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    Summary
    EudraCT Number:2015-005497-38
    Sponsor's Protocol Code Number:RG_15-234
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-04-28
    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 number2015-005497-38
    A.3Full title of the trial
    Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effects of Tamoxifen on the disease course of patients with Myeloproliferative Neoplasms
    A.3.2Name or abbreviated title of the trial where available
    TAMARIN
    A.4.1Sponsor's protocol code numberRG_15-234
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN65011803
    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 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 pointSonia Fox
    B.5.3 Address:
    B.5.3.1Street AddressCRCTU, University of Birmingham
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214159181
    B.5.5Fax number01214146061
    B.5.6E-mailTAMARIN@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 Information not present in EudraCT
    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 nameTamoxifen
    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 INNTamoxifen
    D.3.9.1CAS number 10540-29-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 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
    Myeloproliferative Neoplasms
    E.1.1.1Medical condition in easily understood language
    Blood cancers characterised by an overproduction of blood cells.
    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 LLT
    E.1.2Classification code 10028576
    E.1.2Term Myeloproliferative disorder
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the activity of tamoxifen in reducing the molecular markers of disease burden in MPN (the number of mutated cells) by greater than or equal to 50% after 24 weeks of treatment.
    E.2.2Secondary objectives of the trial
    The study will also look at how many patients have received certain reductions in allele burden (the number of mutated cells)at different timepoints including:
    - Proportion of patients showing a reduction in the peripheral blood mutant allele burden of ≥50% at 12 weeks
    - Proportion of patients showing any reduction in the peripheral blood mutant allele burden at 24 weeks
    - Proportion of patients showing any reduction in the peripheral blood mutant allele burden at 12 weeks

    Safety of tamoxifen in this patient population.

    Number of thrombotic events that occur

    Maintenance of stable disease

    Achievement of disease response

    Look at oestrogen receptor signalling in stem cells from peripheral blood and bone marrow before (peripheral blood only) and after tamoxifen treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age ≥ 60 years (men aged between 50-59 may also be considered following discussion with the Chief Investigator)
    • Women must be post-menopausal (defined as amenorrhoeic for at least 12 consecutive months following cessation of all exogenous hormonal treatments)
    • Confirmed diagnosis of JAK2-V617F or CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) positive Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) (primary or secondary) for ≥ 6 months
    • JAK2-V617F or CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9)mutant allele burden ≥ 20% in peripheral blood granulocyte DNA at study entry (assessed via central review)
    • WHO performance status 0-2
    • For patients with PV or ET, maintenance of platelet count ≤600 x 10^9/L, WBC ≤25 x 10^9/L and venesection requirements ≤1 per month for the previous 3 months (prior to registration), without introduction of any new therapeutic agents for their MPN for 6 months prior to registration
    • For patients with MF, there must not have been any evidence of disease progression* for the previous 6 months (prior to registration) and no new therapeutic agents for their MPN introduced during this period.
    • Patients receiving cytoreductive therapy (with the exception of interferon alpha or investigational agents) for their MPN (not solely aspirin or venesection)
    • Adequate hepatic function, defined as:
    o bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with elevated bilirubin due to Gilbert’s syndrome are eligible)
    o AST/ALT/ALP ≤ 2.5 x ULN
    • Adequate renal function (creatinine clearance >30 mL/min)
    • Male patients must agree to use effective contraception during participation in the trial and for 2 months after the last dose of trial treatment
    • Patient must be able to give written informed consent
    *Defined by IWG-MRT ELN criteria (Appendix 6). Please note no baseline bone marrow is required to confirm absence of “Leukemic transformation confirmed by a bone marrow blast count of ≥20%”.
    E.4Principal exclusion criteria
    • Leukaemic transformation (>20% blasts in blood, marrow or extramedullary site).
    • Accelerated phase of disease as indicated by >10% blasts in the peripheral blood
    • Treatment of ET, PV or MF with Interferon alpha or other investigational agents for their MPN within 6 months prior to trial entry. JAK inhibitors, such as ruxolitinib, are allowed if taken continuously for ≥6 months prior to registration (dose changes during that period will be allowed)
    • Any of the following previous thrombotic events at any time:
    o Portal or other splanchnic venous thrombosis
    o Vascular access complication
    o Ischemia cerebrovascular
    o Stroke
    o Transient Ischaemic attack
    o Superficial thrombophlebitis
    o Venous Thromboembolic events including pulmonary embolism (PE) and deep vein thrombosis (DVT)
    o Peripheral vascular ischemia
    o Visceral arterial ischemia
    o Acute coronary syndrome
    o Myocardial infarction
    • Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
    • Previous endometrial cancer, hyperplasia or polyps
    • Prior treatment with hematopoietic stem cell transplantation
    • Patients who do not carry JAK2V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) mutations, or whose allele burden is <20% at study entry
    • Female patients receiving hormone replacement therapy
    • Hypertriglyceridemia > grade 1
    • Any serious underlying medical condition (at the judgment of the Investigator), which could impair the ability of the patient to participate in the trial (e.g. liver disease, active autoimmune disease, uncontrolled diabetes, uncontrolled infection (HIV, Hepatitis B and C), known genetic defect (apart from MPN) relating to venous thromboembolic events, or psychiatric disorder precluding understanding of trial information)
    • Known hypersensitivity to tamoxifen or hypersensitivity to any other component of tamoxifen
    • Concomitant drugs contraindicated for use with the trial drug according to the Summary of Product Characteristics
    • Known planned scheduled elective surgery during study with the exception of dental and low risk eye surgery (e.g. cataracts)
    E.5 End points
    E.5.1Primary end point(s)
    Reduction in the peripheral blood JAK2V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) mutant allele burden of ≥50% at 24 weeks
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24 of the study
    E.5.2Secondary end point(s)
    1. Proportion of patients with a reduction in the peripheral blood JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) mutant allele burden of ≥50% at 12 weeks
    2. Toxicity measured as the number of grade 3 and 4 adverse events reported
    3. The number of thrombotic events of any grade reported and validated
    4. Duration of haematological response calculated as time from registration to progression for patients who enter the study in response (CR or PR). For patients who enter the trial in stable disease, the time between first recorded response to the date of progression. Progression is defined as loss of response for PV/ET patients and evidence of disease progression for MF patients. PV/ET patients who continue to achieve a response, or MF patients who have no evidence of disease progression at the end of the trial will be censored at date last seen. Haematological response is defined according to 2009 ELN criteria for ET/PV patients and no evidence of disease progression for MF patients according to IWG-MRT response criteria
    5. Proportion of patients in each response category according to IWG-MRT response criteria for MF patients and 2013 ELN response criteria for ET/PV patients at 24 weeks of treatment
    6. Proportion of patients showing an improvement in response category at 24 weeks compared to baseline according to 2009 ELN criteria for ET/PV patients and according to IWG-MRT response criteria for MF patients. Patients who are in a higher category at week 24 compared to baseline will be classed a success. Patients who enter the trial in CR and who maintain a CR will also be classed as a success in this outcome

    Exploratory Outcomes
    7. Expression (RNAseq), DNA-protein interaction (ChipSeq) and methylation studies focused on oestrogen receptor signalling in haematopoietic progenitors obtained from peripheral blood and bone marrow before (peripheral blood only) and after tamoxifen treatment.
    8. Proportion of patients showing a decrease in JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) allele burden at 12 weeks compared to baseline
    9. Proportion of patients showing a decrease in JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) allele burden at 24 weeks compared to baseline
    10. Proportion of patients showing a decrease in requirement for cytoreduction at 24 weeks compared to baseline
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Week 12 of the study
    2. Toxicity will be measured from the start of treatment until 28 days after the last administration of trial treatment
    3. The number of thrombotic events will be measured from the start of treatment until 28 days after the last administration of trial treatment
    4. Duration of haematological response will be assessed at baseline and during 24 weeks of treatment
    5. Week 24 of the study
    6. Week 24 of the study

    Exploratory Outcomes
    7. Oestrogen receptor signalling studies will compare samples taken at baseline with samples taken at week 24
    8. Week 12 of the study
    9. Week 24 of the study
    10. Week 24 of the study
    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 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 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) Yes
    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 concerned15
    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 the last patient’s last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days3
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days3
    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.1.1.1.1Number 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) No
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    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 state42
    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)
    Tamoxifen is to come from standard hospital stock. Therefore, if the patient continues treatment for longer than 24 weeks, this will continue to be supplied from the local hospital.
    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 Decision2016-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-24
    P. End of Trial
    P.End of Trial StatusOngoing
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