E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary myelofibrosis, post-polycytemia vera myelofibrosis and post-essential thrombocytemia myelofibrosis. |
Mielofibrosi primaria e mielofibrosi secondaria a policitemia vera o trombocitemia essenziale. |
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E.1.1.1 | Medical condition in easily understood language |
Bone marrow fibrosis with impaired production of red and/or white blood cells and/or platelets. |
Fibrosi del midollo osseo con insufficiente produzione di globuli rossi e/o globuli bianchi e/o piastrine. |
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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 | 14.1 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of pacritinib with that of best available therapy (BAT) in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF). |
Confrontare l’efficacia del pacritinib con quella della migliore terapia disponibile (BAT) in pazienti affetti da mielofibrosi primaria (PMF), mielofibrosi post-policitemia vera (PPV-MF) o mielofibrosi post-trombocitemia essenziale (PET-MF). |
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E.2.2 | Secondary objectives of the trial |
The key secondary objective is the proportion of patients with > 50% reduction in total score from baseline to Week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF TSS). |
L’obiettivo secondario principale è rappresentato dalla percentuale di pazienti con riduzione ≥50% del punteggio totale alla settimana 24 rispetto al basale riportato sul Modulo di valutazione dei processi neoplastici mieloproliferativi (MPN-SAF TSS). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a) Intermediate-1, intermediate -2, or high-risk PMF, PPV-MF or PET-MF; b) Palpable splenomegaly ≥ 5 cm below lower costal margin (LCM) in midclavicular line by physical examination; c) Score ≥ 3 for at least two symptoms on the MPN-SAF-TSS or score ≥ 4 for at least one symptom on MPN-SAF TSS other than fatigue; d) Age ≥ 18 years old; e) Eastern Cooperative Oncology Group (ECOG) performance status 0-3; f) Peripheral blast count < 10%; g) Absolute neutrophil count > 500/μL; h) Patients who are platelet or red blood cell transfusion-dependent are eligible; i) Adequate liver and renal function, defined by liver transaminases (AST/SGOT and ALT/SGPT) ≤ 3 × ULN AST/ALT ≤ 5 × ULN if transaminase elevation is related to MF), direct bilirubin ≤ 4 x ULN, and creatinine ≤ 2.5 mg/dL; l) At least 6 months from prior splenic irradiation; m) At least 12 months from prior 32P therapy; n) At least 1 week since prior treatment (most recent dose) with a potent CYP3A4 inhibitor; o) At least 4 weeks since any experimental treatment for PMF, PPV-MF, or PET-MF; p) At least 2 weeks since any treatment for PMF, PPV-MF, or PET-MF. |
a) PMF, PPV-MF oppure PET-MF intermedia -1, intermedia -2, o ad alto rischio; b) Splenomegalia palpabile ≥ 5 cm sotto il margine costale inferiore (LCM) nella linea medioclavicolare mediante esame obiettivo; c) Punteggio ≥ 3 per almeno due sintomi su MPN-SAF-TSS oppure punteggio ≥ 4 per almeno un sintomo su MPN-SAF TSS diverso da affaticamento; d) Età ≥ 18 anni; e) Stato prestazionale 0-3 Eastern Cooperative Oncology Group (ECOG); f) Conteggio blasti periferici < 10%; g) Conteggio assoluto dei neutrofili > 500/µl; h) sono eleggibili i pazienti che dipendano da trasfusioni di piastrine o eritrociti; i) Adeguata funzionalità epatica e renale, definita da transaminasi epatiche (AST/SGOT e ALT/SGPT) ≤ 3 x ULN (AST/ALT ≤ 5 x ULN se l’aumento delle transaminasi è collegata a MF), bilirubina diretta ≤ 4 x ULN e creatinina ≤ 2,5 mg/dl; l) Almeno 6 mesi da precedente irradiamento splenico; m) Almeno 12 mesi da precedente terapia 32P; n) Almeno 1 settimana dal precedente trattamento (dose più recente) con potente inibitore CYP3A4; o) Almeno 4 settimane da qualsiasi trattamento sperimentale per PMF, PPV-MF o PET-MF; p) Almeno 2 settimane da qualsiasi trattamento per PMF, PPV-MF o PET-MF. |
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E.4 | Principal exclusion criteria |
a) Any GI or metabolic condition that could interfere with absorption of oral medication; b) Life expectancy < 6 months; c) Prior treatment with a JAK2 inhibitor; d) Completed allogeneic stem cell transplant (ASCT) or eligible for and willing to complete ASCT; e) History of splenectomy or planning to undergo splenectomy; f) Uncontrolled intercurrent illness, including but not limited to ongoing active infection or psychiatric illness or social situation that the treating physician judges would limit compliance with study requirements; g) other malignancy within last 3 years other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with negative prostatespecific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma; h) Inflammatory or chronic functional bowel disorder such as Crohn disease, inflammatory bowel disease, chronic diarrhea, or constipation; i) Clinically symptomatic and uncontrolled cardiovascular disease; l) History of myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure within 6 months prior to study randomization; m) New York Heart Association Class II, III, or IV congestive heart failure (Appendix 9) Ongoing cardiac dysrhythmias of grade 2, QTc prolongation > 480 ms, or other factors that increase the risk for QT interval prolongation (eg, heart failure, hypokalemia defined as serum potassium < 3.0 mEq/L, family history of long QT interval syndrome); n) Erythropoietic agent within 28 days prior to randomization; o) thrombopoietic agent within 14 days prior to randomization |
a) Qualsiasi stato GI o metabolico che potrebbe interferire con l’assorbimento di farmaci per via orale; b) Aspettativa di vita <6 mesi; c) Precedente trattamento con un inibitore del JAK2; d) Completato trapianto allogenico di cellula staminale (ASCT) oppure idoneità e disponibilità a completarlo; e) anamnesi per splenectomia oppure sua programmazione; f) Malattia concomitante non controllata, comprensiva ma non limitata a infezione attiva in corso o a patologia psichiatrica oppure a condizione sociale che il medico curante ritenga possa limitare la compliance ai requisiti dello studio; g) Altra neoplasia riscontrata negli ultimi 3 anni, diversa da carcinoma della pelle a cellule basali o a cellule squamose già trattato, carcinoma in situ della cervice, cancro della prostata non metastatico trattato o confinato all’organo con antigene prostatico specifico negativo, carcinoma mammario in situ dopo completa resezione chirurgica, oppure carcinoma a cellule transizionali e superficiali della vescica; h) Disturbo intestinale infiammatorio o funzionale cronico quale morbo di Crohn, malattia infiammatoria dell'intestino, diarrea cronica o stipsi; i) Patologia cardiovascolare clinicamente sintomatica e incontrollata; l) anamnesi per infarto miocardico, angina instabile/grave oppure insufficienza cardiaca congestizia sintomatica nei 6 mesi precedenti alla randomizzazione per lo studio; m) Insufficienza cardiaca congestizia di classe II, III o IV secondo la New York Heart Association Class; n) Disritmie cardiache in corso di grado ≥2, prolungamento del QTc >480 ms, oppure altri fattori che aumentino il rischio di prolungamento dell’intervallo QT (per es. insufficienza cardiaca, ipocalemia definita come potassio del siero <3,0 mEq/l, anamnesi familiare per sindrome del QT lungo); o) Agente eritropoietico somministrato nei 28 giorni precedenti la randomizzazione; p) Agente trombopoietico somministrato nei 14 giorni precedenti la randomizzazione. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of the study is the proportion of patients achieving ≥ 35% reduction in spleen volume from baseline to Week 24 as measured by MRI or CT. A patient must have a baseline spleen volume to be included in the analysis. The treatment difference in the proportion will be tested by the Fisher exact test. Patients with a missing Week 24 spleen volume and those who drop out of the study or cross over to treatment with pacritinib prior to Week 24 will be considered to have not achieved the ≥ 35% reduction. |
L’endpoint primario di efficacia dello studio riguarda la percentuale di pazienti che raggiunge una riduzione ≥35% del volume splenico dal valore basale alla settimana 24 riscontrabile mediante RMI o TC. Per l’inclusione nell’analisi, si deve possedere una registrazione al basale del volume splenico del paziente. La differenza in percentuale del trattamento sarà valutata mediante Test esatto di Fisher. Per i pazienti dei quali manca il volume splenico alla settimana 24 e per coloro che si ritirano dallo studio, oppure che passano al trattamento con pacritinib prima della settimana 24, si riterrà che essi non abbiano ottenuto la riduzione ≥35%. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
MRI or CT assessments at: Screening, Wk 12, Wk 24 and termination visit. |
Valutazione con MRI o TAC a: Screening, Settimana 12, Settimana 24 Visita fine studio. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint is the proportion of patients with ≥ 50% reduction in TSS from baseline to Week 24 as measured by the MPN-SAF TSS. The analysis method will be similar to that used for the primary efficacy endpoint. |
L’endpoint secondario di efficacia è rappresentato dalla percentuale di pazienti con riduzione ≥50% del TSS dal basale alla settimana 24 misurata con MPN-SAF TSS. La metodica dell’analisi sarà simile a quella impiegata per l’endpoint primario di efficacia. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The MPN-SAF TSS is completed by patients daily from screening until the termination visit. |
Il questionario MPN-SAF TSS sarà completato dal paziente su base giornaliera fino alla visita di fine 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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
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 | No |
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 |
New Zealand |
Russian Federation |
United States |
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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 end of trial will be on completion of survival follow-up. This will continue until 3 years past Week 24 or 3 years past early termination of study treatment, whichever occurs first. |
Lo studio terminerà al completamento del follow-up di sopravvivenza, che continuerà per 3 anni dopo la Settimana 24 o 3 dopo la conclusione anticipata del trattamento (quale che sia la prima evenienza). |
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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 | 4 |
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 |