E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myeloid Leukaemia (AML) in elderly population (equal or older than 60 years). |
Leucemia mieloide acuta (AML) in popolazione anziana (uguale o più di 60 anni). |
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E.1.1.1 | Medical condition in easily understood language |
Acute Myeloid Leukaemia (AML) in elderly population (equal or older than 60 years). |
Leucemia mieloide acuta (AML) in popolazione anziana (uguale o più di 60 anni). |
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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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10024291 |
E.1.2 | Term | Leukaemias acute myeloid |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10024324 |
E.1.2 | Term | Leukaemias |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to assess, the effect of 10-day decitabine at a dose of 20 mg/m2 versus conventional induction chemotherapy (“3+7”) on overall survival (OS) in older AML patients. |
L'obiettivo primario di questo studio è di valutare, attraverso una sperimentazione randomizzata di fase III, l'effetto della terapia della durata di 10 giorni con decitabina alla dose di 20 mg/m2 rispetto alla chemioterapia di induzione convenzionale (“3+7”) sulla sopravvivenza globale (OS) in pazienti anziani affetti da leucemia mieloide acuta (AML). |
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E.2.2 | Secondary objectives of the trial |
Between two treatment arms:
♦ To compare efficacy : complete response rate, response rate and disease-free survival (DFS) and progression-free survival (PFS)
♦ To compare safety and toxicity profile
♦ To determine feasibility of allogeneic hematopoietic cell transplantation with reduced intensity conditioning
♦ To determine transplant outcome in terms of disease free survival, incidence of non-relapse related mortality (NRM) and incidence of relapse
♦ To determine health/economic impact by of days staying in hospital and transfusion needs for selected sites
♦ To compare Quality of Life (QoL) of patients
♦ To determine impact of baseline physical and functional conditions
♦ To identify, by translational research, potential biomarkers which are of prognostic importance; in addition, in decitabine arm, identification of DNA methylation signature of response will be assessed
♦ To determine prognostic value of minimal residual disease (MRD) regarding risk of relapse |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
♦Age ≥ 60 years
♦ WHO Performance status: ≤ 2
♦ Eligible for standard intensive chemotherapy
♦Patients of reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly
♦ Have newly diagnosed AML that is cytopathologically confirmed according to WHO classification (Patients can be diagnosed with AML two months prior to randomization)
♦De novo or secondary AML is allowed
WBC is ≤30x109/L (measured within 72 hours prior to randomization)
♦ The following laboratory assessments should be done within 7 days prior to randomization and should be within the following range:
♦ SGOT (AST) and SGPT (ALT) < 2.5 x the upper limit of normal range (at the laboratory where the analyses were performed) unless considered AML-related
♦ Total serum bilirubin level < 2.5 x the upper limit of normal range (at the laboratory where the analyses were performed) unless considered AML-related or due to Gilbert’s syndrome
♦ Serum creatinine concentration < 2.5 x the upper limit of normal range (at the laboratory where the analyses were performed) unless considered AML-related
♦ The following treatments for previous MDS or MPN are allowed as long as treatment has stopped one month before inclusion:
-Growth factors, thrombomimetics, immunosuppression (cyclosporin A, steroids, Antithymocyte globulin etc.), chelation, interferons, anagrelide
-Lenalidomide, low-dose chemotherapy (low-dose melphalan, hydroxyurea, low-dose cytarabine etc.), tyrosine-kinase inhibitors, histone deacetylase inhibitors (e.g. Valproic acid, panobinostat etc.), mTOR inhibitors, other experimental treatment that is not based on inhibition of DNA methyltransferase
♦ Before patient registration/randomization, written informed consent must be given according to ICH/GCP and national/local regulations |
♦ età ≥ 60 anni
♦ WHO performance status: ≤ 2
♦Eleggibilità per una chemioterapia intensiva standard
♦ I pazienti potenzialmente fertili devono utilizzare misure di controllo delle nascite adeguate, come definito dallo sperimentatore, durante il periodo di trattamento dello studio e per almeno 3 mesi dopo l'ultimo trattamento in studio. Un metodo altamente efficace di controllo delle nascite è definito come quelli che provocano basso tasso di fallimento (cioè meno di 1% all'anno) se utilizzato in modo coerente e corretto
♦ Avere nuova diagnosi di leucemia mieloide acuta che sia citopatologicamente confermata secondo la classificazione WHO i (pazienti possono essere diagnosticati con AML due mesi prima della randomizzazione)
♦ è consentita la leucemia mieloide acuta secondaria o de novo;
WBC è ≤30x109 / L (misurata nelle 72 ore precedenti la randomizzazione)
♦ Le seguenti valutazioni di laboratorio devono essere effettuate entro 7 giorni prima della randomizzazione e dovrebbero essere compresi nel seguente intervallo:
♦ SGOT (AST) e SGPT (ALT) <2,5 x il limite superiore del range normale (presso il laboratorio in cui sono state eseguite le analisi) a meno che ritenuto AML-correlato
♦ totale livello di bilirubina sierica <2,5 x il limite superiore del range normale (presso il laboratorio in cui sono state eseguite le analisi) a meno che ritenuto AML-correlato oa causa di sindrome di Gilbert
♦ La concentrazione sierica di creatinina <2,5 x il limite superiore del range normale (presso il laboratorio in cui sono state eseguite le analisi) a meno che ritenuto AML-correlato
♦ I seguenti trattamenti per precedente MDS o MPN sono permessi a patto che il trattamento sia fermato un mese prima dell'inclusione:
Fattoridi crescita, trombomimetici, immunosoppressione (ciclosporina A, steroidi, antitimocita globulina ecc), chelanti, interferoni, anagrelide
-Lenalidomide, Chemioterapia a basso dosaggio (basso dosaggio melfalan, idrossiurea, basse dosi di citarabina, ecc), inibitori della tirosin-chinasi, inibitori della deacetilasi istoniche (ad esempio acido valproico, panobinostat ecc), inibitori di mTOR, altro trattamento sperimentale che non è basata sulla inibizione della DNA metiltransferasi
♦ Prima della registrazione / randomizzazione del paziente, deve essere fornito il consenso informato scritto secondo ICH / GCP e le normative locali / nazionali. |
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E.4 | Principal exclusion criteria |
♦ Presence of acute promyelocytic leukaemia (APL, i.e. AML-M3 with t(15;17)(q22;q12); PML-RARA fusion gene and cytogenetic variants)
♦ Presence of blast crisis of chronic myeloid leukaemia
♦ Presence of active central nervous system (CNS) leukaemia
♦ No prior treatment for AML (relapsed AML is not allowed), these are any antileukaemic therapy including investigational agents and hypomethylating agents (decitabine, 5-azacytidine). Exception: Treatment with Hydroxyurea (HU) is allowed to control the leukocytosis if given for a maximum of 5 days and is stopped at least two days prior to the start of any of the protocol regimens
♦ No prior treatment for MDS or MPN with:
-hypomethylating agents (decitabine, 5-azacytidine), OR
-intensive chemotherapy or transplantation within the last three years
♦ Presence of concomitant severe cardiovascular disease which would make intensive chemotherapy impossible, i.e. arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, reduced left ventricular function assessed by MUGA scan or echocardiogram.
♦ Presence of concomitant malignancy requiring chemotherapy or any malignancy (except basal and squamous cell carcinoma of the skin) for which the patient received chemotherapy within 6 months prior to randomization
♦ Presence of active uncontrolled infection
♦ Presence of any psychological, familial, sociological or geographical condition in the opinion of the investigator potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial |
♦ Presenza di leucemia promielocitica acuta (APL, cioè AML-M3 con t (15; 17) (q22, q12); PML-RARA gene di fusione e varianti citogenetiche)
♦ Presenza di crisi blastica della leucemia mieloide cronica
♦ Presenza di leucemia attiva nel sistema nervoso centrale (CNS)
♦ Nessun precedente trattamento per la leucemia mieloide acuta (non è consentita AML in recidiva), si tratta di una terapia antileucemica compresi gli agenti di sperimentazione e agenti ipometilanti (decitabina, 5-azacitidina). Eccezione: Il trattamento con idrossiurea (HU) è autorizzato per controllare la leucocitosi somministrata per un massimo di 5 giorni e viene interrotta almeno due giorni prima dell'inizio di uno qualsiasi dei regimi terapeutici
♦ Nessun trattamento preliminare per MDS o MPN con:
agenti - ipometilanti (decitabina, 5-azacitidina), O
-Chemioterapia intensiva o il trapianto negli ultimi tre anni
♦ Presenza di gravi malattie cardiovascolari concomitanti che renderebbero impossibile la chemioterapia intensiva, ad esempio le aritmie che richiedono un trattamento cronico, insufficienza cardiaca congestizia o cardiopatia ischemica sintomatica, ridotta funzione ventricolare sinistra valutata da MUGA scan o ecocardiogramma.
♦ Presenza di neoplasia concomitante richiedente chemioterapia o qualsiasi tumore maligno (ad eccezione di carcinoma a cellule basali e squamose della pelle) per il quale il paziente ha ricevuto chemioterapia nei 6 mesi precedenti la randomizzazione
♦ Presenza di infezione non controllata attiva
♦ Presenza di qualsiasi condizione psicologica, familiare, sociologica o geografica che, a giudizio dello sperimentatore potenzialmente possa ostacolare il rispetto del protocollo di studio il e programma di follow-up; queste condizioni dovrebbero essere discusse con il paziente prima della registrazione nello studio |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival |
La sopravvivenza globale |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from randomization until death |
Tempo dalla randomizzazione fino alla morte |
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E.5.2 | Secondary end point(s) |
♦ CR/CRi rate, response rate (CR/CRi and PR), overall CR/CRi rate, DFS, PFS
♦ Safety and toxicity
♦ Transplantation feasibility: percentage of patients transplanted
♦ Outcome post-transplantation: PFS, incidence of relapse or progression, and incidence of NRPM (or TRM)
♦ Days of staying in hospital and transfusion needs
♦ HRQoL (EORTC QLQ-C30, ELD14)
♦ The prognostic value of baseline physical and functional conditions using a comprehensive geriatric assessment tools (short |
♦ Sicurezza e tossicità
♦ Fattibilità del Trapianto: percentuale di pazienti trapiantati
♦ Esito post-trapianto: PFS, l'incidenza di recidiva o progressione, e l'incidenza di NRPM (o TRM)
♦ giorni di permanenza in ospedale e necessità di trasfusioni
♦ HRQoL (EORTC QLQ-C30, ELD14)
♦ Il valore prognostico delle condizioni fisiche e funzionali di base con una completa valutazione geriatrica |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression Free Survival (time from randomization till progression, relapse or death without progression) |
Sopravvivenza libera da progressione (tempo dalla randomizzazione fino alla progressione, recidiva o morte senza progressione |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Health-related Quality of Life |
Qualità motivi di salute della Vita |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
cross-over possible (patients progressing in decitabine arm standard arm chemotherapyis recommended) |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 | No |
E.8.7 | Trial 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
|
The end of trial is defined as follows
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The long-term follow-up for OS (i.e. an additional 2 years of FU after the analysis of the first endpoint)
4. The database has been fully cleaned and frozen for these 2 analyses |
La fine del processo è definito come segue
1. trenta giorni dopo che tutti i pazienti hanno interrotto il trattamento protocollo
2 la sperimentazione è matura per l'analisi dell'endpoint primario, come definito nel protocollo
3.-Follow-up a lungo termine per l’OS (cioè ulteriori 2 anni di FU dopo l'analisi dell’end point primario)
4 Il database è stato completamente pulito e congelato per questi 2 analisi |
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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 | 8 |
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 | 8 |
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 |