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    Summary
    EudraCT Number:2021-005013-14
    Sponsor's Protocol Code Number:MKIA-088-002
    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:2021-10-12
    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 number2021-005013-14
    A.3Full title of the trial
    A Phase I/II Combination Study of NMS-03592088 And Azacitidine for the Treatment of Patients With FLT3-Mutated AML with Relapsed /Refractory Disease or Who Are Unfit For Intensive Chemotherapy, or of CMML Patients.
    Studio di combinazione di Fase I/II di NMS-03592088 e Azacitidina nel trattamento di pazienti con LMA FLT3-mutata con malattia refrattaria o recidivata o non idonea alla chemioterapia intensiva, o di pazienti con LMMC.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of experimental drug NMS-03592088 in combination with azacitidine in adult patients with blood malignancies
    Studio del farmaco sperimentale NMS-03592088 in combinazione con azacitidina in pazienti adulti con tumori maligni del sangue
    A.3.2Name or abbreviated title of the trial where available
    Ph I/II Study of NMS-03592088+Aza in R/R or unfit FLT3-mut AML or CMML Pts
    Studio di fase I/II di NMS-03592088+Aza in pazienti con LMA FLT3-mutata R/R o non idonea alla chemio
    A.4.1Sponsor's protocol code numberMKIA-088-002
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00000000
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    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 SponsorNERVIANO MEDICAL SCIENCES 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 supportNerviano Medical Sciences S.r.l.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNerviano Medical Sciences S.r.l.
    B.5.2Functional name of contact pointGlobal Clinical Development
    B.5.3 Address:
    B.5.3.1Street AddressViale Pasteur 10
    B.5.3.2Town/ cityNerviano (Mi)
    B.5.3.3Post code20014
    B.5.3.4CountryItaly
    B.5.4Telephone number390331581566
    B.5.5Fax number0000000
    B.5.6E-mailregulatory@nervianoms.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 nameNon applicabile
    D.3.2Product code [NMS-03592088]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 1409989-68-9
    D.3.9.2Current sponsor codeNMS-03592088
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Azacitidina Accord
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare S.L.U.
    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 nameAzacitidina
    D.3.2Product code [Azacitidina]
    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 codeAzacitidina
    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 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 nameNon applicabile
    D.3.2Product code [NMS-03592088]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 1409989-68-9
    D.3.9.2Current sponsor codeNMS-03592088
    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 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
    Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)
    Leucemia mieloide acuta (LMA) e leucemia mielomonocitica cronica (LMMC)
    E.1.1.1Medical condition in easily understood language
    Blood malignancies
    Tumori maligni del sangue
    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 10028552
    E.1.2Term Myeloid leukaemia, acute
    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
    • To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of NMS-03592088 in combination with AZA in adult patients with FLT3-mutated acute myeloid leukemia (AML) who have relapsed/refractory disease or are not eligible for intensive induction chemotherapy, or in Chronic Myelomonocytic Leukemia (CMML) patients (Phase I).
    • To determine the antitumor activity of NMS-03592088 in combination with AZA in adult patients with FLT3-mutated acute myeloid leukemia (AML) who have relapsed/refractory disease or are not eligible for intensive induction chemotherapy, or in Chronic Myelomonocytic Leukemia (CMML) patients (Phase II).
    • Determinare la dose massima tollerata (maximum tolerated dose, MTD) e la dose raccomandata per la fase II (recommended phase II dose, RP2D) di NMS- 03592088 in combinazione con azacitidina (AZA) in pazienti adulti con leucemia mieloide acuta (LMA) FLT3-mutata che hanno una malattia recidivata/refrattaria o non sono idonei alla chemioterapia di induzione intensiva, o in pazienti con leucemia mielomonocitica cronica (LMMC) (Fase I).
    • Determinare l'attività antitumorale di NMS-03592088 in combinazione con AZA in pazienti adulti con leucemia mieloide acuta (LMA) FLT3-mutata che hanno malattia recidivata/refrattaria o non sono idonei per la chemioterapia di induzione intensiva, o in pazienti con leucemia mielomonocitica cronica (LMMC) (Fase II).
    E.2.2Secondary objectives of the trial
    • To characterize the safety profile and tolerability of NMS-03592088 in combination with AZA.
    • To evaluate the pharmacokinetics (PK) in plasma and, limited to Phase I, also in urine of NMS-03592088 and its metabolites (NMS-03593860 and NMS 03603422) when administered in combination with AZA.
    •To evaluate additional measures of antitumor efficacy of NMS-03592088 when administered in combination with AZA.
    • Definire il profilo di sicurezza e tollerabilità di NMS-03592088 in combinazione con AZA.
    • Valutare la farmacocinetica (pharmacokinetics, PK) di NMS-03592088 nel plasma e, limitatamente alla Fase I, anche nelle urine e dei suoi metaboliti (NMS-03593860 e NMS-03603422) quando somministrati in combinazione con AZA.
    • Valutare ulteriori misure di efficacia antitumorale di NMS-03592088 quando sommini-strato in combinazione con AZA.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with confirmed diagnosis of de novo or secondary AML as defined by the 2017 ELN recommendations (Dohner H et al., Blood, Jan 2017) positive for FLT3 ITD and/or TKD point mutations in the BM or PB as determined by the local standard test performed at study entry. Patients with an allelic frequency = or > 5 % as determined by local laboratories will be considered to have FLT3-ITD positive disease.
    • Patients must be refractory to at least 1 cycle of induction chemotherapy or relapsed after achieving remission with a prior intensive treatment which may include HSCT. Patients must have received = or < 3 prior therapeutic regimens. Treatments given only for cytoreductive purposes (e.g. hydroxyurea) do not count as prior therapeutic regimen. Patients who received the combination of AZA and a FLT3 inhibitor as last regimen prior to study entry are excluded.
    • Patients deemed unfit for intensive induction chemotherapy or unsuitable or unwilling to receive standard therapy due to age, comorbidities or other factors. Patients must have received no more than 1 prior therapeutic regimen and the regimen should not include the combination of AZA and a FLT3 inhibitor. Treatments given only for cytoreductive purposes (e.g. hydroxyurea) do not count as prior therapeutic regimen.
    2. Patients with confirmed diagnosis of CMML, as defined by WHO criteria. Patients who have received prior AZA are eligible if the treating physician feels that participation to the study is in the best patients' interest.
    3. Adult (age = or > 18 years) patients.
    4. ECOG performance status < or = 2.
    5. In the absence of rapidly progressing disease, the interval from prior antitumor treatment to time of study drugs administration should be at least 2 weeks for any agents other than hydroxyurea.
    6. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTCAE version 5.0 Grade < or = 1, unless there is evidence of rapidly progressive disease.
    7. Adequate hepatic function, as defined by serum transaminases (i.e., AST/ALT) < or = 2.5 x ULN, ALP < or = 2.5 x ULN and total bilirubin < or = 1.5 x ULN unless abnormality considered due to Gilbert’s syndrome.
    8. Adequate renal function, as defined by the estimated glomerular filtration rate (eGFR) = or > 60 mL/min as calculated by the BSA-unadjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
    9. Patients must use highly effective contraception or abstinence. Female patients of childbearing potential must agree to the use of highly effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment. Male patients must be surgically sterile or must agree to use highly effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment.
    10. Capability to swallow capsules intact (without chewing, crushing, or opening)
    11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures
    12. Signed and dated IEC or IRB-approved informed consent form indicating that the patient is aware of the neoplastic nature of his/her disease and has been informed of the procedures to be followed, the investigational nature of the therapy, potential benefits, side effects, discomforts, risks and alternative treatments.
    1. Pazienti con diagnosi confermata di LMA primaria o secondaria come definito in base alle raccomandazioni ELN 2017 (Dohner H et al., Blood, Jan 2017) positiva per mutazioni puntiformi FLT3 ITD e/o TKD nel BM o PB come determinato dal test standard locale eseguito all'ingresso nello studio. I pazienti con una frequenza allelica = or > 5 % come determinato dai laboratori locali saranno considerati avere una malattia FLT3-ITD positiva.
    • I pazienti devono essere refrattari ad almeno 1 ciclo di chemioterapia di induzione o recidivati dopo aver raggiunto la remissione con un precedente trattamento intensivo che può includere l'HSCT. I pazienti devono aver ricevuto < o = 3 regimi terapeutici precedenti. I trattamenti somministrati solo a scopo citoriduttivo (es. idrossiurea) non sono considerati come regime terapeutico precedente. I pazienti che hanno ricevuto la combinazione di AZA + un inibitore FLT3 come ultima terapia prima dell'ingresso nello studio sono esclusi.
    • Pazienti ritenuti non idonei alla chemioterapia di induzione intensiva o inadatti o non disposti a ricevere la terapia standard a causa dell'età, delle comorbilità o di altri fattori. I pazienti non devono aver ricevuto più di 1 regime terapeutico precedente e il regime non deve includere la combinazione di AZA + un inibitore FLT3. I trattamenti somministrati solo a scopo citoriduttivo (es. idrossiurea) non contano come regime terapeutico precedente.
    2. Pazienti con diagnosi confermata di LMMC, come definito dai criteri WHO. I pazienti che hanno ricevuto AZA in precedenza sono ammissibili se il medico curante ritiene che la partecipazione allo studio sia nell'interesse dei pazienti.
    3. Pazienti adulti (età = o > 18 anni).
    4. Performance Status < o = 2 secondo la scala ECOG
    5. In assenza di una malattia in rapida progressione, l'intervallo dal precedente trattamento antitumorale al momento della somministrazione del trattamento sperimentale deve essere di almeno 2 settimane per qualsiasi agente diverso dall'idrossiurea.
    6. Tutti gli effetti tossici acuti (alopecia esclusa) derivanti da una terapia precedente devono essersi risolti a un Grado < o = 1 come classificato nella versione 5.0 di NCI CTCAE, a meno che non vi sia evidenza di una rapida progressione della malattia.
    7. Adeguata funzionalità epatica, definita in base ai valori dalle transaminasi sieriche (cioè AST/ALT) < o = 2,5 x ULN, ALP < o = 2,5 x ULN e bilirubina totale < o = 1,5 x ULN salvo anomalie considerate correlate alla sindrome di Gilbert.
    8. Adeguata funzionalità renale, come definita dal tasso di filtrazione glomerulare stimata (eGFR) = o > 60 mL/min come calcolata dall'equazione della Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) non normalizzata per la BSA.
    9. I pazienti devono usare una contraccezione altamente efficace. Le pazienti donne in età fertile devono accettare l'uso di una contraccezione altamente efficace o l'astinenza durante il periodo di terapia e nei 90 giorni successivi all’interruzione del trattamento dello studio. I pazienti di sesso maschile devono essere chirurgicamente sterili o devono accettare di usare una contraccezione altamente efficace o l’astinenza durante il periodo di terapia e nei 90 giorni successivi all’interruzione del trattamento dello studio.
    10. Capacità di ingerire le capsule intere (senza masticarle, romperle o aprirle)
    11. Disponibilità e capacità di rispettare le visite programmate, il piano di trattamento, le analisi di laboratorio e altre indicazioni o procedure dello studio
    12. Modulo di consenso informato approvato dal Comitato Etico (CE) o dall’IRB, firmato e datato con il quale il paziente dichiara di essere consapevole della natura neoplastica della sua malattia ed è stato informato delle procedure da seguire, della natura sperimentale della terapia, dei potenziali benefici, effetti collaterali, disagi, rischi e trattamenti alternativi.
    E.4Principal exclusion criteria
    1. Current enrollment in another interventional clinical study
    2. Diagnosis of acute pro-myelocytic leukemia or BCR-ABL-positive leukemia
    3. Currently active second malignancy, except for adequately treated basal or squamous cell skin cancer and/or cone biopsied in situ carcinoma of the cervix uteri and/or superficial bladder cancer.
    4. Patients with known leukemia involvement of CNS.
    5. Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start and/or persistent non-hematologic toxicities of Grade = or > 2 related to the transplant
    6. Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive treatment
    7. Patients with QTcF interval = or > 480 milliseconds or with risk factors for torsade de pointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history of prolonged QTc interval or family history of long QT syndrome). For patients receiving treatment with concomitant medications known to prolong the QTc interval, replacement with another treatment should be considered. If replacement or discontinuation is not clinically feasible, a careful risk/benefit evaluation should be performed prior to enrollment.
    8. Pregnancy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within the screening period prior to start of study drug.
    9. Breast-feeding or planning to breast feed during the study or within 3 months after study treatment.
    10. Known hypersensitivity to any components of the NMS-03592088 drug product or AZA drug product.
    11. Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis
    12. Known active, life threatening or clinically significant uncontrolled systemic infection.
    13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
    14. Known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection requiring systemic treatment.
    15. Known active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
    16. Known active gastrointestinal ulcer
    17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
    1. Arruolamento contemporaneo in un altro studio clinico interventistico
    2. Diagnosi di leucemia pro-mielocitica acuta o leucemia positiva per BCR-ABL
    3. Presenza di un secondo tumore maligno attivo, ad eccezione del carcinoma epiteliale basocellulare o squamoso adeguatamente trattato e/o il carcinoma in situ della cervice uterina rilevato mediante biopsia conoide e/o il carcinoma superficiale della vescica.
    4. Pazienti con noto coinvolgimento leucemico del SNC.
    5. Trapianto di cellule staminali ematopoietiche (HSCT) nei 3 mesi precedenti l’inizio del trattamento e/o tossicità non ematologiche persistenti di grado = o > 2 correlate al trapianto
    6. Graft versus host disease (GVHD) acuta o cronica attiva che richiede un trattamento immunosoppressivo
    7. Pazienti con intervallo QTcF = o > 480 millisecondi o con fattori di rischio per torsade de pointes (torsione di punta) (per esempio, insufficienza cardiaca incontrollata, ipokaliemia incontrollata, storia di intervallo QTc prolungato o storia familiare di sindrome del QT lungo). Per i pazienti in trattamento con farmaci concomitanti noti per prolungare l’intervallo QTc, deve essere considerata la sostituzione con un altro trattamento. Se la sostituzione o l’interruzione non è clinicamente fattibile, un’attenta valutazione dei rischi/benefici dovrebbe essere eseguita prima dell’arruolamento.
    8. Gravidanza. Tutte le pazienti di sesso femminile con potenziale riproduttivo devono avere un test di gravidanza negativo (su siero o urina) entro il periodo di screening precedente l’inizio del trattamento.
    9. Allattamento o previsione di allattamento durante lo studio o nei 3 mesi successivi alla fine del trattamento dello studio.
    10. Ipersensibilità nota a qualsiasi componente del farmaco NMS-03592088 o del farmaco AZA.
    11. Uno qualsiasi dei seguenti eventi nei 6 mesi precedenti: infarto del miocardio, angina instabile, impianto di bypass aortocoronarico/periferico, insufficienza cardiaca congestizia sintomatica, ictus cerebrovascolare o attacco ischemico transitorio, embolia polmonare, trombosi venosa profonda
    12. Infezione sistemica attiva nota non controllata, potenzialmente letale o clinicamente significativa.
    13. Malattia nota legata al virus dell’immunodeficienza umana (HIV) o alla sindrome da immunodeficienza acquisita (AIDS)
    14. Documentata infezione attiva da virus dell’epatite B (HBV) o da virus dell’epatite C (HCV) per cui sia necessaria una terapia sistemica.
    15. Documentata malattia gastrointestinale attiva (per esempio, morbo di Crohn, colite ulcerosa, o sindrome dell’intestino corto) o altre sindromi da malassorbimento che potrebbero influire sull’assorbimento del farmaco.
    16. Documentata ulcera gastrointestinale attiva
    17. Altre gravi condizioni mediche o psichiatriche acute o croniche o anomalie di laboratorio che potrebbero aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco in studio o che possano interferire con l’interpretazione dei risultati dello studio e che, secondo il parere dello Sperimentatore, potrebbero rendere il paziente inadatto a partecipare a questo studio o che, secondo il parere dello Sperimentatore e/o dello Sponsor potrebbero compromettere il conseguimento degli obiettivi del protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    • First-cycle dose limiting toxicities (DLTs);
    Phase II:
    • FLT3-mut AML: Composite Complete Remission Rate (CRc: CR +CRi), i.e. Complete Remission (CR)+ Complete Remission with Incomplete Hematologic Recovery (CRi), as determined by the Investigators based on the 2017 European LeukemiaNet (ELN) recommendations.
    • CMML: Overall Response Rate, i.e. Complete Response (CR) + Complete cytogenetic remission (CCR) + Partial remission (PR) + Marrow response (MR) + Clinical Benefit (CB) as defined by disease specific International Working Group (IWG) criteria.
    Fase I:
    • Tossicità limitanti della dose (dose limiting toxicity, DLT) al primo ciclo;
    Fase II:
    • LMA con FLT3-mutato: Tasso di Remissione Completa Composita (CRc: CR +CRi), cioè Remissione Completa (CR)+ Remissione Completa con recupero ematologico incompleto (CRi), come determinato dagli Sperimentatori sulla base delle raccomandazioni European LeukemiaNet (ELN) del 2017.
    • LMMC: Tasso di Risposta Globale, cioè Risposta Completa (CR) + Remissione citogenetica completa (CCR) + Remissione Parziale (PR) + Risposta Midollare (MR) + Beneficio Clinico (CB) come definito dai criteri dell'International Working Group (IWG) specifici della malattia.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I: during the first two cycles
    Phase II: all the study duration
    Fase I: durante i primi due cicli
    Fase II: tutta la durata dello studio
    E.5.2Secondary end point(s)
    Plasma pharmacokinetic profile and corresponding parameters of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422;; Renal clearance and fraction of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422 excreted in urine (only Phase I); FLT3-mut AML: best response by remission category defined as Complete Remission (CR), Complete Remission with partial hematologic recovery (CRh), Complete Remission with Incomplete Hematologic Recovery (CRi), Morphologic Leukemia-free State (MLFS) as determined based on the 2017 ELN recommendations and as defined by Shallis RM et al.,; CR/CRh rate; Overall Response Rate (ORR: CRc + CRh + PR); Overall Survival (OS), Time to Response (TTR), Duration of Response (DoR), Event-free Survival (EFS) and Relapse-free Survival (RFS) as determined by the Investigators based on the 2017 ELN recommendations and disease-specific International Working Group criteria.; Overall safety profile of the combination of NMS-03592088 and AZA characterized by type, frequency, severity (graded using the NCI CTCAE Version 5.0), timing of the AEs and laboratory abnormalities, and relationship of the AEs to study treatment.
    Valutazione del profilo di farmacocinetica e dei parametri corrispondenti di NMS-03592088 e dei suoi metaboliti NMS-03593860 e NMS-03603422; Valutazione della clearance renale e della frazione di NMS-03592088 e dei suoi metaboliti NMS-03593860 e NMS-03603422 escreti nell’ urina (solo Fase I); LMA con FLT3-mutato: migliore risposta per categoria di remissione definita come Remissione Completa (CR), Remissione Completa con recupero ematologico parziale (CRh), Remissione Completa con Recupero Ematologico Incompleto (CRi), Stato morfologico libero da leucemia (MLFS) come determinato in base alle raccomandazioni ELN 2017 e come definito da Shallis RM et al.; tasso di CR/CRh; Tasso di Risposta Complessiva (ORR: CRc + CRh + PR); Sopravvivenza Globale (OS), Tempo Di Risposta (TTR), Durata Della Risposta (DoR), Sopravvivenza libera da eventi (EFS) e Sopravvivenza libera da recidiva (RFS) come determinato dagli Sperimentatori sulla base delle raccomandazioni ELN 2017 e dei criteri patologici specifici dell'International Working Group.; Profilo di sicurezza generale della combinazione di NMS-03592088 e AZA valutato sulla base di parametri quali tipo, frequenza, gravità (classificata usando la Versione 5.0 di NCI CTCAE), tempistica degli eventi avversi e anomalie di laboratorio, e relazione degli eventi avversi al trattamento dello studio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I: during first two treatment cycles.
    Phase II: to be defined based on results from phase I.; During first cycle (only phase I); All the study duration; All the study duration; All the study duration
    Fase I: durante i primi due cicli di trattamento.
    Fase II: da definire in base ai risultati della fase I.; Al primo ciclo (solo fase I); Tutta la durata dello studio; Tutta la durata dello studio; Tutta la durata dello studio
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    dose escalation (phase I) followed by phase II
    Dose escalation (fase I) seguita da fase II
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other 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.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    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 months10
    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 months10
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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)
    Therapies for pathology according to clinical practice.
    Terapie per la patologia secondo la pratica clinica.
    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 Decision2022-01-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-06-16
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