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    Summary
    EudraCT Number:2019-000916-27
    Sponsor's Protocol Code Number:RG_19-030
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-09-14
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-000916-27
    A.3Full title of the trial
    Investigation into the combination of PLX2853 with ruxolitinib in patients with intermediate-2 or high risk myelofibrosis not receiving an adequate response with ruxolitinib alone.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the combination of two drugs (PLX2853 and ruxolitinib) in patients with intermediate-2 or high risk myelofibrosis who are not receiving an adequate response with ruxolitinib alone.
    A.3.2Name or abbreviated title of the trial where available
    PROMise
    A.4.1Sponsor's protocol code numberRG_19-030
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Birmingham
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Birmingham
    B.5.2Functional name of contact pointRebecca Collings
    B.5.3 Address:
    B.5.3.1Street AddressCentre for Clinical Haematology, Queen Elizabeth Hospital Birmingham
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01213717868
    B.5.5Fax number01213717878
    B.5.6E-mailpromise@trials.bham.ac.uk
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePLX2853
    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 INNPLX2853
    D.3.9.2Current sponsor codePLX2853
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 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 Yes
    D.2.1.1.1Trade name Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europham Limited
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 nameJakavi
    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 941678-49-5
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 20
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Myelofibrosis
    E.1.1.1Medical condition in easily understood language
    Myelofibrosis
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish the recommended phase 2 dose and safety of PLX2853 in combination with ruxolitinib and to assess how well the combination of PLX2853 and ruxolitinib reduces spleen size in patients with intermediate-2 or high risk myelofibrosis.
    E.2.2Secondary objectives of the trial
    •To assess the safety of the combination of PLX2853 and ruxolitinib
    •To measure the effect of the combination of PLX2853 and ruxolitinib on myelofibrosis-associated symptoms
    •To assess the effect of the combination of PLX2853 and ruxolitinib on bone marrow fibrosis
    •To assess overall haematological response
    •To measure overall survival time
    •To measure leukaemia-free time
    •To measure progression free survival



    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Quality of Life Sub-Study

    Myelofibrosis is associated with a major negative impact on both quality and length of life. Assessment of symptom burden and quality of life are routine assessments for myelofibrosis studies as these symptoms represent a huge burden for patients with negative impact on quality of life. The optional sub-study will utilize the EORTC QLQ-C30, PGIC and MFSAF questionnaires and their results as a secondary outcome measure.
    E.3Principal inclusion criteria
    • Age≥16 years
    • Primary or secondary myelofibrosis OR Dynamic International Prognostic Scoring System (DIPSS) defined risk groups intermediate-2 or high risk
    • Treated with ≥24 weeks of ruxolitinib with ongoing residual splenomegaly >5cm from costal margin
    • Platelets >75x109/L
    • Neutrophils >1.0x109/L
    • <10% blasts in peripheral blood and/or bone marrow
    • Coagulation (INR or PT) and Activated partial thromboplastin time ≤1.5 x ULN
    • Albumin >3.0 g/dL
    • Stable dose of ruxolitinib (no dose modifications) established for 4 weeks prior to trial entry
    • Except as specified above for organ function, all drug-related toxicity from previous therapy for myelofibrosis must be resolved (to Grade ≤1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI CTCAE v4.0]) prior to study treatment administration (Grade 2: alopecia, hot flashes, decreased libido, or neuropathy is allowed).
    • Able to provide written informed consent
    • Able to comply with trial treatment and follow-up
    • Serum total bilirubin ≤2.0 × ULN OR Direct bilirubin ≤ULN for patients with total bilirubin >2.0 × ULN
    o Exception for elevated total bilirubin secondary to Gilbert’s disease, in which case it must be ≤3 x ULN.
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0 × ULN
    E.4Principal exclusion criteria
    • Prior exposure to a bromodomain inhibitor such as OTX-015 or CPI-0610
    • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to trial entry)
    • Patients and partners of childbearing potential (pre-menopausal female capable of becoming pregnant) not willing to use effective contraception from the time of negative pregnancy test during screening to 90 days after the last dose of study drug .Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year.
    • Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal treatment
    • ECOG Performance Status Score ≥ 3
    • Clinically significant cardiac disease, defined as any of the following:
    o Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded.
    o Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval (drugs with a low risk of QTc prolongation that are needed for infection control or nausea may be permitted with approval from the Clinical Coordinator).
    o QT interval corrected for heart rate using the Fridericia method (QTcF) ≥450 msec males or QTcF ≥470 msec (females) at Screening
    o History of clinically significant cardiac disease or congestive heart failure > New York Heart Association Class II. Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months.
    o Uncontrolled hypertension, defined as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg which has been confirmed by 2 successive measurements despite optimal medical management
    o Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 3 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring >1 month before the start of study medication)
    • Inadequate renal function as defined by eGFR or CrCl ≤30 mls/min
    • Current active viral hepatitis including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative. Note that elevated levels of biotin may interfere with viral serology testing.
    • Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry.)
    • Known or suspected allergy to the investigational agent or any agent given in association with this study
    • Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption
    • Patient is participating in any other therapeutic clinical study (observational or registry studies are allowed)
    E.5 End points
    E.5.1Primary end point(s)
    Occurrence of dose limiting toxicity in cycle 1 and reduction in palpable spleen length of >50% from screening to the end of 8 cycles of treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The timepoint of evaluation for Occurrence of dose limiting toxicity, is the end of cycle 1. The timepoint for reduction in palpable spleen length is at the end of 8 cycles of treatment.
    E.5.2Secondary end point(s)
    •Incidence of adverse events, recorded using Common Terminology Criteria for Adverse Events (CTCAE) v4.0, from commencement of protocol treatment to 28 days post treatment discontinuation.
    •Proportion of patients whose ruxolitinib dose was adjusted following administration of PLX2853
    •Overall response after 8 cycles of treatment assessed using International Working Group (IWG) Criteria, where response includes Complete Response and Partial Response
    •Anaemia response after 8 cycles of treatment using International Working Group (IWG) Criteria
    •Rate of red blood cell (RBC) transfusion
    •Percentage reduction in spleen length assessed using ultrasound from screening to the end of treatment.
    •Incidence of molecular response after 4 and 8 cycles of treatment assessed using IWG Criteria
    •Bone marrow fibrosis assessed via bone marrow samples after 8 cycles.
    •Overall survival time defined as the time from date of registration to date of death from any cause. Alive patients will be censored at the date last known alive.
    •Progression-free survival time, defined as the time from date of registration to the earlier of the date of death from any cause or disease progression by the IWG Criteria. Alive patients without disease progression will be censored at the date last known alive.
    •Leukaemia free survival time, defined as the time from date of registration to earliest of date of death or date of progression to leukaemia. Alive patients without progression to leukaemia will be censored at the date last known alive.
    •Total symptom score assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) after 4 and 8 cycles
    •Quality of Life measured by Quality of Life Questionnaire (EORTC QLQ)-C30 and Patient Global Impression of Change (PGIC) questionnaires.
    E.5.2.1Timepoint(s) of evaluation of this end point
    AEs will be evaluated until 28 days post treatment discontinuation. An endpoint of last treatment will be used for patients whose ruxolitinib dose was adjusted and percentage of reduction in spleen length. Incidence of molecular response and total symptom score will be evaluated after 4 and 8 cycles of treatment, with bone marrow fibrosis and overall and anaemia responses being evaluated after 8 cycles. Overall survival time is defined until death from any cause, while Progression free survival time is either date of death from any cause or date of disease progression. Leukaemia free survival is evaluated to the earliest either being date of death, or date of progression to leukaemia. Quality of life will be evaluated after 8 cycles of treatment, and then at annual follow ups.
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned13
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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 6 months after the last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trials Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial.
    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 days1
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    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)
    PLX2853 will be provided free of charge during the trial and they may remain on this drug as long as their is clinical benefit.

    Ruxolitinib is commercially available and therefore this will be provided by sites during and after the end of trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-12
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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