E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelofibrosis |
Mielofibrosi |
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E.1.1.1 | Medical condition in easily understood language |
Bone marrow disorder that disrupts body's normal production of blood cells. The result is extensive scarring in bone marrow, leading to severe anemia, weakness, fatigue and an enlarged spleen. |
Disturbi del midollo osseo che interrompono la normale produzione di cellule del sangue. Estesa cicatrizzazione del midollo osseo, grave anemia,debolezza,affaticamento e ingrossamento della milza |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028537 |
E.1.2 | Term | Myelofibrosis |
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 |
To evaluate the effect of navitoclax in combination with ruxolitinib on splenomegaly response when compared to ruxolitinib in subjects with myelofibrosis. |
Valutare l’effetto di navitoclax in combinazione con ruxolitinib sulla risposta in termini di splenomegalia quando confrontato con ruxolitinib in soggetti affetti da mielofibrosi. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of navitoclax in combination with ruxolitinib on the onset, magnitude, and duration of disease response, including Total Symptom Score (TSS), effects on spleen, bone marrow fibrosis, and anemia. • To evaluate the effect of navitoclax in combination with ruxolitinib on measures of health-related quality of life (HRQoL), including fatigue, and physical functioning. • To evaluate the effect of navitoclax in combination with ruxolitinib on overall survival (OS) and leukemia-free survival. |
• Valutare l’effetto di navitoclax in combinazione con ruxolitinib su insorgenza, entità e durata della risposta della malattia compresi il punteggio totale relativo ai sintomi (Total Symptom Score, TSS), gli effetti su milza, fibrosi midollare e anemia. • Valutare l’effetto di navitoclax in combinazione con ruxolitinib sui parametri relativi alla qualità di vita correlata alla salute (HRQoL), compresa faticabilità e funzione fisica. • Valutare l’effetto di navitoclax in combinazione con ruxolitinib sulla sopravvivenza globale (overall survival, OS) e sulla sopravvivenza libera da leucemia (LFS). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Subject = 18 years of age. • Subject with a documented diagnosis of primary myelofibrosis (MF) or secondary MF (post polycythemia vera [PPV] -MF or post essential thrombocythemia [PET] – MF) as defined by the World Health Organization classification. • Subject must be able to complete the Myelofibrosis Symptom Assessment Form (MFSAF) on at least 4 out of 7 days prior to randomisation. - Subject classified as intermediate-2 or high-risk MF as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+). • Subject has splenomegaly defined as spleen palpation measurement = 5 cm below costal margin or spleen volume = 450 cm^3 as assessed centrally by MRI or CT scan. • Subject has at least 2 symptoms measurable (score = 3) or a total score of = 12, as measured by the MFSAF v4.0. • Subject with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. |
• Soggetto di età = 18 anni. • Soggetto con diagnosi documentata di mielofibrosi (MF) primaria o di mielofibrosi secondaria (MF post-policitemia vera [PPV] o MF post-trombocitemia essenziale [PET]) secondo la classificazione della Organizzazione Mondiale della Sanità • Soggetto in grado di compilare lo strumento MFSAF almeno 4 giorni su 7 giorni prima della randomizzazione ¿ Soggetto con mielofibrosi classificata come rischio intermedio 2 oppure alto rischio sulla base del sistema Dynamic International Prognostic Scoring System Plus (DIPSS+). • Soggetto con splenomegalia definita come milza identificata alla palpazione = 5 cm dall’arcata costale oppure volume splenico = 450 cm3 misurato centralmente mediante scansione RM oppure TAC. • Soggetto che presenta almeno 2 sintomi misurabili (punteggio = 3) oppure un punteggio totale = 12, misurato mediante lo strumento MFSAF v4.0. • Soggetto con punteggio ECOG (Eastern Cooperative Oncology Group) relativo allo stato funzionale pari a 0, 1 o 2 |
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E.4 | Principal exclusion criteria |
• Subject must not have received prior treatment with a JAK-2 inhibitor. • Subject must not have received prior treatment with a BH3-mimetic compound or bromodomain and extra-terminal motif (BET) inhibitor. • Subject must not be eligible for stem cell transplantation at time of study entry due to age, comorbidities, or unfit for unrelated or unmatched donor transplant. • Subject must not receive medication that interferes with coagulation or platelet function within 3 days prior to the first dose of study drug or during the study treatment period. |
• Soggetto che non ha ricevuto trattamento pregresso con un JAK-2 inibitore. • Soggetto che non ha ricevuto trattamento pregresso con un composto BH3-mimetico o inibitore del bromodominio e del dominio extra-terminale (BET). • Soggetto non idoneo al trapianto di cellule staminali al momento dell’ingresso dello studio a causa dell'età, della comorbilità, o dell'inidoneità ad essere utilizzati a causa di trapianto da parte del donatore ineguagliabile.. • Soggetto che non riceva medicinali che interferiscono con la coagulazione o la funzione piastrinica nei 3 giorni precedenti la prima dose del medicinale sperimentale oppure durante il periodo di trattamento sperimentale. |
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E.5 End points |
E.5.1 | Primary end point(s) |
At least 35% reduction in spleen volume from baseline as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, per International Working Group (IWG) criteria. |
Riduzione rispetto al baseline del volume splenico pari ad almeno il 35%, misurata mediante risonanza magnetica (RM oppure tomografia computerizzata (TAC), in accordo ai criteri IWG (International Working Group). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• At least 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 • Duration of SVR35 • Change in fatigue at Week 24 from baseline as measured by the PROMIS Fatigue SF 7a • Time to deterioration of physical functioning, as measured by the physical functioning domain of the EORTC QLQ-C30,or death • Anemia response per IWG criteria • At least 35% reduction in spleen volume from baseline (SVR35) as measured by MRI or CT scan, per IWG criteria • Reduction in grade of bone marrow fibrosis from baseline as measured by the European consensus grading system • Overall survival • Leukemia-free survival • Overall response of clinical improvement per IWG criteria. |
• Riduzione rispetto al baseline del punteggio totale relativo ai sintomi (TSS) pari ad almeno il 50% rilevata alla Settimana 24, misurato mediante lo strumento MFSAF (Myelofibrosis Symptom Assessment Form) v4.0 • Durata della risposta SVR35 • Variazione alla settimana 24 rispetto al baseline della faticabilità misurata mediante lo strumento PROMIS Fatigue SF 7a • Tempo al deterioramento della funzione fisica, misurata sulla base del dominio relativo alla funzione fisica del questionario EORTC QLQ C30, o decesso. • Risposta in termini di anemia in accordo ai criteri IWG • Riduzione del volume splenico rispetto al baseline pari ad almeno 35% (SVR35) misurata mediante RM o TAC, in accordo ai criteri IWG • Riduzione rispetto al baseline del grado di fibrosi midollare misurata sulla base del sistema di valutazione Consensus europeo • Sopravvivenza globale • Sopravvivenza libera da leucemia • Risposta globale di miglioramento clinico in accordo ai criteri IWG. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 24, Time to event, Every 12 weeks |
Settimana 24, Tempo all’evento, Ogni 12 settimane |
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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 | 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 | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
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 |
Canada |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Taiwan |
United States |
Austria |
Belgium |
France |
Germany |
Italy |
Netherlands |
Spain |
Sweden |
United Kingdom |
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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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The date of the last subject's last visit or date of last follow-up contact with the subject, whichever is later. |
La data dell’ultima visita dell’ultimo soggetto oppure la data dell’ultimo contatto di follow-up con il soggetto, quale dei due avvenga per ultimo |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |