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. |
Patologia midollo osseo che altera la normale produzione di cellule del sangue. Ne deriva considerevole tessuto cicatriziale, con anemia grave, debolezza, faticabilità, 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 compared to Best Available Therapy (BAT) on splenomegaly response in subjects with relapsed/refractory Myelofibrosis (MF). |
Valutare l’effetto di navitoclax in combinazione con ruxolitinib rispetto alla migliore terapia disponibile (Best Available Therapy, BAT) sulla risposta in termini di splenomegalia in soggetti affetti da mielofibrosi (MF) recidivante/refrattaria |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of navitoclax in combination with ruxolitinib compared to BAT on measures of health-related quality of life (HRQoL) including total symptom score, fatigue,and physical functioning. • To evaluate the effect of navitoclax in combination with ruxolitinib compared to BAT on the onset, magnitude, and duration of disease response, including effects on spleen, bone marrow fibrosis, and anemia. • To evaluate the effect of navitoclax in combination with ruxolitinib compared to BAT on overall survival (OS) and leukemia-free survival (LFS).
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• Valutare l’effetto di navitoclax in combinazione con ruxolitinib rispetto alla miglior terapia disponibile sui parametri relativi alla qualità di vita correlata alla salute (HRQoL), compresi punteggio totale relativo ai sintomi, faticabilità e funzione fisica. • Valutare l’effetto di navitoclax in combinazione con ruxolitinib rispetto alla migliore terapia disponibile su insorgenza, entità e durata della risposta della malattia compresi gli effetti su milza, fibrosi midollare e anemia. • Valutare l’effetto di navitoclax in combinazione con ruxolitinib rispetto alla migliore terapia disponibile 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 must be able to complete the MFSAF v4.0 on at least 4 out of 7 days prior to randomisation. - Subject has at least 2 symptoms with a score = 3 or a total score of = 12, as measured by the MFSAF v4.0. • Subject with a documented diagnosis of primary MF, post polycythemia vera (PPV)-MF, or post essential thrombocythemia (PET)–MF as defined by the World Health Organization classification. • Subject classified as intermediate-2 or high-risk MF, as defined by the Dynamic International Prognostic Scoring System (DIPSS). XML File Identifier: SrChOEVV+uqliGuLipfecZFKPGA= Page 34/45 • Subject must have received prior treatment with a single JAK2 inhibitor and meet one of the following criteria (in addition to the minimum splenomegaly and symptom burden also required for eligibility): - Prior treatment with JAK2 inhibitor for = 24 weeks that was stopped due to lack of spleen response, or loss of spleen response or symptom control after a previous response, or was continued despite relapsed/refractory status. - Prior treatment with JAK2 inhibitor for < 24 weeks with documented disease progression while on JAK2 inhibitor therapy. • 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 a baseline platelet count = 100 × 10^9 /L. |
• Soggetto di età = 18 anni. • Soggetto in grado di compilare lo strumento MFSAF v4.0 almeno 4 giorni su 7 giorni prima della randomizzazione. - Soggetto che presenta almeno 2 sintomi con un punteggio = 3 oppure un punteggio totale = 12, misurato mediante lo strumento MFSAF v4.0. • Soggetto con diagnosi documentata di mielofibrosi primaria, MF post-policitemia vera (PPV) o MF post-trombocitemia essenziale (PET) secondo la classificazione della Organizzazione Mondiale della Sanità • Soggetto con mielofibrosi classificata come rischio intermedio 2 oppure alto rischio sulla base del sistema Dynamic International Prognostic Scoring System (DIPSS). • Soggetto che ha ricevuto trattamento pregresso con un singolo JAK-2 inibitore e presenta uno dei seguenti criteri (in aggiunta alla splenomegalia minima e al burden associato ai sintomi, criteri che sono analogamente richiesti per l’eleggibilità): - Trattamento pregresso con JAK-2 inibitore per = 24 settimane che è stato interrotto a causa di mancata risposta splenica o perdita di risposta splenica o del controllo dei sintomi dopo una precedente risposta oppure che è stato continuato nonostante lo status di recidivante/refrattaria - Trattamento pregresso con JAK-2 inibitore per < 24 settimane con progressione documentata di malattia in corso di trattamento con JAK-2 inibitore • 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 con livelli di piastrine al baseline = 100 × 109/L. |
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E.4 | Principal exclusion criteria |
• Subject must not have received prior treatment with a BH3-mimetic compound or prior use of >1 JAK2 inhibitor. • 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. • Subject must not receive anticancer therapy including chemotherapy, radiation therapy, hormonal therapy within 30 days prior to first dose of study drug, and during the study treatment period (other than any overlapping therapy as part of the selected BAT) |
• Soggetto che non abbia ricevuto trattamento pregresso con un composto BH3-mimetico oppure uso pregresso di > 1 JAK2 inibitore. • Soggetto che non abbia ricevuto 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. • Soggetto che non è in trattamento con terapie antineoplastiche fra cui chemioterapia, radioterapia, terapia ormonale nei 30 giorni precedenti la prima dose del medicinale sperimentale, e durante il periodo di trattamento sperimentale (diversa da eventuale overlap terapeutico nell’ambito della migliore terapia disponibile selezionata). |
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E.5 End points |
E.5.1 | Primary end point(s) |
At least 35% reduction in spleen volume from baseline at Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, per International Working Group (IWG) criteria.
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Riduzione rispetto al baseline del volume splenico pari ad almeno il 35% rilevata alla Settimana 24, 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) from baseline at Week 24 as measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 • At least 35% reduction in spleen volume from baseline (SVR35) as measured by MRI or CT scan, per IWG criteria • Duration of SVR35 • Change in fatigue 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 • Anemia response per IWG criteria • Overall survival • Leukemia-free survival • Overall response and composite response per IWG criteria. • Reduction in grade of bone marrow fibrosis from baseline as measured by the European consensus grading system |
• 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 • Riduzione del volume splenico rispetto al baseline pari ad almeno 35% (SVR35) misurata mediante RM o TAC, in accordo ai criteri IWG • Durata della risposta SVR35 • Variazione 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 • Risposta in termini di anemia in accordo ai criteri IWG • Sopravvivenza globale • Sopravvivenza libera da leucemia • Risposta globale e risposta composita in accordo ai criteri IWG. • Riduzione rispetto al baseline del grado di fibrosi midollare misurata sulla base del sistema di valutazione Consensus europeo |
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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 | Yes |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
migliore terapia disponibile |
Best available therapy |
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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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 115 |
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 |
Puerto Rico |
Russian Federation |
Taiwan |
United States |
Austria |
Belgium |
Czechia |
France |
Germany |
Greece |
Hungary |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
Switzerland |
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 | 11 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 11 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |