women of
    child-bearing potential, must be willing to use an acceptable
    barrier contraceptive method during the trial or have undergone
    successful vasectomy at least 6 months prior to entry into the
    study. Successful vasectomy needs to have been confirmed by
    semen analysis.
    • Karnofsky performance score (KPS)≥70.
    Additional inclusion criteria to be assessed within 20 days of Temferon administration:
    • Adequate cardiac, renal, hepatic and pulmonary function as evidenced by:
    o Left ventricular ejection fraction (LVEF) ≥ 45% by echo and normal electrocardiogram (ECG) or presence of abnormalities not significant for cardiac disease.
    Absence of severe pulmonary hypertension;
    o Diffusing capacity of the lung for carbon monoxide (DLCO) >50% and forced expiratory volume in 1 sec (FEV1) and forced expiratory vital capacity (FVC) >60% predicted (if non cooperative: pulse oximetry > 95% in room air);
    o Serum creatinine < 2x upper limit normal and estimated
    glomerular filtration rate (eGFR) ≥ 30ml/min/1.73m^2;
    o Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 2.0 mg/dl.
    o Hemoglobin ≥10 g/dL, platelet count ≥100000/mm^3,
    absolute neutrophil count >1500/mm^3.
    Criteri di inclusione allo screening:
    •Pazienti di età compresa tra 18 e ≤70.
    •Glioblastoma sovratentoriale confermato istologicamente a nuova diagnosi, con promotore del gene MGMT non metilato.
    •I pazienti sono stati sottoposti a resezione completa o parziale del tumore.
    •In grado e disposto a fornire il consenso informato scritto e rispettare il protocollo e le procedure dello studio.
    •Idoneo per la radioterapia.
    •Aspettativa di vita di 6 mesi o più allo screening.
    •Le donne in età fertile arruolate nello studio devono sottoporsi a un test di gravidanza negativo allo screening e accettare di utilizzare metodi contraccettivi accettabili durante lo studio.
    •Gli uomini arruolati nello studio con partner donne potenzialmente fertili, devono essere disposti a utilizzare un metodo contraccettivo di barriera accettabile durante lo studio o aver subito una vasectomia di successo almeno 6 mesi prima dell'ingresso nello studio. La vasectomia riuscita deve essere stata confermata dall'analisi dello sperma.
    •Karnofsky performance score (KPS) ≥70.
    Criteri di inclusione aggiuntivi da valutare entro 20 giorni dall'amministrazione di Temferon:
    •Adeguata funzionalità cardiaca, renale, epatica e polmonare come evidenziato da:
    o Frazione di eiezione ventricolare sinistra (LVEF) ≥ 45% mediante eco e elettrocardiogramma normale (ECG) o presenza di anomalie non significative per la cardiopatia.
    o Assenza di grave ipertensione polmonare;
    o Capacità di diffusione del polmone per monossido di carbonio (DLCO)> 50% e volume espiratorio forzato in 1 sec (FEV1) e capacità vitale espiratoria forzata (FVC)> 60% previsto (se non cooperativo: pulsossimetria> 95% nell'aria ambiente); oCreatinina sierica <2x limite superiore tasso di filtrazione glomerulare normale e stimato (eGFR) ≥ 30 ml/min/1,73m^2; oFosfatasi alcalina (ALP), alanina aminotransferasi (ALT) e / o aspartato aminotransferasi (AST) ≤ 2,5 x limite superiore della norma (ULN) e bilirubina totale ≤ 2,0 mg/dl.
    o Emoglobina ≥10 g/dL, conta piastrinica ≥100000/mm^3, conta assoluta dei neutrofili> 1500/mm^3.
    E.4Principal exclusion criteria
    •Use of other investigational agents or procedures within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents) or participation in a previous gene therapy study.
    •Known hypersensitivity to carmustine (or any other nitrosurea), thiotepa, lenograstim, plerixafor, or any excipients used in these products.
    •Receipt of any oral or parenteral chemotherapy or immunotherapy within 2 years of Screening. •Previous allogeneic bone marrow transplantation, kidney or liver transplant.
    •Clinical evidence of persistent raised intracranial pressure following surgical resection. •Clinically relevant active viral, bacterial, or fungal infection at eligibility evaluation.
    •Active autoimmune disease or a relevant history of important autoimmune manifestations, in particular psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis, vasculitis, immune-mediated peripheral neuropathies.
    •History of sarcoidosis.
    •History or current evidence of neuropsychiatric illness including depression, schizophrenia, bipolar disorders, impaired cognitive function, dementia or suicidal tendency.
    •History of severe cardiovascular disease such as prior stroke, coronary artery disease requiring intervention or unresolved arrhythmias in the past 6 months.
    •Evidence of any hematological neoplasm.
    •Positivity for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2) (serology or RNA), and/or Hepatitis B Virus Surface Antigen (HbsAg) and/or Hepatitis B Virus (HBV) DNA and/or Hepatitis C virus (HCV) RNA (or negative HCV RNA but on antiviral treatment) and/or Treponema Pallidum or Mycoplasma active infection.
    •Active alcohol or substance abuse within 6 months of the study.
    •Current pregnancy or lactation.
    •Known bleeding diathesis or history of abnormal bleeding, or any other known coagulation abnormalities that would contraindicate lumbar puncture for CSF or future surgery.
    •Use of immunosuppressants with the exception of steroids. The maximum permitted dexamethasone (or equivalent) dose is 4 mg per day.
    •Uso di altri agenti o procedure sperimentali nelle 4 settimane precedenti l'arruolamento nello studio (entro 6 settimane se si
    usano agenti a lunga durata d'azione) o partecipazione a precedenti studi di terapia genica.
    •Ipersensibilità nota a carmustina (o qualsiasi altra nitrosurea), tiotepa, lenograstim, plerixafor o qualsiasi eccipiente usato in questi prodotti.
    •Ricevimento di qualsiasi chemioterapia o immunoterapia orale o parenterale entro 2 anni dallo Screening.
    •Trapianto allogenico di trapianto di midollo osseo, rene o fegato.
    •Evidenza clinica di persistente aumentata pressione intracranica dopo resezione chirurgica.
    •Infezione virale, batterica o fungina clinicamente rilevante alla valutazione di idoneità.
    •Malattia autoimmune attiva o una storia rilevante di importanti manifestazioni autoimmuni, in particolare psoriasi, lupus eritematoso sistemico (LES), artrite reumatoide, vasculite, neuropatie periferiche immuno-mediate.
    •Storia di sarcoidosi.
    •Storia o evidenza attuale di patologie neuropsichiatriche comprendenti depressione, schizofrenia, disturbi bipolari, compromissione della funzione cognitiva, demenza o tendenza al suicidio.
    •Anamnesi di gravi malattie cardiovascolari come un precedente ictus, malattia coronarica che richiede un intervento o aritmie non risolte negli ultimi 6 mesi.
    •Evidenza di qualsiasi neoplasia ematologica.
    •Positività per il virus dell'immunodeficienza umana di tipo 1 o 2 (HIV-1, HIV-2) (sierologia o RNA) e/o virus dell'antigene di superficie dell'epatite B (HbsAg) e/o virus dell'epatite B (HBV) e/o epatite RNA del virus C (HCV) (o RNA HCV negativo ma con trattamento antivirale) e/o infezione da Treponema Pallidum o Mycoplasma.
    •Attivo uso o abuso di alcool o di sostanze entro 6 mesi dallo studio.
    •Gravidanza o allattamento in corso.
    •Diatesi emorragica nota o anamnesi di emorragia anormale o altre anomalie della coagulazione note che potrebbero controindicare la puntura lombare per CSF o il futuro intervento chirurgico.
    •Uso di immunosoppressori ad eccezione degli steroidi. La dose massima consentita di desametasone (o equivalente) è inferiore a 4 mg al giorno.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is to assess the tolerability and safety of Temferon over the first 90 days following Temferon administration, as evaluated by:
    •Routine clinical and laboratory surveillance;
    •Assessment of autoimmune manifestations;
    •Significant organ toxicities (>grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE v5.0] that are attributed to Temferon exposure or procedures related to the harvesting of HSPCs or administration of Temferon.
    L'endpoint primario è valutare la tollerabilità e la sicurezza di Temferon nei primi 90 giorni successivi alla somministrazione di Temferon, come valutato da:
    •Sorveglianza clinica e di laboratorio di routine
    •Valutazione delle manifestazioni autoimmuni
    •Significativa tossicità d’organo (> grado 2 secondo i criteri per gli eventi avversi del National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAEv5.0] che sono attribuiti all'esposizione a Temferon o procedure relative alla raccolta di cellule staminali (HSPC) o alla somministrazione di Temferon
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to Day +90 after Temferon administration
    Fino al giorno + 90 dopo la somministrazione di Temferon
    E.5.2Secondary end point(s)
    •Long-term tolerability and safety of Temferon up to 2 years following Temferon administration, according to CTCAE v5.0 criteria as evaluated by:
    oRoutine clinical and laboratory surveillance;
    oAssessment of autoimmune manifestations;
    oSignificant organ toxicities (>grade 2 according to CTCAE v5.0) that can be attributed to Temferon exposure.
    •The proportion of patients achieving hematologic recovery by day +30 following BCNU and thiotepa administration from administration of un-manipulated autologous HSPC and Temferon. Hematologic recovery is defined as the first of at least 3 consecutive days with a neutrophil count >0.5 x 10^9/L and platelet count >20 x 10^9/L.
    Safety (Part A only)
    •Determine the maximum tolerated dose (MTD) of Temferon as defined by the presence of a CTCAE Grade 3-5 adverse event (AE) that occurs within the first 30 days and is attributed to Temferon.
    Efficacy (Part A & Part B)
    •Identify the presence of transduced myeloid cells in bone marrow aspirate at Day +30 and +90 following administration of Temferon as determined by VCN.
    •Identify the presence of transduced myeloid cells in peripheral blood (PB) between Day +30 and +90 following administration of Temferon as determined by VCN.
    •Evaluate persistent transduced myeloid cells in PB as assessed by VCN. Persistence is defined as a VCN above the level of detection evident for at least 12 weeks.
    •Determine the proportions of patients achieving complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) at 6 months (Day +180) following Temferon administration, using standard iRANO criteria
    •Clinical response will also be evaluated at day +90, +120 and every 2 months until Day +720. Time to progression/progression- free survival (PFS) will be measured from the first day following Temferon administration until unequivocal progression is identified.
    •Overall Survival (OS) at various timepoints up to 2 years, will be calculated from the first day following Temferon administration. •Changes over time (day +30, +90, +180, +360, +540, +720) in functional status using the Eastern Cooperative Oncology Group Performance Status (ECOG) and Karnofsky Performance Status (KPS).
    •Changes over time (day +90, +180, +360, +720) in quality of life using the EORTC Quality of Life Questionnaire C30 and BN20.
    •Tollerabilità e sicurezza a lungo termine di Temferon fino a 2 anni dopo la somministrazione di Temferon, secondo i criteri CTCAE v5.0 valutati da:
    •Sorveglianza clinica e di laboratorio di routine
    •Valutazione delle manifestazioni autoimmuni
    •Significativa tossicità d’organo (> grado 2 secondo CTCAE v5.0) che può essere attribuita all'esposizione a Temferon •Recupero ematologico entro il giorno +30 dopo la somministrazione di BCNU e thiotepa e l’infusione di HSPC autologhe, non manipolate e di Temferon:
    •Il recupero ematologico è definito come il primo di almeno 3 giorni consecutivi con una conta dei neutrofili> 0,5 x 10^9/L e conteggio delle piastrine> 20 x 10^9/L
    Sicurezza (solo Parte A)
    •Definizione della massima dose tollerata (MTD) di Temferon definita dalla presenza di un evento avverso di grado 3-5 CTCAE (AE) che si verifica entro i primi 30 giorni ed è attribuita a Temferon
    Efficacia (Part A & Part B)
    •Presenza di cellule mieloidi trasdotte nell’aspirato midollare al giorno +30 e +90 dopo la somministrazione di Temferon come determinato dal numero di copie di vettore (VCN)
    •Presenza di cellule mieloidi trasdotte nel sangue periferico (PB) tra il giorno +30 e +90 dopo la somministrazione di Temferon come determinato da VCN
    •Persistenza delle cellule mieloidi trasdotte nel PB valutata mediante VCN. La persistenza è definita come un valore di VCN superiore al livello di rilevamento evidente per almeno 12 settimane
    •Proporzione di pazienti che raggiungono risposta completa (CR), risposta parziale (PR), malattia stabile (SD) e malattia progressiva (PD) 6 mesi (Giorno +180) dopo la somministrazione di Temferon. La valutazione della risposta verrà effettuata secondo iRANO criteria.
    •La risposta clinica sarà valutata anche al giorno +90, +120, e ogni 2 mesi fino a 2 anni. La sopravvivenza fino a progressione / la sopravvivenza libera da malattia (PFS) sarà misurata dal primo giorno dopo la somministrazione di Temferon fino a quando non verrà identificata una progressione univoca.
    •La sopravvivenza globale (OS) a vari tempi fino a 2 anni, sarà calcolata dal primo giorno dopo la somministrazione di Temferon. •Variazioni nel tempo (giorno +30, +90, +180, +360, +540, +720) nello stato funzionale utilizzando Eastern Cooperative Oncology Group Performance Status (ECOG) and Karnofsky Performance Status (KPS)
    •Variazioni nel tempo (giorno +90, +180, +360, +720) della qualità della vita utilizzando il questionario EORTC sulla qualità della vita C30 e BN20.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Multiple timepoints up to 2 years after Temferon administration
    Rilevazioni multiple fino a 2 anni dopo la sommistrazione di Temferon
    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 Yes
    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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    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 concerned2
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA2
    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 Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    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 months3
    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 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 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state21
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 21
    F.4.2.2In the whole clinical trial 21
    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)
    21 patients will be recruited in ITlay. At the end of the clinical study, patients will be invited to participate in a long term follow up study for an additional 6 years
    21 pazienti verranno arruolati in Italia. Al termine della sperimentazione, i pazienti saranno invitati a partecipare ad uno studio di followup a lungo termine di 6 anni.
    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 Decision2018-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-12
    P. End of Trial
    P.End of Trial StatusOngoing
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