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    Summary
    EudraCT Number:2018-000813-19
    Sponsor's Protocol Code Number:EURE-CART-1
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-000813-19
    A.3Full title of the trial
    A Phase I-IIa trial to assess the safety and antitumor activity of autologous CD44v6 CAR T-cells in acute myeloid leukemia and multiple myeloma expressing CD44v6.
    Studio di fase I-IIa per valutare la sicurezza e l’attività antitumorale di cellule CAR T CD44v6 autologhe nella leucemia mieloide acuta e nel mieloma multiplo con espressione di CD44v6.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and antitumor activity of autologous CD44v6 CAR T-cells in acute myeloid leukemia and multiple myeloma expressing CD44v6.
    Sicurezza e attività antitumorale di cellule T autologhe CD44v6 CAR nella leucemia mieloide acuta e nel mieloma multiplo che esprimono CD44v6.
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberEURE-CART-1
    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 SponsorMOLMED S.P.A
    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 supportMolMed S.p.A.
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportEuropean Committee: Grant agreement number 733297- EURE-CART-H2020
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMolMed S.p.A.
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressVia Meucci, 3
    B.5.3.2Town/ cityBresso (MI)
    B.5.3.3Post code20091
    B.5.3.4CountryItaly
    B.5.4Telephone number00390221277234
    B.5.5Fax number00390221277239
    B.5.6E-maileurecart1.team@molmed.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 nameMLM-CAR44.1 T-cells
    D.3.2Product code [MLM-CAR44.1 T-cells]
    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 INNMLM-CAR44.1 T-cells
    D.3.9.2Current sponsor codeMLM-CAR44.1 T-cells
    D.3.9.4EV Substance CodeSUB186020
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1000000 to 10000000
    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.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
    Acute myeloid leukemia and Multiple myeloma
    Leucemia mieloide acuta e Mieloma multiplo
    E.1.1.1Medical condition in easily understood language
    Acute myeloid leukemia and multiple myeloma
    Leucemia mieloide acuta e Mieloma multiplo
    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 LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I:
    1. To determine the maximum tolerated dose (MTD) and recommended phase IIa dose of MLM-CAR44.1 T-cells in patients with relapsed/refractory acute myeloid leukemia (AML) or multiple myeloma (MM) expressing CD44v6.
    2. To evaluate the overall safety of treatment with MLM-CAR44.1 T-cells.

    Phase IIa:
    To evaluate hematological response to MLM-CAR44.1 T-cells in AML and MM.
    Fase I:
    1. Determinare la massima dose tollerata (Maximum Tolerated Dose - MTD) e la dose raccomandata per la Fase IIa di cellule T MLM-CAR44.1 in pazienti con leucemia mieloide acuta (Acute Myeloid Leukemia – AML) o mieloma multiplo (Multiple Myeloma) con espressione di CD44v6.
    2. Valutare la sicurezza globale del trattamento con cellule T MLM-CAR44.1.

    Fase IIa:
    Valutare la risposta ematologica alle cellule T MLM-CAR44.1 nell’AML e nel MM.
    E.2.2Secondary objectives of the trial
    Phase I:
    1. To evaluate hematological response to MLM-CAR44.1 T-cells in AML and MM.
    2. To characterize the in vivo pharmacokinetic profile (engraftment, persistence, trafficking) of MLM-CAR44.1 T-cells.
    3. To assess suicide gene activation and elimination of transduced cells through administration of ganciclovir in case of cytokine release syndrome (CRS) or other MLM-CAR44.1 T-cell related toxicities.
    For more secondary objectives please refer to the protocol.

    Phase IIa:
    1. To evaluate the antitumor activity of MLM-CAR44.1 T-cells.
    For more secondary objectives please refer to the protocol.
    Fase I:
    1. Valutare la risposta ematologica alle cellule T MLM-CAR44.1 nella AML e nel MM.
    2. Caratterizzare il profilo farmacocinetico in vivo (attecchimento, persistenza, spostamento) delle cellule T MLM-CAR44.1.
    3. Valutare l’attivazione del gene suicida e l’eliminazione delle cellule trasdotte tramite la somministrazione di ganciclovir in caso di sindrome da rilascio di citochine (Cytokine Release Syndrome – CRS) o altre tossicità correlate alle cellule T MLM-CAR44.1.
    Per ulteriori obiettivi secondari si prega di far riferimento al protocollo.

    Fase IIa:
    1. Valutare l’attività antitumorale delle cellule T MLM-CAR44.1.
    Per ulteriori obiettivi secondari si prega di far riferimento al protocollo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent before any study-related procedure.
    2. Adults and children:
    a) Adults 18 to 75 years old with AML or MM
    b) Children 1 to 17 years old with AML, only in Phase IIa
    3. Confirmed diagnosis of AML or MM as follows:
    a) AML: Primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization (WHO) classification
    b) MM with measurable disease as defined by the International Myeloma Working Group (IMWG).
    4. Patients with relapse or refractory disease:
    a) AML patients must be unlikely to benefit from cytotoxic chemotherapy as follows:
    • Leukemia refractory to at least 2 induction attempts (use of a hypomethylating agent for at least 4 cycles can be considered a line of treatment).
    • Leukemia in relapse within 1 year following complete response (CR) after at least 2 induction attempts (use of a hypomethylating agent for at least 4 cycles can be considered a first line of treatment).
    • High-risk leukemia in adults according to 2017 European LeukemiaNet (ELN) in first relapse after a hypomethylating agent or a cycle containing cytarabine at a dose = 1g/sqm a day (e.g. FLAG-IDA), except for FLT3-mutated AML.
    • High-risk leukemia in children as defined by the Italian Association of Pediatric Hematology and Oncology (AIEOP).
    b) Patients with MM must have a relapse or refractory disease after at least 4 different prior treatments in 3 treatment lines, or 4 treatments in 2 treatment lines in case of early relapsing patients (relapse in less than 1.5 years). Treatments include:
    • Proteasome inhibitor
    • High-dose alkylating agent if patient less than 70 years old
    • Immunomodulatory drug (IMID)
    • A monoclonal antibody (i.e. anti CD38 monoclonal antibody)¿¿
    5. Positive CD44v6 expression on tumor cells by flow cytometry.
    6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
    7. Life expectancy of at least 12 weeks.
    8. Adequate organ function:
    a) Alanine aminotransferase (ALT) level within 2.5 times the institutional upper limit of normal (ULN).
    b) aspartate aminotransferase (AST) level = 2.5 x ULN.
    c) Total bilirubin level = 1.5 x ULN, or = 2.5 x ULN in case of history of Gilbert’s disease.¿
    d) Serum creatinine = 2.0 mg/dL or a calculated or measured creatinine clearance = 45mL/min.
    e) Corrected Diffusing Capacity of Carbon Monoxide (DLCO) (via Dinakara Equation) or FEV1 of ¿ 66% without dyspnea on slight activity after hemoglobin correction.
    f) Left ventricular ejection fraction ¿ 45%.
    9. Recovery from toxicities of clinical consequence attributed to previous chemotherapy to CTCAE v5.0 Grade 1 (i.e., certain toxicities such as alopecia will not be considered in this category).
    10. Ability to comply with study procedures, including hospitalization and protocol-specified acquisition of blood and/or bone marrow specimens.¿
    11. Willing to be followed up long-term (15 years) as required by health authorities for cell and gene therapy products
    12. Women of childbearing potential must have test negative for pregnancy at enrolment and during the study and agree to use an effective method of contraception.
    1) Consenso informato scritto ottenuto prima di qualsiasi procedura correlata allo studio.
    2) Pazienti adulti e bambini
    a) Adulti di età compresa tra 18 e 75 anni con AML o MM
    b) Bambini di età compresa tra 1 e 17 anni con AML, solo in Fase IIa
    3) Diagnosi confermata di AML o MM come segue:
    a) AML: AML primaria o secondaria (qualsiasi sottotipo ad esclusione della leucemia promielocitica acuta) secondo la classificazione dell’Organizzazione Mondiale della Sanità (World Health Association – WHO)
    b) MM con malattia misurabile come definito dal Gruppo di Lavoro Internazionale sul Mieloma (International Myeloma Working Group - IMWG).
    4) Pazienti con malattia recidivante o refrattaria:
    a) I pazienti con AML devono avere scarse probabilità di trarre beneficio dalla chemioterapia citotossica come segue:
    • Leucemia refrattaria ad almeno 2 tentativi di induzione (l’utilizzo di un agente ipometilante per almeno 4 cicli può essere considerato una linea di trattamento)
    • Leucemia in recidiva nell’anno seguente la risposta completa (Complete Response – CR) dopo almeno 2 tentativi di induzione (l’utilizzo di un agente ipometilante per almeno 4 cicli può essere considerato una prima linea di trattamento)
    • Leucemia ad alto rischio negli adulti secondo ELN (European LeukemiaNet) 2017 in prima recidiva dopo un agente ipometilante o un ciclo contenente citarabina ad una dose = 1g/mq al giorno (ad es. FLAG-IDA), con eccezione di AML con mutazione FLT3.
    • Leucemia ad alto rischio nei bambini come definito dall’Associazione Italiana di Ematologia e Oncologia Pediatrica (Italian Association of Pediatric Hematology and Oncology - AIEOP).
    b) I pazienti con MM devono presentare una recidiva o malattia refrattaria dopo almeno 4 diversi trattamenti precedenti in 3 linee di trattamento, o 4 trattamenti in 2 linee di trattamento in caso di pazienti con recidiva precoce (recidiva in meno di un anno mezzo). I trattamenti comprendono:
    • Inibitore del proteasoma
    • Agente alchilante ad alto dosaggio se il paziente è di età inferiore ai 70 anni
    • Farmaco immunomodulante (Immunomudolatory Drug – IMID)
    • Un anticorpo monoclonale (ovvero un anticorpo monoclonale anti CD38)
    5. Positività per espressione di CD44v6 sulle cellule tumorali tramite citometria di flusso.
    6. ECOG (Eastern Cooperative Oncology Group) performance status 0-2.
    7. Aspettativa di vita di almeno 12 settimane.
    8. Adeguata funzionalità d’organo:
    a) Livello di alanina aminotransferasi (ALT) entro 2.5 volte il limite di normalità (ULN: Upper Limit of Normal) superiore istituzionale.
    b) Livello di aspartato aminotrasferasi (AST) = 2.5 x ULN.
    c) Livello di bilirubina totale = 1.5 x ULN, o = 2.5 x ULN in caso di anamnesi di malattia di Gilbert.
    d) Creatinina sierica = 2.0 mg/dL o clearance della creatinina calcolata o misurata = 45mL/min.
    e) Diffusione alveolo-capillare del monossido di carbonio (Diffusing Capacity of Carbon Monoxide - DLCO) corretta (tramite equazione di Dinakara) o FEV1¿ 66% senza dispnea con attività leggera dopo la correzione dell’emoglobina.
    f) Frazione di eiezione ventricolare sinistra ¿ 45%.
    9. Recupero da tossicità data dalle conseguenze cliniche attribuite a precedente chemioterapia a Grado 1 secondo i CTCAE v5.0 (determinate tossicità quali l’alopecia non saranno considerate in questa categoria).
    10. Capacità di aderire alle procedure di studio, compresi il ricovero e il prelievo di campioni di sangue e/o di midollo osseo come specificato nel protocollo.
    11. Disponibilità a partecipare a follow-up a lungo termine (15 anni) come richiesto dalle Autorità Regolatorie per i prodotti cellulari e di terapia genica.
    12. Le donne potenzialmente fertili devono avere un test di gravidanza negativo all’arruolamento e durante lo studio e devono acconsentire all’utilizzo di un metodo contraccettivo efficace.
    E.4Principal exclusion criteria
    1. History of or candidate for allogeneic stem cell transplantation.¿
    2. Cardiovascular, pulmonary, renal, and hepatic ¿functions that in the judgment of the investigator are insufficient to undergo investigational CAR T-cell therapy.
    3. Any history of or suspected current autoimmune disorders (apart from vitiligo, resolved childhood atopic dermatitis, Graves’ disease clinically controlled).
    4. History of rheumatologic disorders requiring specific treatment at any time in the patient’s medical history.
    5. Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is allowed. ¿¿
    6. Known or suspected central nervous system (CNS) leukemia. ¿
    7. Presence or history of myeloid sarcoma or any extramedullary mass.
    8. Any medical or psychiatric condition that may limit compliance or increase safety risks, such as:
    a) Active uncontrolled infection (including, but not limited to viral, bacterial, fungal, or mycobacterial infection).¿
    b) Patients with known multiple antibiotic resistant infections in their clinical history.
    c) Known human immunodeficiency virus infection, active or chronic hepatitis B or C infection.
    d) Grade 3 or 4 bleeding.
    e) Uncontrolled hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 100 mm Hg).
    f) Clinically significant arrhythmia, clinically significant baseline QTcF, or QTcF > 480 msec.
    g) Unstable angina.
    h) Myocardial infarction within 6 months prior to study drug administration.
    i) Clinically significant heart disease (e.g. CHF NYHA III or IV, unstable coronary artery disease, myocardial infarction < 6 mo. prior to study entry).
    j) Pregnancy or breast feeding.
    k) Major surgery or trauma within 4 weeks before enrollment. ¿
    l) Dementia or altered mental status that would preclude sufficient understanding to provide informed consent.
    Once all the above eligibility criteria are confirmed, a lymphocyte apheresis product of non-mobilized cells must be received and accepted by the manufacturing site. Note: the lymphocyte apheresis product will not be shipped or assessed for acceptance by the manufacturing site until documented confirmation of all other inclusion/exclusion criteria have been satisfied.

    Prior to lymphocyte apheresis (week -9 to -7), the following criteria must be met:
    1. Peripheral blast count = 20,000/mm3 (AML).
    2. No treatment with any other investigational agent in the previous 4 weeks.
    3. No treatment with an immunostimulatory agent (IMIDs are allowed) or any cell therapy in the previous 30 days.
    4. Negative to the following tests: HCV (Antibody, NAT), HIV 1-2 (p24, AB, Ag and NAT), total Ig Treponema Pallidum (if positive perform specific test), Australia HBsAg, total anti HB core Ab (if positive perform HBV DNA NAT), mycoplasma (PCR or IgM) and HTLV I-II.

    Prior to lymphodepleting chemotherapy and MLM-CAR44.1 T-cell infusion (day -5 to day -3), the following criteria must be met:
    1. Evidence of active disease at the beginning of lympho-depleting chemotherapy.
    2. The following medications are excluded and should not be administered concomitantly or following lymphodepleting chemotherapy:
    a) Monoclonal antibodies in the 8 weeks prior to MLM-CAR44.1 T-cell infusion are prohibited.
    For more exclusion criteria please refer to the protocol.
    1. Anamnesi di o paziente candidato per trapianto allogenico di cellule staminali.
    2. Funzionalità cardiovascolare, polmonare, renale ed epatica che, a giudizio dello sperimentatore, non sono sufficienti per sottoporre il paziente alla terapia sperimentale con cellule CAR T.
    3. Anamnesi di o sospetta presenza di disturbi autoimmuni (ad eccezione di vitiligine, dermatite atopica infantile risolta, malattia di Graves controllata da un punto di vista clinico).
    4. Anamnesi di disturbi reumatologici che richiedono un trattamento specifico in qualsiasi momento della storia medica del paziente.
    5. Secondo tumore primario che richiede terapia attiva. È consentita la terapia ormonale adiuvante.
    6. Nota o sospetta leucemia del sistema nervoso centrale (Central Nervous System – CNS).
    7. Presenza o anamnesi di sarcoma mieloide o qualsiasi massa extra-midollare.
    8. Qualsiasi condizione medica o psichiatrica che possa limitare l’aderenza al protocollo o aumentare i rischi di sicurezza, quali:
    a) Infezione attiva non controllata (compresa a titolo esemplificativo ma non esaustivo, infezione virale, batterica, micotica o micobatterica).
    b) Pazienti con infezioni multiresistenti agli antibiotici note nella loro storia clinica.
    c) Infezione nota da virus dell’immunodeficienza umana, infezione da epatite B o C attiva o cronica.
    d) Emorragia di Grado 3 o 4.
    e) Ipertensione non controllata (pressione sistolica > 180 mm Hg o pressione diastolica > 100 mm Hg).
    f) Aritmia clinicamente significativa; QTcF, or QTcF > 480 msec al basale clinicamente significativo.
    g) Angina instabile.
    h) Infarto miocardico nei 6 mesi precedenti la somministrazione del farmaco in studio.
    i) Patologia cardiaca clinicamente significativa (ad es. scompenso cardiaco congestizio NYHA III o IV, patologia coronarica instabile, infarto miocardico nei 6 mesi precedenti l’ingresso in studio).
    j) Gravidanza o allattamento.
    k) Intervento chirurgico o trauma maggiore nelle 4 settimane precedenti l’arruolamento.
    l) Demenza o stato mentale alterato che potrebbe precludere una capacità di comprensione sufficiente a fornire il consenso informato.
    Una volta confermati tutti i precedenti criteri di eleggibilità, deve essere ricevuto ed accettato dal sito di produzione un prodotto di linfocitoaferesi di cellule non mobilizzate. Nota: il prodotto di linfocitoaferesi non sarà spedito o valutato per l’accettazione da parte del centro di produzione fino a che non sarà ottenuta conferma documentata del fatto che tutti gli altri criteri di inclusione/esclusione sono stati soddisfatti.

    Prima della linfocitoaferesi (dalla settimana -9 alla settimana -7), devono essere soddisfatti i seguenti criteri:
    1. Conta dei blasti periferici = 20,000/mm3 (AML).
    2. Nessun trattamento con qualsiasi altro farmaco sperimentale nelle 4 settimane precedenti.
    3. Nessun trattamento con un farmaco immunostimolante (gli IMID sono consentiti) o con qualsiasi terapia cellulare nei 30 giorni precedenti.
    4. Negatività ai seguenti test: HCV (anticorpo, NAT), HIV 1-2 (p24, AB, Ag e NAT), Treponema Pallidum Ig totali (se positivo effettuare test specifico), HbsAg Australia, anti HB core Ab totale (se positivo effettuare HBV DNA NAT), micoplasma (PCR o IgM) e HTLV I-II.

    Prima della chemioterapia per la linfodeplezione e dell’infusione con cellule T MLM-CAR44.1 (dal giorn0 -5 al -3), devono essere soddisfatti i seguenti criteri:
    1. Evidenza di malattia attiva all’inizio della chemioterapia per la linfodeplezione.
    2. I seguenti trattamenti sono esclusi e non devono essere somministrati in modo concomitante o successivamente alla chemioterapia per la linfodeplezione:
    a) Sono proibiti gli anticorpi monoclonali nelle 8 settimane precedenti l’infusione di cellule T MLM-CAR44.1.
    Per ulteriori criteri di esclusione si prega di far riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    Safety:
    1. MTD established through BOIN design and the following DLTs:
    a. Grade 4 CRS
    b. Grade 3 or higher CRS not responsive to therapy with steroids and or tocilizumab/siltuximab within 24 hours
    c. Grade 3 or higher toxicity possibly related to treatment with MLM-CAR44.1 T-cells excluding hematological toxicities
    d. Skin toxicities:
    - NCI-CTC grade 3 or higher erythroderma (generalized exfoliative dermatitis)
    - Stevens-Johnson syndrome
    - Any other grade 3 or higher skin toxicity histologically confirmed as being related to CAR T-cell treatment
    e. Grade 3 or higher neurotoxicity
    2. Type, frequency and severity of adverse events and monitoring of systemic reactions (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
    3. Absence of replication competent retrovirus (RCR) monitored by DNA PCR for the Galv gene.

    Phase IIa:
    Hematologic disease response:
    - AML: CR, CRi and PR rate as per ELN criteria.
    - MM: ORR: (sCR, CR, VGPR, and PR) as per IMWG criteria.
    Fase I:
    Sicurezza:
    1. MTD stabilita tramite disegno BOIN e le seguenti DLT verificatesi entro 30 giorni dopo l’infusione di cellule CAR T:
    a) CRS di Grado 4
    b) CRS di Grado 3 o superiore che non risponde alla terapia con steroidi e/o tocilizumab/siltuximab entro 24 ore
    c) Tossicità di Grado 3 o superiore possibilmente correlata al trattamento con le cellule T MLM-CAR44.1 ad esclusione delle tossicità ematologiche
    d) Tossicità cutanee:
    - Eritroderma (dermatite esfoliativa generalizzata) di Grado 3 o superiore NCI-CTC
    - Sindrome di Steven-Johnson
    - Qualsiasi altra tossicità cutanea di Grado 3 o superiore con conferma istologica della correlazione con il trattamento con le cellule CAR T
    e) Neurotossicità di Grado 3 o superiore
    2. Tipo, frequenza e severità degli eventi avversi e monitoraggio delle reazioni sistemiche (febbre, tachicardia, nausea e vomito, dolore articolare, eruzione cutanea) per 30 giorni dopo l’infusione di cellule CAR T
    3. Assenza di retrovirus competente per la replicazione (Replication Competent Retrovirus RCR) monitorata tramite DNA PCR per il gene Galv 3, 6, 12 mesi dopo l’infusione e successivamente con cadenza annuale come definito nel follow-up a lungo termine

    Fase IIa:
    Risposta ematologica di malattia:
    • AML: tasso di CR, CRi e PR in base ai criteri ELN, 2 mesi dopo l’infusione delle cellule T MLM-CAR44.1.
    • MM: ORR: (sCR, CR, VGPR e PR) in base ai criteri IMWG, 3 mesi dopo l’infusione delle cellule T.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I:
    1. Within 30 days following CAR T-cell infusion
    2. For 30 days following CAR T-cell infusion
    3. 3, 6, 12 months after infusion and then yearly

    Phase IIa:
    - 2 months after MLM-CAR44.1 T-cell infusion
    - 3 months after T-cell infusion
    Fase I:
    1. entro 30 giorni dopo l’infusione di cellule CAR T
    2. per 30 giorni dopo l’infusione di cellule CAR T
    3. 3, 6, 12 mesi dopo l’infusione e successivamente con cadenza annuale

    Fase IIa:
    - 2 mesi dopo l’infusione delle cellule T MLM-CAR44.1
    - 3 mesi dopo l’infusione delle cellule T
    E.5.2Secondary end point(s)
    Phase I:
    1. Hematologic disease response:
    a. AML: complete response (CR), incomplete response (CRi) and partial response (PR) according to ELN criteria.
    b. MM: overall response rate (ORR): stringent complete response (sCR), CR, very good partial response (VGPR) and partial response (PR) according to IMWG criteria.
    2. Levels of circulating MLM-CAR44.1 T-cells by flow cytometry.
    3. Suicide gene activation and elimination of transduced cells through administration of ganciclovir in case of cytokine release syndrome or other significant MLM-CAR44.1 T-cell related toxicities.
    4. To set-up a validation process among the participating centers for the CD44v6 marking of tumor cells (AML and MM).; Phase IIa:
    1. Hematologic disease response:
    a. AML: CR, CRi and PR rate as per ELN criteria. Morphologic leukemia-free state (MLFS).
    b. MM: ORR (sCR, VGPR and PR) as per IMWG criteria.
    2. Overall Survival (OS) at 2 years.
    3. Disease-Free Survival (DFR) in AML patients.
    4. Event Free Survival (EFS) in AML patients.
    5. Progression Free Survival (PFS) in MM patients at 2 years.
    6. Duration of Remission (DOR) in MM patients.
    Fase I:
    1. Risposta ematologica
    a. AML: risposta completa (Complete Response - CR), risposta incompleta (incomplete Response - CRi) e risposta parziale (Partial Response) in base ai criteri ELN 1 e 2 mesi dopo l’infusione di cellule T MLM-CAR44.1.
    b. MM: tasso di risposta globale (Overall Response Rate – ORR): risposta completa stringente (Stringent Complete Response - sCR), risposta completa (Complete Response – CR), risposta parziale molto buona (Very Good Partial Response -VGPR) e risposta parziale (Partial Response - PR) in base ai criteri IMWG 1 e 3 mesi dopo l’infusione delle cellule T.
    2. Livelli di cellule T MLM-CAR44.1 circolanti tramite citometria di flusso.
    3. Attivazione del gene suicida ed eliminazione delle cellule trasdotte tramite la somministrazione di ganciclovir in caso di sindrome da rilascio di citochine o altre tossicità significative correlate alle cellule T MLM-CAR44.1.
    4. Messa a punto di un processo di validazione tra i centri partecipanti per la marcatura CD44v6 delle cellule tumorali (AML e MM).; Fase IIa:
    1. Risposta ematologica di malattia:
    a. AML: tasso di CR, Cri e PR in base ai criteri ELN. Stato morfologico libero da malattia (Morphologic Leukemia-Free State - MLFS).
    b. MM: ORR (sCR, CR, VGPR e PR) in base ai criteri IMWG.
    2. Sopravvivenza globale (Overall Survival - OS)
    3. Sopravvivenza libera da malattia (Disease-Free Survival – DSF) nei pazienti con AML4. Sopravvivenza libera da eventi (Event Free Survival – EFS) nei pazienti con AML
    5. Sopravvivenza libera da progressione (Progression Free Survival – PFS) nei pazienti con MM
    6. Durata della remissione (Duration of Remission – DOR) nei pazienti con MM
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I:
    1a. 1 and 2 months following MLM-CAR44.1 T-cell infusion
    1b. 1 and 3 months following T-cell infusion
    2. At day 7, 14, 21, 28, 60, 90, 180
    3. For each dose level
    4. During the study; Phase IIa:
    1a. 1 month and 6 months after MLM-CAR44.1 T-cell infusion and 1, 2 and 6 months after MLM-CAR44.1 T-cell infusion
    1b. 1, 2 and 6 months after T-cell infusion
    2. From MLM-CAR44.1 T-cell infusion to death due to any cause
    3. From achievement of response to relapse or death due to any cause during response
    4. From the date of MLM-CAR44.1 T-cell infusion to the date of the earliest of the following: last follow-up, resistance, relapse or death due to any cause
    5. From MLM-CAR44.1 T-cell infusion to progression/relapse or death due to any cause
    6. From achievement of response to relapse or dea
    Fase I:
    1a. 1 e 2 mesi dopo l’infusione di cellule T MLM-CAR44.1
    1b. 1 e 3 mesi dopo l’infusione delle cellule T
    2. Al giorno 7, 14, 21, 28, 60, 90, 180
    3. Per ogni livello di dosaggio
    4. Durante lo studio; Fase IIa:
    1a. 1 mese e 6 mesi dopo l’infusione di cellule T MLM-CAR44.1 e 1, 2 e 6 mesi dopo l’infusione di cellule T MLM-CAR44.1
    1b. 1, 2 e 6 mesi dopo l’infusione delle cellule T
    2. Dall’infusione di cellule T MLM-CAR44.1 al decesso per qualsiasi causa
    3. Dall’ottenimento della risposta alla recidiva o al decesso per qualsiasi causa durante la risposta
    4. Dalla data dell’infusione di cellule T MLM-CAR44.1 alla data dei seguenti eventi che per primo si verifica: ultima data di follow-up, resistenza, recidiva o decesso per qualsiasi causa
    5. Dall’infusione di cellule T MLM-CAR44.1 alla
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Antitumor activity of autologous CD44v6 CAR T-cells
    Attività antitumorale di cellule CAR T CD44v6 autologhe
    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) 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 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 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 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 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: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 1
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 58
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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
    Pediatric patients
    Pazienti pediatrici
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 68
    F.4.2.2In the whole clinical trial 68
    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)
    Patients will continue to be followed for 15 years after MLM-CAR44.1 T-cell infusion as per health authority guidelines.
    I pazienti continueranno a essere seguiti per 15 anni dopo l'infusione di cellule T MLM-CAR44.1 secondo le linee guida dell'autorità sanitaria.
    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 Decision2019-03-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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