E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NPM1-MUTATED AML NEWLY DIAGNOSED OR PREVIOUSLY TREATED WITH HYPOMETHYLATING AGENTS |
Leucemia acuta mieloide con mutazione del gene NPM1 in prima diagnosi o precedentemente trattata con agenti ipometilanti |
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E.1.1.1 | Medical condition in easily understood language |
acute myeloid leukemia |
leucemia mieloide acuta |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000880 |
E.1.2 | Term | Acute myeloid leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the clinical efficacy of single agent actinomycin D administered intravenously in newly diagnosed or previously treated with hypometilating agents NPM1-mutated AML patients, measured as the rate of complete remissions. |
Determinare l’efficacia clinica di actinomicina D somministrata per via endovenosa in pazienti affetti da Leucemia Acuta Mieloide con mutazione di NPM1 di nuova diagnosi o precedentemente trattati con agenti ipometilanti, valutata come la percentuale di remissione completa. |
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E.2.2 | Secondary objectives of the trial |
• To assess the safety of actinomycin D • To determine the duration of response to actinomycin D • To assess time to neutrophil (PMN>1000/¿l) and platelet (PLT>50000/¿l) recovery either after the first cycle or after each subsequent cycle • To assess the need for transfusional support (platelets and blood red cells) during the first induction cycle and the subsequent cycles
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- Valutare la sicurezza di actinomicina D - Determinare la durata di risposta al trattamento con actinomicina D - Determinare il tempo necessario alla risalita della conta neutrofila (PMN>1000/mmc) e della conta piastrinica (PLT>50000/mmc) entrambe dopo il primo ciclo e dopo i cicli successivi - Determinare il fabbisogno trasfusionale (PLT e GRC) durante il primo ciclo di induzione ed i cicli successivi.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of NPM1-mutated AML based on detection of NPM1 mutations at molecular analysis58 and/or demonstration of aberrant cytoplasmic expression of nucleophosmin at immunohistochemistry18. 2. Age =70 years, or age 18-70 years and being unsuitable for intensive chemotherapy. Ineligibility for intensive chemotherapy will be based on investigator assessment of patient characteristics such as age, performance status, concomitant co-morbidities and organ dysfunction (Döhner H et al., Blood 2014 Aug 28;124:1426-33). 3. Adequate renal and liver function as defined by the following laboratory values performed within 7 days prior to first dose of actinomycin D: serum creatinine =2.0 mg/dl; serum aspartate transaminase (AST) and serum alanine transaminase (ALT) =3 times the upper limit of normal (ULN), alkaline phosphatase =2.5 times ULN and bilirubin =1.5 times the ULN. Higher values are acceptable if they are directly related to the disease. 4. Negative serum pregnancy test within 7 days prior to commencement of treatment in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for =1 year 5. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as indicated by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception and intrauterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. 6. Signed informed consent. The consent must be obtained prior to performing any study-related procedure.
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1. Diagnosi comprovata di leucemia acuta mieloide con mutazione del gene NPM1 sulla base dell’analisi molecolare o dell’analisi immunoistochimica 2. Età uguale o superiore a 70 anni, oppure età uguale o superiore a 18 anni e non eleggibilità per chemioterapia standard. L’ineIeggibilità sara’ valutata sulla base delle condizioni del paziente alla diagnosi, tenendo conto dell’eta’, del performance score, delle comorbidita’ e di eventuali altre disfunzioni d’organo (Döhner H et al., Blood 2014 Aug 28;124(9):1426-33 3. Funzione renale ed epatica adeguate, definite mediante esami di laboratorio da effettuare nei 7 giorni precedenti l’inizio del trattamento con actinomicina D: creatinina sierica =2.0 mg/dl; aspartato transaminasi sierica (AST) e alanina transaminasi sierica (ALT) =3 volte il valore soglia normale (ULN), fosfatasi alcalina =2.5 volte e bilirubina sierica =1.5 il valore normale. Valori superiori sono accettabili solo se direttamente correlati alla malattia leucemica. 4. Negatività del test di gravidanza al massimo 7 giorni prima dell’inizio del trattamento chemioterapico nelle donne in eta’ fertile. Donne in eta’ non fertile potranno essere incluse se chirugicamente sterili o se in fase post-menopausale da almeno un anno. 5. Contraccezione efficace (fare riferimento al testo del protocollo per maggiori dettagli) in pazienti in eta’ fertile fino a 6 mesi dopo il termine della terapia. 6. Firma del consenso informato.
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E.4 | Principal exclusion criteria |
1. Diagnosis of acute promyelocytic leukemia and all the other NPM1 negative AML 2. Central nervous system (CNS) leukemia involvement because actinomycin D does not cross the blood-brain barrier. 3. Concurrent administration of any anti-leukemic therapy (e.g. chemotherapy, experimental drug, etc.) other than actinomycin D. 4. Known hypersensitivity to actinomycin D 5. Pregnant (negative serum pregnancy test is required in women of child-bearing potential) or lactating women. Unwillingness to practice effective birth control 6. Inability to comply with other requirements of the protocol 7. Unwillingness to participate to the study
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1. Leucemia acute promielocitica o altre leucemie acute mieloidi senza mutazione del gene NPM1 2. Coinvolgimento del sistema nervoso centrale (CNS) 3. Concomitante somministrazione di qualsiasi altro farmaco anti-leucemico (es. chemioterapia, farmaci sperimentali, ecc.) diverso da actinomicina D. 4. Nota ipersensibilita’ ad actinomicina D 5. Gravidanza o allattamento in corso 6. Riluttanza ad adottare metodi contraccettivi efficaci 7. Incapacita’ di attenersi a quanto richiesto dal protocollo 8. Riluttanza a partecipare al protocollo.
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E.5 End points |
E.5.1 | Primary end point(s) |
The complete hematological response rate after two cycles of treatment. The complete hematological response rate is intended as the sum of complete response (CR) and complete response with incomplete marrow recovery (CRi) |
Tasso di risposta completa definito come somma delle remissioni complete (CR) e delle remissioni complete con incompleto recupero ematologico (CRi), valutato dopo due cicli di terapia |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
8 weeks (2 treatment cycles) |
8 settimane (2 cicli di trattamento) |
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E.5.2 | Secondary end point(s) |
• The overall survival (OS) • The disease free survival (DFS) as defined by relapse and death in remission. • Cumulative incidence of relapse • The immunohistochemical response evaluated in the bone marrow biopsy by detection of aberrant cytoplasmic dislocation of nucleophosmin (NPM1). • Molecular response (MRD), as defined by 3-log reduction in NPM1 mutant transcripts copies assessed by quantitative RT-PCR on peripheral blood and bone marrow. • Rate of adverse events (AE) and severe adverse events (SAE)
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• Tasso di sopravvivenza globale (overall survival, OS) e di sopravvivenza libera da malattia (disease free survival, DFS). • Incidenza cumulativa di recidiva (CIR) • Tasso di risposta immunoistochimica • Risposta molecolare • Frequenza e severità degli eventi avversi (AE) e degli eventi avversi severi (SAE).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |