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    Summary
    EudraCT Number:2012-004239-21
    Sponsor's Protocol Code Number:PAC325
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2013-01-11
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-004239-21
    A.3Full title of the trial
    A randomized controlled phase III study of oral Pacritinib vs. Best Available Therapy in patients with Primary Myelofibrosis, post-Polycytemia Vera Myelofibrosis, or Post-Essential Thrombocytemia Mielofibrosis.
    Studio randomizzato, controllato di fase III con pacritinib orale vs. ''migliore terapia disponibile'' in pazienti con mielofibrosi primaria, mielofibrosi post-policitemia vera, o mielofibrosi post-trombocitemia essenziale.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing current standard therapies with pacritinib taken by mouth for the treatment of myelofibrosis (either diagnosed alone or after polycytemia vera or essential thrombocytemia).
    Studio di confronto delle attuali terapie standard e del pacritinib preso per via orale nel trattamento della mielofibrosi (sia diagnosticata come tale o secondaria a policitemia vera o trombocitemia essenziale).
    A.4.1Sponsor's protocol code numberPAC325
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCELL THERAPEUTICS INC.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCell Therapeutics Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCTI Life Sciences Ltd
    B.5.2Functional name of contact pointCommunications Manager
    B.5.3 Address:
    B.5.3.1Street AddressVia Amedei 8
    B.5.3.2Town/ cityMilan
    B.5.3.3Post code20123
    B.5.3.4CountryItaly
    B.5.4Telephone number+39-02-8965-9700
    B.5.5Fax number+39-02-8965-9719
    B.5.6E-mailebellacicca@cti-lifesciences.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/10/768
    D.3 Description of the IMP
    D.3.1Product namePacritinib
    D.3.2Product code SB1518
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPacritinib citrate
    D.3.9.1CAS number 937272-79-2
    D.3.9.2Current sponsor codeSB1518
    D.3.9.3Other descriptive namepyrimidine-based macrocycle
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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.
    E.1.1.1Medical 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.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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).
    E.2.2Secondary 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).
    E.2.3Trial contains a sub-study No
    E.3Principal 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 &lt; 10%; g) Conteggio assoluto dei neutrofili &gt; 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.
    E.4Principal 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 &lt;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 &gt;480 ms, oppure altri fattori che aumentino il rischio di prolungamento dell’intervallo QT (per es. insufficienza cardiaca, ipocalemia definita come potassio del siero &lt;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.
    E.5 End points
    E.5.1Primary 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%.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Exploratory
    Esploratorio
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    migliore terapia disponibile
    best available therapy
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA56
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    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).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 270
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Most patients will receive normal standard of care. However, for those subjects still receiving clinical benefit from pacritinib at the end of the trial and where it is not yet commercially available, the Sponsor will continue to provide access to pacritinib within the limits set by regulatory authorities (method of provision to be determined).
    I pazienti riceveranno le normali cure disponibili. Tuttavia, per quei pazienti che mostreranno ancora un beneficio clinico dal trattamento con pacritinib alla fine dello studio, e qualora il pacritinib non fosse ancora disponibile sul mercato, lo Sponsor si impegna a fornire ancora il farmaco a questi pazienti nelle modalità previste dalle disposizioni di legge.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-01-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-12
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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