| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute promyelocytic leukemia |
| Leucemia promielocitica acuta |
|
| E.1.1.1 | Medical condition in easily understood language |
| Blood cancer characterized by rapid development in excess of a specific type of cells contained in the blood and bone marrow which do not accrue over and invade the bone . |
| Tumore del sangue, caratterizzato da un rapido sviluppo per eccesso di uno specifico tipo di cellule contenute nel sangue e nel midollo osseo le quali non maturano oltre ed invadono il midollo. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001019 |
| E.1.2 | Term | Acute promyelocytic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To compare event-free survival (EFS) of the experimental treatment arm including ATO/ATRA and idarubicin with standard treatment based on ATRA plus chemotherapy (AIDA regimen) in newly diagnosed high-risk APL |
| Comparare la sopravvivenza libera da eventi (EFS) nel braccio di trattamento sperimentale con ATO/ATRA e idarubicina con il trattamento standard basato su ATRA più chemioterapia (regime AIDA) in pazienti con LAP ad alto rischio di nuova diagnosi |
|
| E.2.2 | Secondary objectives of the trial |
- To compare CR, OS and CIR rates in the two arms
- To compare early death rate during induction
- To compare cumulative incidence of secondary MDS or AML
- To compare quality of life in the two arms
- To compare the toxicity profile in the two arms
- To compare the kinetics of MRD in the two arms
- To compare the duration of patient hospitalization in the two arms
- To compare health economics in the two arms
|
- remissione completa (CR), sopravvivenza globale (OS), incidenza cumulata di recidiva (CIR)
- incidenza cumulata di mielodisplasia o leucemie secondarie
- mortalità precoce durante la terapia di induzione
- qualità della vita
- profilo di tossicità
- cinetica della malattia minima residua
- durata dei ricoveri durante il trattamento
- impatto economico dei trattamenti
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1.0-Tue Jun 09 00:00:00 CEST 2015- -The broad goal of QoL evaluation in this phase III study is to examine possible differences in key QoL aspects of high-risk APL adult patients treated with ATRA-chemotherapy (standard arm) versus ATRA-ATO therapy (experimental arm). This information will help better understand the overall treatment effectiveness of the newer therapy (i.e., ATRA-ATO) being tested. Based on our previous report, key selected scales have been chosen for the primary objective. QoL results of this trial will be reported in accordance with high methodological quality criteria for documenting patient-reported outcomes in RCTs so recommended by the CONSORT PRO Extension.
To investigate possible differences in the following a priori selected scales: physical and cognitive functioning as well as fatigue, nausea and vomiting, constipation and appetite loss (outcome measure: EORTC QLQ-C30).
• To investigate possible differences between treatment arms over time in all other QoL parameters assessed with the EORTC QLQ-C30 not considered in the primary objective.
• to evaluate the relationship between self-reported fatigue (outcome measure: FACIT-Fatigue scale) and the overall change over time in other QoL parameters measured by the EORTC QLQ-C30 (i.e., functional and other symptom aspects).
• To investigate the prognostic value of QoL parameters for overall survival. Fatigue and physical functioning will be regarded as the primary outcomes for prognostic factor analysis.
|
1.0-Tue Jun 09 00:00:00 CEST 2015-Quality of Life Assessment-The broad goal of QoL evaluation in this phase III study is to examine possible differences in key QoL aspects of high-risk APL adult patients treated with ATRA-chemotherapy (standard arm) versus ATRA-ATO therapy (experimental arm). This information will help better understand the overall treatment effectiveness of the newer therapy (i.e., ATRA-ATO) being tested. Based on our previous report, key selected scales have been chosen for the primary objective. QoL results of this trial will be reported in accordance with high methodological quality criteria for documenting patient-reported outcomes in RCTs so recommended by the CONSORT PRO Extension.
To investigate possible differences in the following a priori selected scales: physical and cognitive functioning as well as fatigue, nausea and vomiting, constipation and appetite loss (outcome measure: EORTC QLQ-C30).
• To investigate possible differences between treatment arms over time in all other QoL parameters assessed with the EORTC QLQ-C30 not considered in the primary objective.
• to evaluate the relationship between self-reported fatigue (outcome measure: FACIT-Fatigue scale) and the overall change over time in other QoL parameters measured by the EORTC QLQ-C30 (i.e., functional and other symptom aspects).
• To investigate the prognostic value of QoL parameters for overall survival. Fatigue and physical functioning will be regarded as the primary outcomes for prognostic factor analysis.
|
|
| E.3 | Principal inclusion criteria |
- Informed consent
- newly diagnosed APL by cytomorphology, confirmed also by molecular analysis*
- Age ≥18 and ≤ 65 years
- ECOG performance status 0-2
- WBC at diagnosis > 10 Gpt/l
- serum total bilirubin ≤ 3.0 mg/dl (≤ 51 µmol/l)
- serum creatinine ≤ 3.0 mg/dl (≤ 260 µmol/l)
- women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:
o Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml)
o Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
o Continuous and correct application of a contraception method with a Pearl Index of <1% (e.g. implants, depots, oral contraceptives, intrauterine device – IUD).
o Sexual abstinence
o Vasectomy of the sexual partner
* The confirmation of diagnosis at genetic level (microspeckled PML nuclear distribution by PGM3 monoclonal antibody and/or PML/RARa fusion by RT-PCR or fluorescence in situ hybridization (FISH) and/or demonstration of t(15;17) at karyotyping) will be mandatory for patient eligibility. However, in order to avoid delay in treatment initiation, patients can be randomized on the basis of morphologic diagnosis only and before the results of genetic tests are available.
|
Consenso informato
- Nuova diagnosi di LAP citomorfologica, confermata anche dalla analisi
molecolare*
- Età ≥18 e ≤ 65 anni
- Performance status ECOG 0-2
- WBC alla diagnosi > 10 GPt/l
- bilirubina sierica totale ≤ 3.0 mg/dl (≤ 51 µmol/l)
- creatinina sierica ≤ 3.0 mg/dl (≤ 260 µmol/l)
- le donne devono rispettare almeno uno dei seguenti criteri per risultare
eleggibili per l’inclusione nello studio:
o Post-menopausa (12 mesi di amenorrea fisiologica o 6 mesi di amenorrea con FSH sierico > 40 U/ml)
o Postoperatoria (i.e. 6 settimane) dopo ovariectomia bilaterale con o senza isterectomia
o Utilizzo continuo e corretto di un metodo contraccettivo con un indice di Pearl <1% (i.e impianti, depots, contraccettivi orali, dispositivi intrauterini).
o Astinenza sessuale
o Vasectomia del partner sessuale
* La conferma della diagnosi a livello molecolare (distribuzione nucleare microspeckled di PML tramite l’anticorpo monoclonale PGM3 e/o il gene di fusione PML/RARa tramite RT-PCR o fluorescence in situ hybridization (FISH) e/o dimostrazione della traslocazione t(15;17) al cariotipo) sarà obbligatoria per la eleggibilità dei pazienti. Tuttavia, allo scopo di evitare ritardi nell’inizio del trattamento, I pazienti possono essere randomizzati sulla base della sola diagnosi morfologica e prima che I risultati dei test genetici siano disponibili.
|
|
| E.4 | Principal exclusion criteria |
- Patients who are not eligible for chemotherapy as per discretion of the treating physician
- Age <18 and > 65 years
- WBC at diagnosis ≤ 10 Gpt/l
- APL secondary to previous radio- or chemotherapy for non-APL disease
- ECOG performance status >2
- other active malignancy at time of study entry
- lack of diagnostic confirmation at genetic level
- Significant arrhythmias, ECG abnormalities or neuropathy:
Congenital long QT syndrome;
History or presence of significant ventricular or atrial tachyarrhythmia;
Clinically significant resting bradycardia (<50 beats per minute)
QTc >500msec on screening ECG for both genders (using the QTcF formula detailed on page 43-44)
Right bundle branch block plus left anterior hemiblock, bifascicular block
- other cardiac contraindications for intensive chemotherapy (L-VEF <50%)
- uncontrolled, life-threatening infections
- severe non controlled pulmonary or cardiac disease
-severe hepatic or renal dysfunction
- known HIV and/or hepatitis C infection
- pregnant or breast-feeding patients
- allergy to trial medication or excipients in study medication
- substance abuse, medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results
- use of other investigational drugs at the time of enrolment or within 30 days before study entry
|
- Pazienti che non sono eliggibili per la chemioterapia a discrezione del medico
curante
- Età <18 e > 65 anni
- WBC alla diagnosi ≤ 10 GPt/l
- LAP secondaria a precedente radio o chemioterapia per patologia diversa
dalla LAP
- Performance status ECOG>2
- altre forme tumorali attive al momento dell’entrata nello studio
- mancata conferma diagnostica a livello genetico
- Aritmie significative, anomalie all’ECG o neuropatia:
- Sindrome congenita del QT lungo;
- Storia di presenza di tachiaritmie ventricolari o atriali significative;
- Bradicardia a riposo clinicamente significativa (<50 battiti per minuto)
- QTc >500msec all’ECG di screening in ambo i sessi
- Blocco di branca destro più emiblocco sinistro anteriore, blocco bifascicolare,
- altre controindicazioni cardiache alle chemioterapia intensiva (FEV-S <50%)
- infezioni incontrollate, che pongono a rischio di vita
- gravi e non controllabili patologie polmonari e cardiache
- insufficienza epatica o renale grave
- infezioni da HIV ed epatite C note
- pazienti in corso di gravidanza o allattamento
- allergia ai principi attivi o ad eccipienti contenuti nei farmaci dello studio
- abuso di sostanze, condizioni mediche, psicologiche o sociali che possano
interferire con la partecipazione dei pazienti allo studio o alla valutazione dei ù
risultati dello studio
- utilizzo di altri farmaci sperimentali al tempo dell’arruolamento o entro 30 giorni prima dell’arruolamento nello studio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is event-free survival at 2 years. This is a time to event endpoint. This cumulative endpoint includes the following events: no achievement of hematological complete remission after induction therapy; no achievement of molecular remission after the last consolidation course (Arm A after 4 courses; Arm B after 3 courses) (molecular resistance); relapse (hematological/molecular); death including early death (within 30 days after randomization) or development of secondary myelodysplasia or leukemia . |
L’endopoint primario è la sopravvivenza libera da eventi a 2 anni. Gli eventi inclusi sono: fallito raggiungimento della remissione completa ematologica dopo la terapia di induzione; fallito raggiungimento della remissione molecolare dopo l’ultimo ciclo di consolidamento (Braccio A dopo 4 cicli; braccio B dopo 3 cicli) (resistenza molecolare); recidiva (ematologica/molecolare); mortalità che include la mortalità precoce (entro 30 giorni successivi la randomizzazione) o sviluppo di mielodisplasia o leucemia secondarie.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 2.5 years from last patient's randomization |
| A 2.5 anni dalla randomizzazione dell'ultimo paziente |
|
| E.5.2 | Secondary end point(s) |
- Rate of hematological CR after induction
- Rate of early death during induction
- Rate of overall survival (OS) at 2 years
- Rate of cumulative incidence of secondary myelodysplasia or leukemia
- Rate of cumulative incidence of relapse (CIR) at 2 years
- Incidence of hematological and non-hematological toxicity
- Rate of molecular remission after 3 consolidation cycles
- Assessment of PML/RARA transcript level reduction during treatment
- To investigate differences in the following a priori Quality of Life selected scales: physical and cognitive functioning as well as fatigue, nausea and vomiting, constipation and appetite loss
- Total hospitalization days during therapy and health economic impact
|
| Remissione completa (CR); mortalità precoce durante la terapia di induzione; sopravvivenza globale (OS) a 2 anni; incidenza cumulata di mielodisplasia o leucemia secondarie; incidenza cumulata di recidiva (CIR) a 2 anni; profilo di tossicità ematologica e non ematologica; incidenza di remissione molecolare dopo 3 cicli di consolidamento; analisi della riduzione del livello del trascritto PML/RARA durante il trattamento; analisi della qualità della vita tramite differenti scale di riferimento (funzioni fisiche e cognitive); cinetica della malattia minima residua; durata dei ricoveri durante il trattamento; impatto economico dei trattamenti. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At 2.5 years from the last patient's randomization, if not otherwise specified |
| A 2.5 anni dall'ultimo paziente arruolato, se non diversamente specificato. |
|
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life |
| Qualità della vita |
|
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Terapia standard con ATRA e chemioterapia basata su antracicline (regime AIDA) |
| Standard ATRA and anthracycLine-based chemotherapy (AIDA regimen) |
|
| 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 | 54 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
