| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Myeloid Leukemia (AML) |
| PAZIENTI CON 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 | 14.1 |
| 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 |
| One year transplant-related mortality (TRM) of AML patients undergoing allogeneic hematopoietic stem cell transplantation after a reduced toxicity conditioning regimen (I.V.BuFlu) as compared to the conventional I.V. BuCy2 program |
| Valutazione comparativa della mortalita` correlata al trapianto (TRM) a 1 anno dal trapianto allogenico di cellule staminali emopoietiche a seguito di condizionamento con I.V. Bu+Flu o I.V. Bu+Cy2 nei pazienti di eta` compresa fra 40 e 65 anni affetti da Leucemia Mieloide Acuta in remissione completa. |
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| E.2.2 | Secondary objectives of the trial |
| Assessment in the two arms of the safety and efficacy profile defined as: early and/or late graft rejection, hematopoietic recovery, chimerism, toxicity and incidence of VOD, incidence and severity of acute (aGvHD) and chronic graft-versus-host disease (cGvHD), cumulative incidence of TRM, relapse, event-free (EFS) and overall survival (OS) |
| Valutazione comparativa nei due bracci del profilo di sicurezza ed efficacia definito da: rigetto al trapianto,fallimento nell attecchimento,ricostituzione ematologica,chimerismo,tossicita` and incidenza di VOD,incidenza e grado di GvHD acuta e cronica,incidenza cumulativa di TRM,ricaduta di malattia,event-free survival (EFS) e overall survival (OS) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Patients  Age  40 and  65 years  Diagnosis of AML (FAB or WHO classification) in Complete Remission (CR)  Availability of an HLA compatible sibling or unrelated donor  Performance status : ECOG<3  Written and signed informed consent  Central Venous access (Central KT) secured through an indwelling catheter.  Life expectancy not severely limited by concomitant illness. Donors  Age between 18 years and 65 years inclusive.   Availability of an HLA-identical sibling donor (MRD) or HLA-compatible unrelated donor (MUD). Donor selection is based on molecular high-resolution typing (4 digits) of the HLA gene loci class I (HLA- A, B, and C) and class II (DRB1). In case, no class I and class II completely identical donor (8 out of 8 gene loci) can be identified, one antigen/allele disparity (class I) or one allele disparity (class II, DRB1) between patient and donor are acceptable. In any cases the degree of histocompatibility between patient and donor must fulfill with the minimal degree of matching established by the Italian Bone Marrow Donor Registry. |
|  Eta`  40 e  65 anni  Diagnosi di LMA (secondo criteri FAB o WHO) in remissione completa  Disponibilita` di un donatore HLA compatibile (familiare o non familiare)  Performance status : ECOG<3  Consenso informato scritto firmato  Funzioni cardiache e polmonari adeguate (LVEF 40% con ecocardiogramma) o DLCO 50% prima dell arruolamento a questo protocollo  Creatinina sierica <1.5 mg/dL o Creatinine Clearance >50 ml/min  Bilirubina sierica <1.5 mg/dl, SGPT <3 x il valore piu` alto del range di normalita`  HIV negativita`  Disponibilita` di accesso venoso centrale (Central KT)  Aspettativa di vita non gravemente limitata da malattie concomitanti. Donatore  Eta`  18 e  65 anni.   Disponibilita` di un donatore HLA identico familiare o donatore HLA compatibile non familiare. La selezione del donatore si basa su una tipizzazione HLA ad alta risoluzione molecolare (4 DIGITS) dei loci di classe I (HLA- A, B, e C) e loci di classe II (DRB1). Se un donatore completamente identico in classe I e II (8/8) non puo` essere identificato, la diversita` di un antigene/allele (classe I) o di un allele (classe II, DRB1) puo` essere accettata. In ogni caso i criteri di istocompatibilita` tra paziente e donatore devono soddisfare i criteri minimi stabiliti dal Registro dei Donatori di Midollo Osseo. |
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| E.4 | Principal exclusion criteria |
| Patients  AML patients in 1st CR with: o t(15;17) or PML/RARα positive APL o t(8;21)(q22;q22) with WBC count at diagnosis less than 20 x 109/L without additional adverse cytogenetic abnormalities. o inv(16) or t(16;16)(p13;q22) without additional adverse cytogenetic abnormalities.  Previous allogeneic transplantation  Poorly controlled arterial hypertension with blood pressure above 150/90 on standard medication  Acute Myocardial Infarction (AMI) within the last 12 months  Positive pregnancy test (in women not in menopause)  Positive HIV serology  Any major organ dysfunction  Pulmonary dysfunction (FEV1 <40%, DLCO <50%,)  Hepatic dysfunction (Serum bilirubin >1.5 mg% or serum transaminases >2x UNL)  Chronic active hepatitis or cirrhosis  Cardiac dysfunction (LVEF <40)  Chronic renal insufficiency (Serum creatinine >1.5 mg/dl or creatinine cleareance <=50 ml/min)  Invasive fungal infection still evolutive at the time of registration.  Central nervous system involvement.  Uncontrolled oral/dental infections  Patient has another progressive malignant disease or a history of other malignancies within 2 years prior to study entry.  Severe psychiatric illness or any disorder that compromises ability to give truly informed consent for participation in this study. |
| Paziente  Pazienti affetti da LMA in prima remissione completa con: o t(15;17) o PML/RARα APL positivo o t(8;21)(q22;q22) senza ulteriori anomalie citogenetiche avverse e con conta leucocitaria alla diagnosi inferiore a 20 x 109/L o inv(16) o t(16;16)(p13;q22) senza ulteriori anomalie citogenetiche avverse.  Precedente trapianto allogenico  Ipertensione arteriosa poco controllata con pressione sanguigna superiore a 150/90 con terapie standard  Infarto acuto del miocardio nei precedenti 12 mesi  Test di gravidanza positivo  HIV positivita`  Qualsiasi disfunzione grave ad organi  Disfunzione polmonare ((FEV1 <40%, DLCO <50%)  Disfunzione epatica (Bilirubina sierica >1.5 mg% o transaminasi >2 x UNL)  Epatite cronica attiva o cirrosi  Disfunzione cardiaca (LVEF <40)  Insufficienza renale cronica (Creatinina sierica >1.5 mg/dl o creatinine cleareance <=50 ml/min)  Infezione funginea invasiva non risolta al momento della registrazione.  Interessamento del sistema nervoso centrale.  Infezioni orali/dentali non controllate  Il paziente ha ulteriori malattie maligne in corso o ha una storia recente di altre malattie (nei 2 anni precedenti l entrata in questo studio).  Grave malattia psichiatrica o altro disturbo che comprometta l abilita` a fornire un consenso veramente informato alla participazione a questo studio. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Cumulative incidence of TRM (defined as non-relapse mortality) at 1 year post transplant in each arm |
| Incidenza cumulativa di TRM (definita come mortalita' non correlata alla malattia) a 1 anno dal trapianto in entrambi i bracci. |
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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 | 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) | 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 | No |
| 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 | 30 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 72 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 72 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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