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    Summary
    EudraCT Number:2019-002477-56
    Sponsor's Protocol Code Number:IMGN632-0802
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-06-17
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-002477-56
    A.3Full title of the trial
    A Phase 1b/2 Study of IMGN632 as Monotherapy or Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia
    Uno studio di fase 1b/2 su IMGN632 come monoterapia o terapia combinata con venetoclax e/o azacitidina in pazienti affetti da leucemia mieloide acuta CD123-positiva
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of IMGN632 alone or in combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia
    Uno studio di IMGN632 da solo o in combinazione con venetoclax e/o azacitidina in pazienti affetti da leucemia mieloide acuta CD123-positiva
    A.3.2Name or abbreviated title of the trial where available
    IMGN632 alone and in combination in the treatment of the AML CD123+
    IMGN632 solo e in combinazione nel trattamento della LMA CD123+
    A.4.1Sponsor's protocol code numberIMGN632-0802
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04086264
    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 SponsorIMMUNOGEN, INC.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportImmunoGen, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImmunoGen, Inc.
    B.5.2Functional name of contact pointKen Dhimitri
    B.5.3 Address:
    B.5.3.1Street Address830 Winter Street
    B.5.3.2Town/ cityWaltham
    B.5.3.3Post code02451
    B.5.3.4CountryUnited States
    B.5.4Telephone number0017818950600
    B.5.5Fax number0017812075341
    B.5.6E-mailIMGN0802@immunogen.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 nameIMGN632
    D.3.2Product code [IMGN632]
    D.3.4Pharmaceutical form Powder 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.3.9.2Current sponsor codeIMGN632
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Vidaza
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVidaza
    D.3.2Product code [Non applicabile]
    D.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINA
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor codeNon applicabile
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Venclyxto
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Deutschland GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVenclyxto
    D.3.2Product code [Venclyxto]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVenetoclax
    D.3.9.1CAS number 1257044-40-8
    D.3.9.2Current sponsor codeNon applicabile
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number96
    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
    CD123 positive Acute Myeloid Leukemia
    Leucemia Mieloide Acuta CD123-positiva
    E.1.1.1Medical condition in easily understood language
    Acute Myeloid Leukemia
    Leucemia Mieloide Acuta
    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
    1. Dose Escalation (Regimens A-C):
    Evaluate the safety and tolerability and identify a recommended Phase 2 dose (RP2D) of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C) in patients with relapsed or refractory CD123- positive AML.
    2. Dose Expansion Cohorts:
    (Regimens A-C) Assess preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B), azacitidine+venetoclax (Regimen C) in patients with either relapsed or untreated AML and assess MRD levels.
    (Regimen D (Cohort D1 and D2)): Assess preliminary anti-leukemia activity of IMGN632 as monotherapy in MRD+ Fit (Cohort D1) and MRD+ Unfit AML (Cohort D2) patient populations and assess MRD levels.
    1-Coorti di aumento progressivo della dose (Regimi A-C)
    Valutare la sicurezza e la tollerabilità e identificare una dose raccomandata in Fase 2 (RP2D) di IMGN632 quando somministrato in combinazione con azacitidina (Regime A), venetoclax (Regime B) o azacitidina + venetoclax (Regime C) in pazienti CD123 positivi affetti da LMA recidivante o refrattaria.
    2 Coorte di espansione della dose
    Regimi A-C
    • Valutare l'attività antileucemica preliminare di IMGN632 quando somministrato in combinazione con azacitidina (Regime A), venetoclax (Regime B) o azacitidina + venetoclax (Regime C) in pazienti con LMA recidivante o non trattata.
    • Valutare i livelli di MRD

    Regime D (Coorte D1 e D2)
    • Valutare l'attività antileucemica preliminare di IMGN632 come monoterapia nelle popolazioni di pazienti con LMA MRD + “in buone condizioni” (Coorte D1) e MRD + “in cattive condizioni” (Coorte D2) .
    • Valutare i livelli di MRD
    E.2.2Secondary objectives of the trial
    Regimens A-C:
    1. Evaluate the safety and tolerability of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C) in patients with AML (Dose Expansion Phase).
    2. Characterize the pharmacokinetics (PK) of IMGN632 when used in combination with azacitidine and/or venetoclax.
    3. Evaluate concentrations of azacitidine, venetoclax and azacitidine + venetoclax when administered in combination with IMGN632.
    4. Characterize the immunogenicity of IMGN632.
    5. Assess MRD levels (Dose Escalation Phase).

    Regimen D: (Cohort D1 and D2):
    1. Evaluate the safety and tolerability of IMGN632 as monotherapy in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients.
    2. Characterize the PK of IMGN632.
    3. Characterize the immunogenicity of IMGN632.
    Regimi A-C
    1. Valutare la sicurezza e la tollerabilità di IMGN632 quando somministrato in combinazione con azacitina (Regime A), venetoclax (Regime B) o azacitidina + venetoclax (Regime C) in pazienti affetti da LMA (fase di espansione del dosaggio)
    2. Caratterizzare la farmacocinetica (PK) di IMGN632 quando usato in combinazione con azacitidina e/o venetoclax
    3. Valutare le concentrazioni di azacitidina, venetoclax e azacitidina + venetoclax quando somministrati in combinazione con IMGN632
    4. Caratterizzare l'immunogenicità di IMGN632
    5. Valutare i livelli di MRD (fase di aumento progressivo del dosaggio) Regime D (Coorte D1 e D2)
    Regime D (Coorte D1 e D2)
    1. Valutare la sicurezza e la tollerabilità di IMGN632 come monoterapia nei pazienti con LMA MRD+ "in buone condizioni" (Coorte D1) e MRD+ "in cattive condizioni" (Coorte D2)
    2. Caratterizzare la PK di IMGN632
    3. Caratterizzare l'immunogenicità di IMGN632
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient = or >18 years of age.
    2. Patients must have confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on WHO classification.
    3. Disease characteristics and allowable prior therapy:
    a. Patients must be evaluated for any available standard of care therapies and, in the opinion of the treating physician, be deemed appropriate for this experimental therapy.
    b. Treatment-naïve (untreated) patients will be allowed in the Expansion Phase for Regimens A (IMGN632 + azacitidine) and C (triplet) (IMGN632 + azacitidine + venetoclax) in separate cohorts. No prior treatments with hypomethylating agents (HMAs) for MDS are allowed.
    Note: Patients who are MRD+ following frontline treatment are eligible for the Regimen D Cohorts D1 and D2 (Expansion Phase).
    c. Patients must have CD123-positive AML as confirmed by local flow cytometry (or immunohistochemistry [IHC]).
    d. Patients may have received prior CD123-targeted therapies, except IMGN632, as long as CD123 remains detectable during screening.
    e. Relapsed or refractory CD123-positive AML patients will be allowed to enroll in the Escalation Phase of Regimens A, B, and C (Triplet) (IMGN632 + azacitidine, venetoclax, or azacitidine + venetoclax, respectively) and the relapsed CD123-positive AML patients will be allowed to enroll the Expansion Phase of Regimens A - C.
    Note: Patients may also have received up to 2 prior lines of therapy, eg. frontline treatment (induction, consolidation [including transplant], and maintenance) and 1 salvage regimen.
    f. Patients enrolling in Regimen D must be in CR (CR/CRh/CRp/CRi) for no more than 6 months and be MRD+ at the time of screening, confirmed by central laboratory testing, after intensive induction/consolidation therapy (which may include stem cell transplant). Note: Fit patients who previously received intensive treatment (eg 3+7, HiDAC, etc.) are eligible for Regimen D Cohort D1. Unfit patients who previously received non intensive treatment (eg, HMA, low dose cytarabine, etc.) are eligible for Regimen D Cohort D2.
    4. ECOG = 1. If nonambulatory due to a chronic disability, must be Karnofsky performance status > 70.
    5. Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
    6. Total WBC must be less than 25 x 10e9 cells/L. Hydroxyurea may be used to control blood counts before Cycle 1 Day 1, according to institutional practice. During the Escalation Phase in Regimens A-C, hydroxyurea may also be used during Cycle 1.
    7. AST and ALT < = 3 × the upper limit of normal (ULN).
    8. Total bilirubin = or < 1.5 × the ULN within 14 days of enrollment.
    9. Serum creatinine = or < 1.5 mg/dL within 14 days of enrollment.
    10. LVEF = 45% based on locally available assessment, eg, ECHO or other modality.
    11. Patients with prior autologous and allogeneic bone marrow transplant are eligible if: the transplant must have been performed more than 120 days before the date of dosing on this study, the patient must not have active = Grade 2 graft versus host disease, and the patient must be off all systemic immunosuppression for at least 2 weeks before dosing
    12. Voluntary written informed consent available.
    13. Women of childbearing potential (WCBP), , must agree to use acceptable contraceptive methods while on study drug and for at least 7 months after the last dose of IMGN632
    14. WCBP must have a negative pregnancy test within 3 days before C1D1
    15. Male patients must agree use acceptable methods of contraception throughout the study and for at least 4 months after the last dose of IMGN632.
    16. Patients with prior malignancy are eligible; however, the patient must be in remission from the prior malignancy and have completed all chemotherapy and radiotherapy for the prior malignancy at least 6 months before enrollment, and all treatment-related toxicities must have resolved to Grade 1 or less.
    Note: prostate cancer or breast cancer on adjuvant hormonal therapy are eligible.
    1. Età = > 18 anni
    2. I pazienti con diagnosi confermata di LMA (esclusa la leucemia promielocitica acuta) in base alla classificazione dell'OMS.
    3. Caratteristiche della malattia e terapia preventiva ammissibili:
    a. I pazienti devono essere valutati per qualsiasi standard di cura disponibile e, a parere del medico curante, devono essere ritenuti appropriati per questa terapia sperimentale.
    b. I pazienti naïve di trattamento saranno ammessi nella fase di Espansione per i regimi A (IMGN632+azacitidina) e C (tripletta)(IMGN632+azacitidina e venetoclax) in coorti separate. Non sono consentiti trattamenti precedenti con agenti ipometilanti(HMA) per MDS. Nota: pazienti MRD+dopo prima linea sono arruolabili in Regime D (coorti D1 e D2)(Fase di espansione).
    c. I pazienti devono avere LMA CD123+ come confermato dalla locale citometria di flusso (o immunoistochimica [IHC])
    d. I pazienti possono aver ricevuto terapie precedenti mirate a CD123, ad eccezione di IMGN632, purché CD123 rimanga rilevabile durante lo screening
    e. I pazienti affetti da LMA in recidiva o refrattari, CD123 +, potranno essere candidabili alla Fase di aumento della dose dei Regimi A, B e C (tripletta) (IMGN632+azacitidina, +venetoclax o +azacitidina e venetoclax), e i pazienti in recidiva LMA CD123+, alla Fase di Espansione dei Regimi A – C. Nota: possono aver ricevuto fino a 2 precedenti linee di trattamento, ad es.: la prima linea (induzione, consolidamento [compreso il trapianto] e manmantenimento) e 1 regime di salvataggio.
    f. I pazienti che si iscrivono al Regime D devono essere in CR (CR//CRh/CRp/CRi) per non più di 6 mesi ed essere MRD+ al momento dello screening, con conferma dal laboratorio centrale, dopo induzione/consolidamento (incluso trapianto di cellule staminali). Nota: I pazienti in buone condizioni che hanno precedentemente ricevuto trattamento intensivo (es 3 + 7, HiDAC..) sono eleggibili per regime D coorte D1. I pazienti in cattive condizioni che hanno precedentemente ricevuto trattamento non intensivo (es. HMA, citarabina a basse dosi..) sono eleggibili per regime D coorte D2
    4. ECOG performance <=1. Se il paziente non è ambulatoriale a causa di una disabilità cronica, la performance Karnofsky deve essere > 70.
    5. Le precedenti tossicità legate al trattamento devono essere state risolte al grado 1 o al basale (esclusa l'alopecia).
    6. Il numero totale di GB < 25 x 10^9 cellule/L. L’idrossiurea può essere utilizzata prima del ciclo 1 Giorno 1, secondo la pratica istituzionale. Durante la fase di Escalation nei regimi A-C, l'idrossiurea può essere utilizzata anche durante il Ciclo 1.
    7. AST e ALT <= a 3 volte rispetto al limite superiore di normalità.
    8. Bilirubina totale <= 1,5 volte rispetto al limite superiore di normalità, entro 14 giorni dall'arruolamento.
    9. Creatinina serica <= a 1,5 mg/dL, entro 14 giorni dall'arruolamento
    10. LVEF >= 45%, basata sulle procedure locali es ECO o altro
    11. Sono ammissibili i pazienti con precedente trapianto di midollo osseo autologo e allogenico. I pazienti con trapianto allogenico devono soddisfare le seguenti condizioni: il trapianto deve essere stato eseguito più di 120 giorni prima della data di somministrazione in questo studio, il paziente non deve avere un Graft >= grado 2 rispetto alla malattia ospite e il paziente deve avere sospeso tutte le immunosoppressioni sistemiche per almeno 2 settimane prima della somministrazione
    12 Consenso informato scritto firmato prima di qualunque procedura.
    13 Le donne potenzialmente fertili (WCPB) devono usare metodi contraccettivi accettabili fino a 7 mesi dall'ultima dose.
    14 WCBP devono avere test di gravidanza negativo entro 3 giorni da C1G1
    15 Maschi fertili devono usare metodi contraccettivi accettabili fino a 4 mesi dall'ultima dose.
    16 precedenti malignità sono eleggibili se in remissione e chemio e radio terminate 6 mesi prima dell’arruolamento; tutte le tossicità correlate <= G1. Tumore a prostata e seno con terapia ormonale sono eleggibili
    E.4Principal exclusion criteria
    1. Patients who have received any anticancer therapy, including investigational agents, within 14 days (or within 28 days for checkpoint inhibitors) before drug administration on this study (hydroxyurea is allowed before beginning study treatment). Patients must have recovered to baseline from all acute toxicity from this prior therapy.
    2. Patients who have been previously treated with IMGN632.
    3. Patients with myeloproliferative neoplasm–related secondary AML are excluded from the Dose Expansion Phase of the study.
    4. Patients with active central nervous system (CNS) AML will be excluded. A lumbar puncture does not need to be performed unless there is clinical suspicion of CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS AML is allowed with the approval of the sponsor.
    5. Patients with a history of sinusoidal obstruction syndrome/venous occlusive disease of the liver.
    6. Myocardial infarction within 6 months before enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities before study entry.
    7. Clinically relevant active infection including known active hepatitis B or C, HIV infection, or cytomegalovirus or any other known concurrent infectious disease that, in the judgment of the investigator, would make a patient inappropriate for enrollment into this study (testing not required).
    8. Patients who have undergone a major surgery within 4 weeks (or longer if not fully recovered) before study enrollment.
    9. Serious or poorly controlled medical conditions that could be exacerbated by treatment or that would seriously compromise safety assessment or compliance with the protocol, in
    the judgment of the investigator.
    10. Women who are pregnant or breastfeeding.
    11. Prior known hypersensitivity reactions to monoclonal antibodies (= Grade 3).
    12. Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
    1. I pazienti che abbiano ricevuto qualsiasi terapia antitumorale, compresi agenti sperimentali, entro 14 giorni (o entro 28 giorni per i checkpoint-inhibitors) prima della somministrazione dei farmaci in questo studio (l'idrossiurea è consentita prima dell'inizio del trattamento di studio). I pazienti devono aver recuperato il livello basale da tutta la tossicità acuta delle terapie precedenti.
    2. Pazienti precedentemente trattati con IMGN632.
    3. I pazienti con LMA secondaria mieloproliferativa neoplasm-related sono esclusi dalla fase di Espansione della dose dello studio.
    4. Saranno esclusi i pazienti con LMA attiva per il Sistema nervoso centrale. Una puntura lombare non deve essere eseguita a meno che non vi sia il sospetto clinico di coinvolgimento del SNC a giudizio dello sperimentatore. La terapia simultanea per la profilassi del SNC o la continuazione della terapia per la LMA SNC controllata è consentita con l'approvazione dello sponsor.
    5. Pazienti con una storia di sindrome da ostruzione sinusoidale/malattia occlusiva venosa del fegato.
    6. Infarto miocardico entro 6 mesi prima dell'arruolamento o Classe III o IV di insufficienza cardiaca della New York Heart Association, angina incontrollata, gravi aritmie ventricolari incontrollate o prove elettrocardiografiche di ischemia acuta, o attive anomalie del sistema di conduzione, prima dell'ingresso nello studio.
    7. Infezione attiva clinicamente rilevante, tra cui nota epatite B o C attiva, infezione da HIV o citomegalovirus o qualsiasi altra malattia infettiva nota che, a giudizio dello sperimentatore, renderebbe il paziente inappropriato per l'arruolamento in questo studio (verifica non richiesta).
    8. Pazienti che hanno subito un intervento chirurgico importante entro 4 settimane (o più a lungo se non hanno completamente recuperato) prima dell'arruolamento nello studio.
    9. Condizioni mediche gravi o scarsamente controllate che potrebbero essere esacerbate dal trattamento o che comprometterebbero seriamente la valutazione della sicurezza o il rispetto del protocollo, a giudizio dello sperimentatore.
    10 Donne gravide o in allattamento
    11 Reazioni allergiche note a anticorpi monoclonali (>G3)
    12 Reazioni allergiche note ai farmaci in studio e/o a uno dei loro eccipienti.
    E.5 End points
    E.5.1Primary end point(s)
    1. Dose Escalation (Regimens A-C):
    a. RP2D of IMGN632 when administered in combination with azacitidine (Regimen A), venetoclax (Regimen B), azacitidine+venetoclax (Regimen C) b.Treatment-emergent adverse events (TEAEs), laboratory test results, physical examination, electrocardiograms (ECGs), and vital signs
    2. Dose Expansion Cohorts
    a. Regimen A -C
    (IMGN632+azacitidine), Regimen B (IMGN632+venetoclax), Regimen C (IMGN632+azacitidine+venetoclax)
    i. Composite CR rate (CRMRD-, CR, CRh, CRp, CRi).
    ii. Overall response rate (ORR) (CRMRD-, CR, CRh, CRp, CRi, MLFS, PR).
    iii. Duration of remission (DOR).
    iv. MRD levels using central flow cytometry–based testing.
    b. Regimen D (Cohort D1 and D2):
    i. MRD+ to MRD- conversion rate and relapse-free survival (RFS) in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients.
    ii. MRD levels using central flow cytometry–based testing.
    1-Coorti di aumento progressivo della dose (Regimi A-C)
    a. RP2D di IMGN632 quando somministrato in combinazione con azacitidina (regime A), venetoclax (regime B), azacitidina-venetoclax (Regime C)
    b. eventi avversi emergenti da trattamento (TEAE), risultati dei test di laboratorio, esame fisico, e segnali vitali
    2. Coorti di Espansione della dose
    a. (Regimi A-C) :
    i.il tasso di risposta di CR composto (CR completa [CRMRD- , CR], CRh, CRp, CRi)
    ii.tasso di risposta obiettiva (ORR) (CRMRD- , CR, CRh, CRp, Cri, stato leucemia-free morfologico [MLFS], risposta parziale [PR])
    iiiDurata della remissione (DOR)
    iv. livelli di MRD utilizzando test basati sulla citometria di flusso centrale
    b. Regime D (coorti D1 e D2)
    i. Tasso di conversione MRD+ a MRD- e sopravvivenza senza ricadute (RFS) in pazienti con LMA MRD+ in buone condizioni (Coorte D1) e MRD+ in cattive condizioni (Coorte D2)
    ii livelli di MRD utilizzando test basati sulla citometria di flusso centrale
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Safety and Tolerability are assessed throughout the study and at the end of the treatment and end of the study
    2. Anti-tumor activity data will be collected at the end of each cycle until a response or progression has reached.
    1. La sicurezza e la tollerabilità sono valutate durante tutto lo studio e alla fine del trattamento e alla fine dello studio
    2. I dati sull'attività antitumorale saranno raccolti alla fine di ogni ciclo fino a quando non sarà raggiunta una risposta o una progressione.
    E.5.2Secondary end point(s)
    a. Regimens A-C:
    i. Treatment-emergent adverse events (TEAEs) (Expansion Cohort).
    ii. IMGN632 PK parameters for intact ADC, total antibody, and free payload (FGN849) include, but are not limited to, Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time-concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs (tmax)
    iii. Blood concentration of azacitidine, venetoclax, azacitidine and venetoclax measured before and after their administration
    iv. Anti-drug antibody-ADA response
    v. MRD levels using central flow cytometry–based testing (Dose Escalation Phase).
    b. Regimen D (Cohort D1 and D2)
    i.TEAEs
    ii. IMGN632 PK parameters for intact ADC, total antibody, and free payload (FGN849) include, but are not limited to, Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs (tmax).
    iii. ADA response
    a. Regime A – C
    i. eventi avversi emergenti da trattamento (TEAE),(Coorti di Espansione della dose)
    ii. IMGN632 parametri farmacocinetici per ADC intatto, anticorpo totale, e carico utile libero (FGN849) includono, ma non sono limitati a, Ciclo 1 e Ciclo 3 concentrazione plasmatica massima (Cmax), area sotto la curva di concentrazione del tempo (AUC), emivita terminale (t1/2), clearance (CL), volume di distribuzione allo Steady State (Vss) e l'ora in cui si verifica Cmax (tmax)
    iii. Concentrazione nel sangue di azacitidina, venetoclax, azacitidina e venetoclax misurata prima e dopo la loro somministrazione
    iv. Risposta ADA (anticorpi anti farmaco)
    v. Livelli di MRD utilizzando test centrali basati sulla citometria di flusso (fase di aumento progressivo della dose)

    b. Regime D (Coorti D1 e D2)
    i. eventi avversi emergenti da trattamento (TEAE)
    ii. IMGN632 parametri farmacocinetici per ADC intatto, anticorpo totale, e carico utile libero (FGN849) includono, ma non sono limitati a, Ciclo 1 e Ciclo 3 concentrazione plasmatica massima (Cmax), area sotto la curva di concentrazione del tempo (AUC), emivita terminale (t1/2), clearance (CL), volume di distribuzione allo Steady State (Vss) e l'ora in cui si verifica Cmax (tmax)
    iii. Risposta ADA
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Safety and Tolerability are assessed throughout the study and at the end of the treatment and end of the study
    2. Anti-tumor activity data will be collected at the end of each cycle until a response or progression has reached.
    1. La sicurezza e la tollerabilità sono valutate durante tutto lo studio e alla fine del trattamento e alla fine dello studio
    2. I dati sull'attività antitumorale saranno raccolti alla fine di ogni ciclo fino a quando non sarà raggiunta una risposta o una progressione.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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
    Phase 1b/2 safety and tolerability
    fase 1b/2 Sicurezza e tollerabilità
    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 Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    France
    Germany
    Italy
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study will be defined as the latter of the completion of the safety follow-up visit for the last patient remaining on treatment or 1 year from the last accrued patient’s first visit.
    La fine dello studio sarà definita come l'ultima del completamento della visita di follow-up di sicurezza per l'ultimo paziente rimasto in trattamento, o 1 anno dalla prima visita dell'ultimo paziente arruolato
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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.1.1.1In 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) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 128
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 146
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 114
    F.4.2.2In the whole clinical trial 274
    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)
    There are no plans for treatment or care after subjects have ended their participation in the study.
    Non ci sono piani per il trattamento o l'assistenza dopo che i soggetti hanno terminato la loro partecipazione allo studio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-23
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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