E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Myelofibrosis, Post-essential thrombocythemia myelofibrosis, Post polycythaemia vera myelofibrosis |
mielofibrosi primaria, mielofibrosi post-policitemia vera o mielofibrosi post-trombocitemia essenziale |
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E.1.1.1 | Medical condition in easily understood language |
Primary or Secondary Myelofibrosis (MF) |
Mielofibrosi Primaria o secondaria (mf) |
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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) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074691 |
E.1.2 | Term | Post polycythaemia vera myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074692 |
E.1.2 | Term | Post essential thrombocythaemia myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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 determine a recommended dosage of pacritinib for further clinical studies |
Determinare un dosaggio raccomandato di pacritinib per ulteriori studi clinici |
|
E.2.2 | Secondary objectives of the trial |
1. To examine the dose¿response relationship for efficacy, as measured by spleen volume reduction (SVR) using magnetic resonance imaging (MRI) or computed tomography (CT) and total symptom score (TSS) using the MPN-SAF TSS 2.0 2. To examine the dose¿response relationship for safety with a focus on adverse events (AE) of interest 3. To further characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of pacritinib |
1. Esaminare la correlazione dose¿risposta per l'efficacia, misurata dalla riduzione del volume splenico (Spleen Volume Reduction, SVR) mediante risonanza magnetica (RM) o tomografia computerizzata (TC) e dal punteggio dei sintomi totali (Total Symptom Score, TSS) usando l'MPN-SAF TSS 2.0 2. Esaminare la correlazione dose¿risposta per la sicurezza concentrandosi sugli eventi avversi (Adverse event, AE) di interesse 3. Caratterizzare ulteriormente la farmacocinetica (PK) e la farmacodinamica (PD) di pacritinib |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. PMF, PPV-MF, or PET-MF (as defined by Tefferi and Vardiman 2008) 2. DIPSS Intermediate-1, Intermediate -2, or High risk (Passamonti et al 2010) 3. Prior ruxolitinib treatment failure or intolerance as defined by: a. Treatment for =6 months with inadequate efficacy response (any measure) in the judgement of the investigator b. Treatment for =28 days complicated by either i. Red blood cell transfusion ii. National Cancer Institute (NCI) CTCAE grade =3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while being treated with a dosage of <20 mg BID 4. Palpable splenomegaly =5 cm below the lower costal margin in the midclavicular line as assessed by physical examination 5. Platelet count of =100,000/µL at any time during the screening period and prior to first dose of pacritinib, including patients who are platelet transfusion-dependent 6. TSS of =10 on the MPN-SAF TSS 2.0 7. Age =18 years old 8. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 9. Peripheral blast count of <10% 10. Absolute neutrophil count of >500/µL 11. Adequate liver and renal function, defined by liver transaminases (aspartate aminotransferase [AST]/serum glutamic oxaloacetic transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic pyruvic transaminase [SGPT]), =3 × the u pper l imit o f n ormal ( ULN) ( AST/ALT = 5 × U LN i f t ransaminase elevation is related to MF), direct bilirubin =4× ULN, and creatinine =2.5 mg/dL 12. Adequate coagulation function, defined by prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT), or thrombin time (TT) of =1.5 × ULN 13. Left ventricular cardiac ejection fraction of =45% by echocardiogram or multigated acquisition (MUGA) scan 14. QTc interval of <450 ms as assessed by ECG and corrected by the Fredericia method 15. If fertile, willing to use effective birth control methods during the study 16. Willing to undergo and able to tolerate frequent MRI or CT assessments during the study 17. Able to understand and willing to complete symptom assessments using a patient-reported outcomes instrument 18. Provision of informed consent |
1. PMF, PPV-MF o PET-MF (come definiti da Tefferi and Vardiman 2008) 2. Rishio secondo DIPSS intermedio-1, intermedio-2 o elevato (Passamonti et al 2010) 3. Precedente insuccesso del trattamento con ruxolitinib o intolleranza al trattamento, definiti da: a. trattamento per =6 mesi con risposta inadeguata per l'efficacia (qualsiasi misurazione) secondo il giudizio dello sperimentatore b. trattamento per =28 giorni con complicanze o per i. trasfusione di emazie ii. o AE riguardanti trombocitopenia, anemia, ematoma e/o emorragia di grado =3 secondo i criteri CTCAE del National Cancer Institute (NCI) durante il trattamento con una dose <20 mg BID 4. Splenomegalia palpabile =5 cm sotto il margine costale inferiore nella linea medio-clavicolare, valutata mediante esame obiettivo 5. Conta delle piastrine =100.000/µl in qualsiasi momento durante il periodo di screening e prima della prima dose di pacritinib, compresi i pazienti dipendenti da trasfusione di piastrine 6. TSS =10 secondo l'MPN-SAF TSS 2.0 7. Età =18 anni 8. Stato di validità (Eastern Cooperative Oncology Group, ECOG) da 0 a 2 9. Conta dei blasti periferici <10% 10. Conta assoluta dei neutrofili >500/µl 11. Funzionalità epatica e renale adeguata, definita da livelli di transaminasi epatiche (aspartato aminotransferasi [AST]/transaminasi glutammico-ossalacetica sierica [SGOT] e alanina aminotransferasi [ALT]/transaminasi glutammico-piruvica sierica [SGPT]), =3 × il limite superiore di normalità (ULN) (AST/ALT =5 × ULN se l'aumento delle transaminasi è correlato a MF), bilirubina diretta =4× ULN e creatinina =2,5 mg/dl 12. Funzionalità della coagulazione adeguata, definita da tempo di protrombina (PT)/rapporto internazionale normalizzato (INR), tempo di tromboplastina parziale (PTT), o tempo di trombina (TT) =1,5 × ULN 13. Frazione di eiezione cardiaca ventricolare sinistra =45% misurata con ecocardiogramma o scansione con acquisizione a gate multipli(MUGA) 14. Intervallo QTc <450 ms valutato dall'ECG e corretto con il metodo Fredericia 15. Se fertile, disponibilità a utilizzare metodi contraccettivi efficaci durante lo studio 16. Disponibilità a sottoporsi a valutazioni RM o TC frequenti e capacità di tollerarle durante lo studio 17. Capacità di comprendere e disponibilità a compilare le valutazioni sui sintomi usando lo strumento degli esiti riferiti dal paziente 18. Manifestazione del consenso informato firmato |
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E.4 | Principal exclusion criteria |
1. Life expectancy <6 months 2. Completed allogeneic stem cell transplant (ASCT) or are eligible for and willing to complete ASCT 3. History of splenectomy or planning to undergo splenectomy 4. Splenic irradiation within the last 6 months 5. Previously treated with pacritinib 6. Treatment with anticoagulation or antiplatelet agents, except for aspirin dosages of =100 mg per day, within the last 2 weeks 7. Treatment with a potent cytochrome P450 (CYP450) inducer within the last 2 weeks 8. Treatment with medications that can prolong the QTc interval within the last 2 weeks 9. Significant recent bleeding history defined as NCI CTCAE grade =2 within the last 3 months, unless precipitated by an inciting event (e.g., surgery, trauma, injury) 10. Any history of CTCAE grade =2 non-dysrhythmia cardiac conditions within the last 6 months. Patients with asymptomatic grade 2 non-dysrhythmia cardiac conditions may be considered for inclusion, with the approval of the medical monitor, if stable and unlikely to affect patient safety. 11. New York Heart Association Class II, III, or IV congestive heart failure 12. Any history of CTCAE grade =2 cardiac dysrhythmias within the last 6 months. Patients with non-QTc CTCAE grade 2 cardiac dysrhythmias may be considered for inclusion, with the approval of the medical monitor, if the dysrhythmias are stable, asymptomatic, and unlikely to affect patient safety. 13. QTc prolongation >450 ms or other factors that increase the risk for QT interval prolongation (e.g., heart failure, hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent and refractory to correction], family history of long QT interval syndrome, or concomitant use of medications that may prolong QT interval) 14. Any gastrointestinal or metabolic condition that could interfere with absorption of oral medication 15. Inflammatory or chronic functional bowel disorder such as Crohn’s Disease, inflammatory bowel disease, chronic diarrhea, or constipation 16. Other malignancy within the 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 prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma 17. Uncontrolled intercurrent illness, including, but not limited to, ongoing active infection or psychiatric illness or social situation that, in the judgment of the treating physician, would limit compliance with study requirements 18. Known seropositivity for human immunodeficiency virus 19. Known active hepatitis A, B, or C virus infection 20. Women who are pregnant or lactating |
1. Aspettativa di vita <6 mesi 2. Pregresso trapianto allogenico di cellule staminali (Allogeneic Stem Cell Transplant, ASCT) o idoneità e disponibilità a sottoporsi al trapianto ASCT 3. Anamnesi di splenectomia o splenectomia programmata 4. Irradiazione splenica negli ultimi 6 mesi 5. Precedentemente trattamento con pacritinib 6. Trattamento con agenti anticoagulanti o antipiastrinici, eccetto aspirina a dosi =100 mg/die nelle 2 ultime settimane 7. Trattamento con un induttore potente del citocromo P450 (CYP450) nelle ultime 2 settimane 8. Trattamento con medicinali che possono prolungare l'intervallo QT nelle ultime 2 settimane 9. Anamnesi di recente emorragia significativa di grado =2 secondo i criteri NCI CTCAE negli ultimi 3 mesi, se non dovuta a un evento provocatore (ad es., intervento chirurgico, trauma, lesione) 10. Qualsiasi anamnesi di cardiopatia non disritmica di grado =2 secondo i criteri CTCAE negli ultimi 6 mesi. Pazienti affetti da cardiopatie non disritmiche di grado 2 possono essere valutati per l'inclusione, con l'approvazione del supervisore medico, se tali condizioni sono stabili e difficilmente influiranno sulla sicurezza del paziente. 11. Insufficienza cardiaca congestizia di classe II, III o IV secondo la NYHA (New York Heart Association) 12. Qualsiasi anamnesi di disritmia cardiaca di grado =2 secondo i criteri CTCAE negli ultimi 6 mesi. Pazienti affetti da disritmie cardiache di grado 2 (non QTc) possono essere valutati per l'inclusione, con l'approvazione del supervisore medico, se le disritmie sono stabili, asintomatiche e difficilmente influiranno sulla sicurezza del paziente. 13. Prolungamento dell'intervallo QTc >450 ms o altri fattori che aumentano il rischio di prolungamento dell'intervallo QT (ad es., insufficienza cardiaca, ipokaliemia [definita da un livello di potassio sierico <3,0 mEq/l, persistente e refrattaria a correzione], anamnesi familiare di sindrome del QT lungo o uso concomitante di medicinali che possono prolungare l'intervallo QT) 14. Qualsiasi condizione gastrointestinale o metabolica che potrebbe interferire con l'assorbimento di medicinali orali 15. Disturbi funzionali intestinali infiammatori o cronici, quali morbo di Crohn, malattia infiammatoria intestinale o stipsi 16. Altre neoplasie nei 3 anni precedenti diverse da: carcinoma a cellule squamose o basali della pelle trattato terapeuticamente, carcinoma in situ della cervice, carcinoma della prostata organo-confinato o non metastatico trattato con antigene prostatico specifico negativo, carcinoma in situ della mammella dopo resezione completa o carcinoma superficiale della vescica a cellule transizionali 17. Malattia concomitante non controllata, incluse a titolo esemplificativo ma non esaustivo infezioni attive in atto o malattie psichiatriche o situazioni sociali che, secondo il giudizio del medico curante, limiterebbero la compliance del paziente ai requisiti dello studio 18. Nota sieropositività per il virus dell'immunodeficienza umano 19. Infezione nota da virus dell'epatite A, B o C 20. Pazienti gestanti o che allattano al seno |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from baseline. The primary safety measure for dosage selection is the percentage of patients with CTCAE grade =3 cardiac AEs (Standardized MedDRA Query [SMQ]), CTCAE grade =3 hemorrhage AEs (SMQ), CTCAE grade =4 thrombocytopenia toxicity (central laboratory based), or CTCAE grade =4 anemia toxicity (central laboratory based). |
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from baseline. The primary safety measure for dosage selection is the percentage of patients with CTCAE grade =3 cardiac AEs (Standardized MedDRA Query [SMQ]), CTCAE grade =3 hemorrhage AEs (SMQ), CTCAE grade =4 thrombocytopenia toxicity (central laboratory based), or CTCAE grade =4 anemia toxicity (central laboratory based). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is measured at Weeks 12 and 24. |
The primary endpoint is measured at Weeks 12 and 24. |
|
E.5.2 | Secondary end point(s) |
Other supportive measures for evaluation as part of the dose¿response relationship include: the percentage of patients who achieve at least 35% reduction in spleen volume; % TSS reduction from baseline; and the percentage of patients with at least 50% reduction in TSS. All other safety data including AEs, death, and clinical laboratory measures will be used as supportive measures for evaluation of pacritinib dose-safety relationship. |
Other supportive measures for evaluation as part of the dose¿response relationship include: the percentage of patients who achieve at least 35% reduction in spleen volume; % TSS reduction from baseline; and the percentage of patients with at least 50% reduction in TSS. All other safety data including AEs, death, and clinical laboratory measures will be used as supportive measures for evaluation of pacritinib dose-safety relationship. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoint is measured at Weeks 12 and 24. |
The secondary endpoint is measured at Weeks 12 and 24. |
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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 | No |
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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 |
France |
Germany |
Hungary |
Italy |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 15 |