E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic Syndrome |
Sindrome mielodisplastica |
|
E.1.1.1 | Medical condition in easily understood language |
Hematologic Malignancies |
Sindrome mielodisplastica |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 assess the efficacy of venetoclax in combination with AZA compared to placebo with AZA in treatment-naive higher-risk MDS.
The hypotheses corresponding to the primary objective is that venetoclax will improve the complete remission (CR) rate and overall survival (OS) when added to standard of care AZA treatment in patients newly diagnosed with higher-risk MDS. |
Valutare l’efficacia di venetoclax in combinazione con AZA rispetto a placebo in combinazione con AZA in pazienti affetti da MDS ad alto rischio naïve rispetto al trattamento. L’obiettivo primario si basa sull’ipotesi che venetoclax migliorerà il tasso di remissione completa (RC) e il tasso di sopravvivenza globale (overall survival, OS) quando aggiunto al trattamento con AZA che rappresenta lo standard di cura in pazienti con nuova diagnosi di sindrome mielodisplastica ad alto rischio. |
|
E.2.2 | Secondary objectives of the trial |
1.To evaluate the safety of venetoclax in combination with AZA compared to placebo with AZA in higher-risk MDS populations
2.To evaluate patient-reported outcomes (PROs) for subjects on venetoclax in combination with AZA compared to placebo with AZA. |
1. Valutare la sicurezza di venetoclax in combinazione con AZA rispetto a placebo in combinazione con AZA nelle popolazioni con MDS ad alto rischio. 2. Valutare gli esiti segnalati dai pazienti (patient-reported outcomes, PRO) per i soggetti in trattamento con venetoclax in combinazione con AZA rispetto a placebo in combinazione con AZA |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adult male or female, at least 18 years old. Diagnosis of MDS according to the 2016 WHO classification with presence of < 20% bone marrow blasts per bone marrow biopsy/aspirate at screening. Subject meets the following disease activity criteria: •Overall IPSS-R score > 3 (intermediate, high, or very high; Appendix E); •Eastern Cooperative Oncology Group (ECOG) performance status < or = 2; •HSCT eligible with no pre-arranged HSCT at the time of Study Day 1, or HSCT ineligible without plan for HSCT at the time of Study Day 1. No prior therapy for MDS with any hypomethylating agent (for example, azacitidine, decitabine), chemotherapy or allogeneic stem cell transplantation. |
Soggetti di ambo i sessi, di età > o = 18 anni. Diagnosi di MDS in accordo ai criteri di classificazione 2016 dell’Organizzazione Mondiale della Sanità (OMS) con presenza di blasti midollari < 20% sulla base della biopsia osteomidollare/agoaspirato midollare eseguito allo screening. I soggetti devono presentare i seguenti criteri relativi all’attività della malattia: • Punteggio Globale IPSS R > 3 (intermedio, alto oppure molto alto; Appendice E); • Punteggio ECOG (Eastern Cooperative Oncology Group) relativo allo stato funzionale < oppure = 2; • Idoneo al trapianto di cellule staminali ematopoietiche (HSCT) senza HSCT programmato al momento del Giorno 1 dello Studio, oppure non idoneo ad HSCT senza HSCT programmato al momento del Giorno 1 dello Studio. Nessuna terapia pregressa per MDS con alcun agente ipometilante (ad esempio, azacitidina, decitabina), chemioterapia oppure trapianto allogenico di cellule staminali |
|
E.4 | Principal exclusion criteria |
No previous diagnosis of:
•Therapy-related MDS (t-MDS)
•MDS evolving from a pre-existing myeloproliferative neoplasm (MPN)
•MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN
•No prior therapy for MDS with any hypomethylating agent (for example, azacitidine, decitabine), chemotherapy or allogeneic stem cell transplantation. |
Nessuna diagnosi pregressa di: • MDS indotta da terapia (therapy-related MDS, t-MDS) • MDS che rappresenta l’evoluzione da un pre-esistente neoplasma mieloproliferativo (MPN) • MDS/MPN fra cui leucemia mielomonocitica cronica (CMML), leucemia mieloide cronica atipica (aCML), leucemia mielomonocitica giovanile (JMML) e MDS/MPN non classificabile • Terapia pregressa per MDS con qualsiasi agente ipometilante (ad esempio, azacitidina, decitabina), chemioterapia oppure trapianto allogenico di cellule staminali |
|
E.5 End points |
E.5.1 | Primary end point(s) |
- Complete Remission and Overall Survival |
Remissione completa e sopravvivenza globale |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Interim complete remission analysis will occur afer randomization of 422 subjects and followed up for 12 months. Interim analysis of overall survival after approximately 267 death events |
- Sarà realizzata un’analisi ad interim per la remissione completa una volta che 422 soggetti siano stati randomizzati e seguiti fino a 12 mesi. Analisi ad interim di sopravvivenza globale dopo circa 267 eventi di decesso. |
|
E.5.2 | Secondary end point(s) |
- Modified overall response (mOR) defined as CR + partial response [PR] + marrow CR (mCR)
- Red blood cell (RBC) transfusion independence (TI) rate for subjects who are transfusion dependent at baseline
- Change from baseline in fatigue as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue SF 7a
- Change from baseline in physical functioning, as measured by the EORTC QLQ-C30 physical functioning domain
- Platelet Transfusion independence (TI) rate for subjects who are transfusion dependent at baseline
- Overall response based on CR+PR
- Time to deterioration in physical functioning, as measured by the EORTC QLQ-C30 physical functioning domain |
- Risposta globale modificata (modified overall response, mOR) definita quale RC + risposta parziale [RP] + RC midollare (mRC) - Tasso di indipendenza da trasfusione (TI) di emazie (GR) per i soggetti che erano trasfusione dipendenti al baseline - Variazione rispetto al baseline della faticabilità misurata sulla base dello strumento PROMIS (Patient-Reported Outcomes Measurement Information System-Fatigue SF 7a - Variazione rispetto al baseline della funzione fisica, misurata sulla base del dominio relativo alla funzione fisica dello strumentoEORTC QLQ-C30 - Tasso di indipendenza da trasfusione (TI) di piastrine per i soggetti che erano trasfusione dipendenti al baseline - Risposta globale sulla base di RC+RP - Tempo al deterioramento della funzione fisica, misurato sulla base del dominio relativo alla funzione fisica dello strumento EORTC QLQ-C30 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 5 years |
Fino a 5 anni |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 | Information not present in EudraCT |
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 |
Australia |
Brazil |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Taiwan |
United States |
United Kingdom |
|
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
|
Last subject's last visit or date of the last follow-up contact, whichever is later. |
Ultima visita dell’ultimo soggetto oppure data dell’ultimo contatto di follow-up, quale dei due avvenga per ultimo. |
|
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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |