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    Summary
    EudraCT Number:2020-000111-69
    Sponsor's Protocol Code Number:PAC303
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-05-31
    Trial 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 ConcernedSpain - AEMPS
    A.2EudraCT number2020-000111-69
    A.3Full title of the trial
    PACIFICA Phase 3: A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician’s Choice in Patients with Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis with Severe Thrombocytopenia (Platelet Counts <50,000/μL)
    Estudio de fase 3 PACIFICA: Estudio de fase 3, aleatorizado, comparativo, en el que se compara pacritinib con el tratamiento elegido por el médico en pacientes con mielofibrosis primaria, mielofibrosis tras policitemia vera o mielofibrosis tras trombocitemia esencial con trombocitopenia grave (cifra de plaquetas <50 000 µl)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PACIFICA Phase 3: A Study of Pacritinib Versus Physician’s Choice in Patients with Myelofibrosis
    Estudio de fase 3 PACIFICA: Un estudio de pacritinib comparado con el tratamiento elegido por el médico en pacientes con mielofibrosis
    A.3.2Name or abbreviated title of the trial where available
    PACIFICA
    A.4.1Sponsor's protocol code numberPAC303
    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 SponsorCTI BioPharma Corp.
    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 supportCTI BioPharma Corp.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCTI BioPharma Corp.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address3101 Western Avenue, Suite 800
    B.5.3.2Town/ citySeattle
    B.5.3.3Post codeWA 98121
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 206 284 6206
    B.5.6E-mailjvolpone@ctibiopharma.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 numberEU3-10-767-003, EU3-10-768-003, EU3-10-769-003
    D.3 Description of the IMP
    D.3.1Product namePacritinib
    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
    D.3.9.1CAS number 937272-79-2
    D.3.9.2Current sponsor codeSB1518
    D.3.9.3Other descriptive namePACRITINIB
    D.3.9.4EV Substance CodeSUB114513
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRuxolitinib
    D.3.4Pharmaceutical form Tablet
    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 INNruxolitinib
    D.3.9.1CAS number 1092939-17-7
    D.3.9.3Other descriptive nameRUXOLITINIB PHOSPHATE
    D.3.9.4EV Substance CodeSUB32897
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameHydroxyurea
    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 INNHYDROXYCARBAMIDE
    D.3.9.1CAS number 8029-68-3
    D.3.9.4EV Substance CodeSUB08076MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDanazol
    D.3.4Pharmaceutical form Capsule
    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 INNDANAZOL
    D.3.9.1CAS number 17230-88-5
    D.3.9.4EV Substance CodeSUB06897MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePrednisone
    D.3.4Pharmaceutical form Tablet
    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 INNPREDNISONE
    D.3.9.1CAS number 53-03-2
    D.3.9.3Other descriptive namePREDNISONE
    D.3.9.4EV Substance CodeSUB10020MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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-essential thrombocythemia myelofibrosis with Severe Thrombocytopenia (Platelet Counts <50,000/μL), Post polycythaemia vera myelofibrosis
    Mielofibrosis primaria, mielofibrosis tras trombocitemia esencial con trombocitopenia grave (cifra de plaquetas <50 000 µl), mielofibrosis tras policitemia vera
    E.1.1.1Medical condition in easily understood language
    Primary or Secondary Myelofibrosis (MF)
    Mielofibrosis primaria o secundaria
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10077161
    E.1.2Term Primary myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10074691
    E.1.2Term Post polycythaemia vera myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10074692
    E.1.2Term Post essential thrombocythaemia 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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to compare the efficacy of pacritinib with that of P/C therapy, as assessed by the proportion of patients achieving a ≥35% SVR between baseline and Week 24 as measured by MRI (preferred) or CT scans.
    El objetivo principal es comparar la eficacia de pacritinib con el tratamiento elegido por el médico (E/M), de acuerdo con la proporción de pacientes que en la semana 24 alcancen una reducción del volumen esplénico (RVE) ≥35 % respecto a la visita inicial, de acuerdo con los resultados de una resonancia magnética nuclear (RMN) o una tomografía axial computarizada (TAC).
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are as follows:
    1. To compare the efficacy of pacritinib with P/C therapy, as assessed by the proportion of patients achieving a ≥50% reduction in TSS between baseline and Week 24
    2. To compare the percentage of patients who self-assess as “very much improved” or “much improved” as measured by the Patient Global Impression of Change (PGIC) in patients treated with pacritinib versus those treated with P/C
    3. To compare the OS of patients treated with pacritinib versus those treated with P/C
    4. To compare the safety of pacritinib versus P/C therapy
    Los objetivos secundarios son los siguentes:
    1. Comparar la eficacia de pacritinib con el tratamiento E/M, de acuerdo con la proporción de pacientes que en la semana 24 alcancen una reducción ≥50 % en la puntuación total de los síntomas (PTS) respecto a la visita inicial.
    2. Comparar el porcentaje de pacientes que consideren que han presentado una "notable mejoría" o "mucha mejoría", de acuerdo con la impresión global del cambio percibido por el paciente (PGIC), entre los pacientes que han recibido pacritinib y los que han recibido el tratamiento E/M.
    3. Comparar la supervivencia global (SG) de los pacientes tratados con pacritinib con la de los pacientes que reciben el tratamiento E/M.
    4. Comparar la seguridad de pacritinib con la del tratamiento E/M.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.PMF, PPV-MF, or PET-MF (as defined by Tefferi and Vardiman 2008)
    2.Platelet count of <50,000/μL at Screening (Day -35 to Day -3) (based on two measurements taken on different days; both measurements must be <50,000/μL)
    3.DIPSS Intermediate-1, Intermediate-2, or High risk (Passamonti et al 2010)
    4.Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular line asassessed by physical examination
    5.TSS of ≥10 on the MPN-SAF TSS 2.0 or a single symptom score of ≥5 or two symptoms of ≥3,including only the symptoms of left upper quadrant pain, bone pain, itching, or night sweats. The TSS criteria need only to be met on a single day.
    6.If the patient has received prior JAK2 inhibitor treatment, this treatment must meet at least one ofthe following criteria:
    a.Prior treatment with any JAK2 inhibitor, irrespective of dose, with a duration of 90 days orless. The 90-day period starts on the date of first administration of JAK2 inhibitor therapy andcontinues for 90 calendar days, regardless of whether therapy is administered continuously orintermittently during that interval.
    b.Prior treatment with ruxolitinib, at no more than 10 mg total daily dose on any day, with aduration of 180 days or less. The 180-day period starts on the date of first ruxolitinibadministration and continues for 180 calendar days, regardless of whether therapy isadministered continuously or intermittently. The patient may not have received >10 mg ofruxolitinib on any day during that interval.
    The 90- or 180-day period may overlap with the Screening period but may not extend into the washout period (14 days prior to treatment Day 1).
    7.Age ≥18 years
    8.Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
    9.Peripheral blast count of <10% throughout the Screening period and prior to randomization
    10.Absolute neutrophil count of ≥500/μL
    11.Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition scan
    12.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 upper limit of normal (ULN)(AST/ALT ≤5 × ULN if transaminase elevation is related to MF), direct bilirubin ≤4 × ULN, andcreatinine ≤2.5 mg/dL
    13.Adequate coagulation defined by prothrombin time (PT)/international normalized ratio (INR) andPTT ≤1.5 × ULN
    14.If fertile, willing to use effective birth control methods during the study
    15.Willing to undergo and able to tolerate frequent MRI or CT scan assessments during the study
    16.Able to understand and willing to complete symptom assessments using a patient-reported outcome instrument
    17.Provision of informed consent
    1. MF primaria, MF tras policitemia vera o MF tras trombocitemia esencial (según definen Tefferi and Vardiman 2008)
    2. Cifra de plaquetas <50 000/µl durante la selección (del día -35 al día -3) (de acuerdo con dos mediciones realizadas en días diferentes; ambas mediciones deben ser <50 000/µl).
    3. Riesgo intermedio 1, intermedio 2 o alto de acuerdo con el sistema internacional de puntuación pronóstica dinámica (Passamonti et al 2010)
    4. Esplenomegalia palpable ≥5 cm por debajo del reborde costal inferior en la línea medioclavicular, determinada mediante exploración física.
    5. PTS ≥10 en el cuestionario MPN-SAF TSS 2.0, o una única puntuación ≥5 en un síntoma, o puntuaciones ≥3 en dos síntomas, solo en los síntomas siguientes: dolor en el cuadrante superior izquierdo, dolor óseo, picor o sudación nocturna (anexo 3). Solo se requiere que los criterios de la PTS se cumplan en un único día.
    6. Si el paciente ha recibido tratamiento con un inhibidor de la JAK2, dicho tratamiento debe cumplir al menos uno de los criterios siguientes:
    a. Tratamiento previo con cualquier inhibidor de la JAK2, independientemente de la dosis, con una duración máxima de 90 días. El período de 90 días comienza en la fecha en la que se administre por primera vez el tratamiento con el inhibidor de la JAK2 y continúa durante 90 días naturales, independientemente de que el tratamiento se administre de forma continua o intermitente durante dicho intervalo.
    b. Tratamiento previo con ruxolitinib en una dosis diaria total máxima de 10 mg, con una duración máxima de 180 días. El período de 180 días comienza en la fecha en la que se administre por primera vez ruxolitinib y continúa durante 180 días naturales, independientemente de que el tratamiento se administre de forma continua o intermitente durante dicho intervalo. El paciente no puede haber recibido > 10 mg de ruxolitinib en ningún día de dicho período.
    El período de 90 o 180 días puede solaparse con el período de selección, pero no puede continuar durante el período de reposo farmacológico (14 días anteriores al día 1 de tratamiento).
    7. Edad ≥ 18 años.
    8. Categoría funcional del Eastern Cooperative Oncology Group de 0 a 2.
    9. Cifra de blastocitos en sangre periférica <10 % durante el período de selección, antes de la aleatorización.
    10. Cifra absoluta de neutrófilos ≥500/µl.
    11. Fracción de expulsión del ventrículo izquierdo ≥50 % de acuerdo con los resultados de una ecocardiografía o una ventriculografía isotópica.
    12. Función hepática y renal aceptables, es decir, una concentración de las transaminasas hepáticas (aspartato aminotransferasa [AST] / transaminasa glutámica oxalacética sérica [SGOT] y alanina aminotransferasa [ALT] / transaminasa glutámica pirúvica sérica [SGPT]) ≤3 veces el límite superior de la normalidad (LSN) (AST/ALT ≤5 veces el LSN si la elevación de las transaminasas se debe a la mielofibrosis), bilirrubina directa ≤4 x LSN y creatinina ≤2,5 mg/dl.
    13. Coagulación adecuada, esto es, un tiempo de protrombina/índice internacional normalizado y un tiempo de tromboplastina parcial ≤1,5 veces el LSN.
    14. En el caso de los pacientes fértiles, estar dispuesto a utilizar métodos anticonceptivos durante el estudio.
    15. Estar dispuesto y poder someterse a RMN o TAC frecuentes durante el estudio.
    16. Ser capaz de comprender y estar dispuesto a completar las evaluaciones de los síntomas mediante un cuestionario sobre los resultados percibidos por el paciente.
    17. Firma del consentimiento informado.
    E.4Principal exclusion criteria
    1. Life expectancy <6 months
    2. Completed allogeneic SCT, or are eligible for and willing to complete other approved available therapy including allogeneic SCT
    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 any MF-directed therapy within 14 days prior to treatment Day 1
    7. Prior treatment with more than one JAK2 inhibitor
    8. Treatment with an experimental therapy within 28 days prior to treatment Day 1
    9. Systemic treatment with a strong CYP3A4 inhibitor or a strong CYP450 inducer within 14 days prior to treatment Day 1. Shorter washout periods may be permitted with approval of the Medical Monitor, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1.
    10.Significant recent bleeding history defined as NCI CTCAE grade ≥2 within 3 months prior to treatment Day 1, unless precipitated by an inciting event (e.g., surgery, trauma, or injury)
    11.Systemic treatment with medications that increase the risk of bleeding, including anticoagulants, antiplatelet agents (except for aspirin dosages of ≤100 mg per day), anti-vascular endothelial growth factor (anti-VEGF) agents, and daily use of COX-1 inhibiting Nonsteroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1
    12.Systemic treatment with medications that can prolong the QT interval within 14 days prior to treatment Day 1. Shorter washout periods may be permitted with approval of the Medical Monitor, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1
    13.Any history of CTCAE grade ≥2 non-dysrhythmia cardiac conditions within 6 months prior to treatment Day 1. Patients with asymptomatic grade 2 non-dysrhythmia cardiovascular conditions may be considered for inclusion, with the approval of the Medical Monitor, if stable and unlikely to affect patient safety.
    14.Any history of CTCAE grade ≥2 cardiac dysrhythmias within 6 months prior to treatment Day 1. 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
    15.QT corrected by the Fridericia method (QTcF) 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], or history of long QT interval syndrome)
    16.New York Heart Association Class II, III, or IV congestive heart failure
    17.Any active GI or metabolic condition that could interfere with absorption of oral medication
    18.Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn’s disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation
    19.Other malignancy within 3 years prior to treatment Day 1, other than curatively treated basal cell or squamous cell skin or corneal cancer; curatively treated carcinoma in situ of the cervix; organ-confined prostate cancer with prostate-specific antigen (PSA) <20 ng/mL and National Comprehensive Cancer Network risk of Very Low, Low, or Favorable Intermediate; curatively treated non-metastatic prostate cancer with negative PSA; or in situ breast carcinoma after complete surgical resection
    20.Uncontrolled intercurrent illness, including, but not limited to, ongoing active infection, psychiatric illness, or social situation that, in the judgment of the treating physician, would limit compliance with study requirements
    21.Known seropositivity for human immunodeficiency virus
    22.Known active hepatitis A, B, or C virus infection
    23.Women who are pregnant or lactating
    24.Concurrent enrollment in another interventional trial
    1. Esperanza de vida < 6 meses.
    2. Haber recibido un alotrasplante de células progenitoras o ser tributario de otro tratamiento aprobado disponible (incluido el alotrasplante de células progenitoras) y estar dispuesto a recibirlo.
    3. Haberse sometido a una esplenectomía o tener previsto someterse a una.
    4. Haber recibido radioterapia esplénica en el transcurso de los últimos 6 meses.
    5. Haber recibido anteriormente pacritinib.
    6. Haber recibido cualquier tratamiento para la mielofibrosis en el transcurso de los 14 días anteriores al día 1 de tratamiento.
    7. Haber recibido tratamiento previo con más de un inhibidor de la JAK2.
    8. Haber recibido tratamiento experimental en el transcurso de los 28 días anteriores al día 1 de tratamiento.
    9. Haber recibido tratamiento sistémico con un inhibidor potente del citocromo P450 3A4 o un inductor potente del citocromo P450 en el transcurso de los 14 días anteriores al día 1 de tratamiento. Podrán permitirse períodos de reposo farmacológico más cortos con la aprobación del monitor médico, siempre que el período de reposo farmacológico anterior al día 1 de tratamiento equivalga al menos a cinco semividas del fármaco.
    10. Haber sufrido recientemente hemorragias importantes (grado ≥2 de acuerdo con los criterios terminológicos comunes para los acontecimientos adversos del Instituto Nacional del Cáncer [CTCAE]) en el transcurso de los 3 meses anteriores al día 1 de tratamiento, a menos que las hayan provocado un acontecimiento (por ejemplo, una cirugía, un traumatismo o una lesión).
    11. Haber recibido tratamiento sistémico con medicamentos que aumenten el riesgo de hemorragia, como anticoagulantes, antiagregantes plaquetarios (salvo la administración de ≤100 mg/día de ácido acetilsalicílico), fármacos frente al factor de crecimiento del endotelio vascular (anti-VEGF) y administración diaria de antiinflamatorios no esteroideos (AINE) con acción inhibidora sobre la ciclooxigenasa-1 (COX-1) en el transcurso de los 14 días anteriores al día 1 de tratamiento.
    12. Haber recibido tratamiento sistémico con medicamentos que prolonguen el intervalo QT en el transcurso de los 14 días anteriores al día 1 de tratamiento. Podrán permitirse períodos de reposo farmacológico más cortos con la aprobación del monitor médico, siempre que el período de reposo farmacológico anterior al día 1 de tratamiento equivalga al menos a cinco semividas del fármaco.
    13. Presentar antecedentes de cardiopatías no relacionadas con la presencia de arritmia de grado ≥2 (CTCAE) en el transcurso de los 6 meses anteriores al día 1 de tratamiento. Podrá considerarse la inclusión de los pacientes con enfermedades cardiovasculares asintomáticas de grado 2 y no relacionadas con la presencia de arritmia, siempre que estén estables y sea improbable que pongan en riesgo la seguridad del paciente, con la aprobación del monitor médico.
    14. Cualquier antecedente de arritmias cardíacas de grado ≥2 (CTCAE) en el transcurso de los 6 meses anteriores al día 1 de tratamiento. Podrá considerarse la inclusión de los pacientes con arritmias cardíacas de grado 2 (CTCAE) relacionadas con el intervalo QT no corregido, siempre que sean estables, asintomáticas y sea improbable que pongan en riesgo la seguridad del paciente, con la aprobación del monitor médico.
    15. Prolongación del intervalo QT corregido de acuerdo con el método de Fridericia (QTcF) >450 ms, u otros factores que aumenten el riesgo de prolongación del intervalo QT (por ejemplo, insuficiencia cardíaca, hipopotasemia [concentración sérica de potasio <3,0 mEq/l persistente y que no responda a las medidas correctoras] o antecedentes de síndrome del intervalo QT largo).
    16. Insuficiencia cardíaca de clase II, III o IV, de acuerdo con los criterios de la NYHA
    17. Cualquier enfermedad gastrointestinal o metabólica que pueda interferir en la absorción de los medicamentos administrados por vía oral.
    18. Trastorno gastrointestinal funcional crónico o inflamatorio, activo o sin controlar, como enfermedad de Crohn, enfermedad inflamatoria intestinal, diarrea crónica o estreñimiento crónico.
    19. Haber sufrido otra neoplasia maligna en el transcurso de los 3 años anteriores al día 1 del tratamiento, salvo los casos de carcinomas basocelulares o epidermoides de la piel o de cáncer de córnea tratados con intención curativa; carcinoma in situ del cuello uterino tratado con intención curativa; cáncer de próstata confinado al órgano con una concentración del antígeno prostático específico <20 ng/ml y riesgo muy bajo, bajo o intermedio favorable de acuerdo con los criterios del National Comprehensive Cancer Network; cáncer de próstata no metastásico sin presencia del antígeno prostático específico y tratado con intención curativa; o carcinoma de mama in situ tras la resección quirúrgica completa.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the spleen volume reduction response rate defined as the percentage of patients who achieve at least 35% reduction in spleen volume from baseline as measured by MRI (preferred) or CT scan at Week 24. Patients who do not have a Week 24 spleen assessment will be included as non-responders in this analysis
    El criterio principal de valoración de la eficacia es la tasa de respuesta desde el punto de vista de la RVE, que se define como el porcentaje de pacientes que en la semana 24 alcancen una reducción mínima del 35 % en el volumen esplénico respecto a la visita inicial, de acuerdo con los resultados de una RMN (preferentemente) o de una TAC. En este análisis se considerará que los pacientes que no cuenten con una evaluación del tamaño del bazo en la semana 24 no han respondido al tratamiento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of spleen volume reduction will occur using data from the first 168 patients after they have been followed for 24 weeks.
    En el análisis principal de la RVE se incluirán los datos de los primeros 168 pacientes, una vez que se les haya realizado seguimiento durante 24 semanas.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoint of Total Symptom Score (TSS) response rate is defined as the percentage of patients with at least 50% reduction in TSS from baseline at Week 24. The TSS endpoint score will be calculated as the sum of scores for six items from the MPN SAF TSS 2.0 instrument: satiety, abdominal discomfort, night sweats, itching, bone pain, and pain under ribs on the left side.
    The secondary endpoint of Patient Global Impression of Change response rate is defined as the percentage of patients who self-assess as “very much improved” or “much improved” at Week 24.
    The secondary endpoint of Overall Survival is defined as the time between randomization and death.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24
    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 No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 EEA49
    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
    Belarus
    Canada
    Czech Republic
    France
    Georgia
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Poland
    Russian Federation
    Serbia
    Spain
    Ukraine
    United Kingdom
    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
    LVLS
    última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days23
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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: 139
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 209
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 348
    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)
    After Week 24 assessment, patients benefiting from therapy will receive treatment until patient experiences progressive disease, intolerable AEs, withdraws consent, or initiates new MF-directed therapy. Patients will be followed for survival for 2.5 years from the date of randomization unless consent for follow-up is withdrawn. After the EoT, sponsor may make the study drug available for further treatment for all patients until the study drug becomes available on the market.
    Después de la semana 24, pacientes que se beneficien de la terapia recibirán tratamiento hasta la progresión de la enfermedad o AA intolerables, que retiren el consentimiento, o comiencen un tratamiento nuevo para la mielofibrosis. Se realizará seguimiento de estos pacientes durante los 2,5 años posteriores a la aleatorización si no han retirado el consentimiento para esto. Después de EoT, el promotor puede proporcionar a todos los pacientes hasta que pacritinib esté comercializado.
    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 Decision2020-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-22
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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