E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) |
Leucemia Mieloide Cronica (LMC) in Fase Cronica. |
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E.1.1.1 | Medical condition in easily understood language |
CML is cancer that originates in the bone marrow from blood stem cells, which fail to complete the maturation process and accumulate as immature blasts in the body. |
La LMC è un cancro che ha origine nel midollo osseo dalle cellule staminali del sangue, le quali non riuscendo a completare il processo di maturazione, si accumulano come blasti immaturi nel corpo. |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009013 |
E.1.2 | Term | Chronic 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 |
The study will investigate in newly diagnosed CP-CML patients the efficacy of NIL frontline therapy vs IM followed by a switch to NIL in the case of absence of an optimal response as defined by ELN criteria. |
Lo studio valuterà, in pazienti con LMC in fase cronica di nuova diagnosi, l'efficacia della terapia con NIL in prima linea rispetto a IM seguito da NIL in caso di assenza di risposta ottimale come definito dai criteri ELN. |
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E.2.2 | Secondary objectives of the trial |
1. Monitoring the molecular response. 2. Progression-free survival (PFS) in the two arms of the study. 3. Overall Survival in the two arms of the study. 4. Rates of major molecular response (MR3.0) during the study in the two arms of the study. 5. The dynamics of molecular response 6. The relationship between baseline characteristics and the primary objectives 7. The relationship between early molecular response and the primary objectives 8. To assess the safety profile of both arms. 9. To determine the rate and the time-distribution of the discontinuation causes of the first-line TKI. 10. To investigate quality of life (QoL) differences between treatment arms over time |
1. Monitorare la risposta molecolare 2. Progression Free Survival (PFS) nei due bracci dello studio 3. Overall Survival (OS) nei due bracci dello studio 4. Tasso di risposta molecolare maggiore (MR3.0) durante lo studio nei due bracci dello studio. 5. Dinamica della risposta molecolare. 6. Relazione tra le caratteristiche al baseline e l¿obiettivo primario. 7. Relazione tra la risposta molecolare precoce e l¿obiettivo primario. 8. Valutare il profilo di sicurezza in entrambi i bracci. 9. Determinare il tasso e la distribuzione temporale delle cause d¿interruzione dei TKI. 10. Valutare le differenze di qualit¿ di vita dei pazienti (QoL) nei due bracci di trattamento. |
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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 |
Life quality Version: 1.0 Date: 24/11/2015 Title: Quality of life Objectives: To investigate quality of life (QoL) differences between treatment arms over time
Other types of substudies Specify title, date and version of each substudy with relative objectives: Translational research v. 1.0 24.11.2015 - Deep phenotypic and molecular characterization of INDIVIDUAL LSC within the LSC pool of newly diagnosed CML patients - Deep understanding of the cellular pathways involved in CML LSC persistence and genomic instability - Deep understanding of the physio-pathogenesis of CML by detecting pre-existing mutated (DNMT3A) ancestral clones, leading to leukemia by the addition of following alterations (Bcr-Abl) - To define BM microenvironment markers that nurture and determine stem cell fate in leukemia associated-niches - To define MSC¿s genetic profile in CML patients - To evaluate the role of BM molecular microenvironment underling the variable degree of response to TKI treatment in patients with CP of CML vs. patients with advanced phase CML - To verify the prognostic value of the biological factors that have been assessed in vitro experiments by designing an in vivo mouse model - Flow-cytometry quantification and monitoring of peripheral blood CML LSCs during Sustrenim Study
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Qualita' della vita Versione: 1.0 Data: 24/11/2015 Titolo: Qualità di vita Obiettivi: Valutare le differenze di qualità di vita dei pazienti (QoL) nei due bracci di trattamento.
Altre tipologie di sottostudi specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Ricerca traslazionale v. 1.0 24.11.2015 - Caratterizzazione delle cellule leucemiche - Comprensione dei percorsi cellulari che portano all¿insorgenza della malattia ed alla instabilit¿ genetica delle sue cellule - Comprensione del ruolo della proteina DNMT3 - Definizione dei marcatori presenti nel midollo che determinano il destino delle sue cellule leucemiche - Definizione del profilo genetico delle ellule staminali mesenchimali - Valutazione del ruolo del microambiente all¿interno del midollo osseo - Verifica del ruolo prognostico dei fattori biologici valutati in vitro per la progettazione di uno studio in vivo nel topo - Quantificazione e monitoraggio delle cellule leucemiche del sangue periferico
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E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria: • Patients with a confirmed diagnosis of BCR/ABL+ CML in chronic phase o Documented chronic phase CML must meet all the following criteria: ¿ < 15% blasts in peripheral blood ¿ < 30% blasts plus promyelocytes in peripheral blood ¿ < 20% basophils in the peripheral blood ¿ = 100 x 109/L (= 100,000/mm3) platelets • Age =18 • ECOG performance status of 0-2 • Evidence of typical BCR-ABL transcripts which are amenable to standardized RQ-PCR • Adequate end organ function as defined by: o Total bilirubin < 1.5 x ULN (ULN = upper limit of normal in a local institution lab). Does not apply to patients with isolated hyperbilirubinemia (e.g., Gilbert’s disease) grade < 3 o SGOT (AST) and SGPT (ALT) = 3 x ULN o Serum amylase and lipase = 2 x ULN o Alkaline phosphatase = 2.5 x ULN o Serum creatinine < 1.5 x ULN • Written informed consent prior to any study procedures. |
I pazienti eleggibili per l’inclusione in questo studio devono soddisfare i seguenti criteri: • Pazienti con confermata diagnosi di LMC in fase cronica BCR/ABL+ o LMC in fase cronica dimostrata che deve soddisfare i seguenti criteri: ¿ < 15% blasti nel sangue periferico ¿ < 30% blasti più promielociti nel sangue periferico ¿ < 20% basofili nel sangue periferico ¿ = 100 x 109/L (= 100,000/mm3) piastrine • Età =18 • ECOG performance status 0-2 • Evidenza di trascritti tipici BCR-ABL identificabili tramite RQ-PCR standardizzata • Adeguata funzione dell’organo definita da: o Bilirubina totale < 1.5 x ULN (ULN = limite superiore alla norma del laboratorio locale). Non applicabile per pazienti con iperbilirubinemia isolata (sindrome di Gilbert) grado < 3 o SGOT (AST) e SGPT (ALT) = 3 x ULN o Lipasi e amilasi sieriche = 2 x ULN o Fosfatasi alcalina = 2.5 x ULN o Creatinina sierica < 1.5 x ULN • Consenso informato scritto prima di qualsiasi procedura dello studio.
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E.4 | Principal exclusion criteria |
Previous treatment with BCR-ABL inhibitors for more than 30 days. Expression of any atypical BCR-ABL transcripts, instead of the classical P210-encoding type with the e13a2 or the e14a2 junction at screening. Previous anticancer agents (hydroxyurea, anagrelide, interferon) for CML for more than three months. Poorly controlled diabetes mellitus (defined as HbA1c >8%) Prior documented history of coronary heart disease, including myocardial infarction, coronary bypass, coronary stent, and symptomatic angina as defined at page 30 in Exclusion Criteria. Uncontrolled hypertension History of peripheral arterial occlusive disease. History of acute pancreatitis within 12 months of study entry, or a past medical history of chronic pancreatitis. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers which cannot be either discontinued or switched to a different medication prior to starting study drug. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and for which cannot be either safely discontinued or switched to a different medication prior to starting study drug. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Patients unable to understand and to comply with study instructions and requirements. Refusal to give informed consent.
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Trattamento pregresso con inibitori di BCR-ABL per più di 30 giorni. Espressione di trascritti BCR-ABL atipici, al contrario del classico tipo di trascritto che codifica P210 con e13a2 od e14a2 allo screening. Utilizzo di agenti antineoplastici (idrossiurea, anagrelide, interferone) per il trattamento della LMC per almeno 3 mesi. Diabete mellito poco controllato (definito come HbA1c >8%). Storia documentata di malattie cardiache coronariche, che includono infarto del miocardio, bypass coronarico, stent coronarico e angina sintomatica. Ipertensione non controllata.
Storia pregressa di malattia occlusiva delle arterie periferiche.
Storia di pancreatite acuta entro 12 mesi dall’ingresso in studio, o storia medica pregressa di pancreatite cronica.
Pazienti che ricevono attivamente la terapia con inibitori forti CYP3A4 e/o induttori, i quali non possono essere interrotti o sostituiti da un trattamento differente prima dell’inizio del farmaco in studio. Pazienti che al momento ricevono un trattamento con un qualsiasi farmaco che abbia l’eventuale capacità di prolungare l’intervallo QT e per il quale non si possa interrompere in sicurezza nè sostituire con un trattamento differente prima dell’inizio del farmaco in studio. Donne potenzialmente fertili, definite come tutte le donne fisiologicamente in grado di procreare, a meno che non utilizzino metodi efficaci di contraccezione durante il trattamento in studio. Pazienti incapaci di comprendere e di rispettare le indicazioni ed i requisiti dello studio. Pazienti che rifiutano di firmare il consenso informato.
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E.5 End points |
E.5.1 | Primary end point(s) |
- To evaluate the rates of molecular response (MR4.5) at 24 months - To evaluate the rate of patients who remain in sustained treatment free remission (=MR3.0) without molecular relapse 12 months after entering the TFR phase. The molecular relapse is defined as loss of MMR, or confirmed loss of MR3.0.
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- Valutare il tasso di risposta molecolare (MR4.5) a 24 mesi; - Valutare il tasso di pazienti che mantengono una remissione libera da trattamento sostenuta nel tempo (=MR3.0) senza recidiva molecolare 12 mesi dopo l’ingresso nella fase TFR. La recidiva molecolare è definita come perdita di MMR o confermata perdita di MR3.0.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 24 months for the rates of molecular response (MR4.5) and at 12 months after entering the TFR phase for the rate of patients who remain in sustained treatment free remission (=MR3.0) without molecular relapse. |
24 mesi per il tasso di risposta molecolare (MR4.5) e 12 mesi per il tasso di pazienti che mantengono una remissione libera da trattamento sostenuta nel tempo (=MR3.0) senza recidiva molecolare. |
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E.5.2 | Secondary end point(s) |
To determine the depth of molecular response by 4 years.; To estimate progression-free survival (PFS) in the two arms of the study at 60 months; To estimate the Overall Survival in the two arms of the study at 60 months; To determine the rates of major molecular response (MR3.0) at 1, 2, 3, and 4 year in the two arms of the study.; The dynamics of molecular response; The relationship between baseline characteristics and the achievement of MR4.5 (after treatment NIL frontline therapy vs IM followed by switch to NIL) and the sustained treatment free remission rate (=MR3.0);; The relationship between early molecular response and the achievement of MR4.5 (after treatment NIL frontline therapy vs IM followed by switch to NIL) and the sustained treatment free remission rate (=MR3.0); To assess the safety profile of either NIL and IM arms.; To determine the rate and the time-distribution of the discontinuation of the first-line TKI, for side-effects, toxicity and AEs.; To investigate quality of life (QoL) differences between treatment arms over time |
Determinare la profondit¿ della risposta molecolare a 4 anni; Valutare la progression-free survival (PFS) nei due bracci dello studio a 60 mesi; Valutare l'Overall Survival nei due bracic dello studio a 60 mesi; Determianre il tasso di risposta molecolare maggiore (MR3.0) a 1, 2, 3, e 4 anni nei due bracci dello studio; La dinamica della risposta molecolare; La correlazione tra le caratteristiche al basale ed il raggiungimento della MR4.5 (dopo trattamento con Nilotinib frontline vs Imatinib seguito da passaggio a Nilotinib) e la sustained treatment free remission rate (=MR3.0);; La relazione tra la risposta molecolare precoce ed il raggiungimento della MR4.5 (dopo trattamento con Nilotinib frontline vs Imatinib seguito da passaggio a Nilotinib) ed il tasso di sustained treatment free remission (=MR3.0);; Valutare il profilo di sicurezza dei bracci con Nilotinib e Imatinib ; Determinare il tasso e la distribuzione temporale dell'interruzione dell'inibitore delle tirosi-chinasi per effetti collaterali, tossicit¿ ed eventi avversi; Studiare le differenze di Qualit¿ di vita tra i due bracci di trattamento nel tempo |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
4 years; 60 months; 60 months; At 1, 2, 3, and 4 years; During the study; During the study; During the study; During the study; During the study; During the study |
4 anni; 60 mesi; 60 mesi; A 1, 2, 3, e 4 anni ; Durante lo studio; Durante lo studio; Durante lo studio; Durante lo studio; Durante lo studio ; Durante lo studio |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 58 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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
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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 |