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    Summary
    EudraCT Number:2010-019790-15
    Sponsor's Protocol Code Number:APL-B-020-10
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-09-17
    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 number2010-019790-15
    A.3Full title of the trial
    Open-label, Phase II Clinical Trial of Aplidin (Plitidepsin) in Patients with Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia (Post-PV/ET) Myelofibrosis
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code numberAPL-B-020-10
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    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 SponsorPHARMA MAR
    B.1.3.4CountrySpain
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameAplidin
    D.3.4Pharmaceutical form Powder for infusion*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPlitidepsin
    D.3.9.1CAS number 137219-37-5
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeDepsipeptide ciclico
    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 (PMF), - post-polycythemia vera myelofibrosis (post-PV MF), or - post-essential thrombocythemia myelofibrosis (post-ET MF).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10028537
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the objective response rate (ORR) of plitidepsin according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT, Appendix 1) in patients with: - primary myelofibrosis (PMF), - post-polycythemia vera myelofibrosis (post-PV MF), or - post-essential thrombocythemia myelofibrosis (post-ET MF).
    E.2.2Secondary objectives of the trial
    1- To evaluate the safety and tolerability of plitidepsin in this study population. 2- To determine the effect of plitidepsin on: - bone marrow (BM) or peripheral blood histologic and cytogenetic findings, and - peripheral blood granulocyte JAK2V617F allele burden. 3- To determine the quality of life (QoL) and symptoms assessment according to the Myelofibrosis Symptom Assessment Form (MFSAF) (Appendix 2), after treatment with plitidepsin.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Diagnosis of PMF or post-ET/PV MF as per revised World Health Organization (WHO) criteria (Appendix 3). 2)High-risk or intermediate-2 risk MF as defined by the International Prognostic Scoring System (IPSS) (Appendix 4); or intermediate-I risk MF associated with symptomatic splenomegaly/hepatomegaly and/or unresponsive to available therapy. 3)At least 18 years of age, with life expectancy of >/=12 weeks. 4)Able to provide informed consent and being willing to sign an informed consent form (ICF). 5)Eastern Cooperative Oncology Group (ECOG) performance status </=2 (Appendix 5). 6)Evidence of acceptable organ function within seven days of initiating study drug, as evidenced by the following: a)Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 3.0 x upper limit of normal (ULN). b)Direct bilirubin </= 1.0 x ULN. c)Absolute neutrophil count (ANC) >/= 1.0 x 10^9/L. d)Platelet count >/= 25 x 10^9/L. e)Left ventricular ejection fraction (LVEF) within normal limits. f)Creatine phosphokinase (CPK) </= 2.5 x ULN. g)Creatinine clearance >/= 40 mL/min.
    E.4Principal exclusion criteria
    1.Previous treatment with plitidepsin. 2.Any of the following therapies within two weeks prior to initiation of study drug: a)chemotherapy (e.g., hydroxyurea), b)immunomodulatory drug therapy (e.g., thalidomide), c)immunosuppressive therapy, d)corticosteroids >10 mg/day prednisone or equivalent, or e)erythropoietin. 3.Incomplete recovery from major surgery within four weeks of study entry. 4.Radiation therapy within four weeks of study entry. 5.Women of childbearing potential, unless surgically sterile for at least three months (i.e., hysterectomy), or postmenopausal for at least 12 months (follicle-stimulating hormone, FSH > 30 U/mL), or unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) throughout the treatment period and for six months after discontinuation of the treatment. Permitted methods for preventing pregnancy must be communicated to the study patients and their understanding has to be confirmed. 6. Men who partner with a woman of childbearing potential, unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) throughout the treatment period and for six months after discontinuation of the treatment. Permitted methods for preventing pregnancy must be communicated to the study subjects and their understanding has to be confirmed. 7.Women who are pregnant or are currently breastfeeding. 8.Myopathy grade > 2 or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 x ULN in two different determinations performed one week apart). 9.Known positive status for human immunodeficiency virus (HIV). 10.Active hepatitis B or C virus (HBV or HCV) infection and/or significant non-neoplastic liver disease (i.e. cirrhosis). 11.Diagnosis of another invasive malignancy unless free of disease for at least three years following therapy with curative intent. Patients with early-stage basal cell or squamous cell skin cancer, cervical intraepithelial neoplasia, cervical carcinoma in situ, or superficial bladder cancer, may be eligible to participate at the Investigator`s discretion. 12.Any acute active infection. 13.Serious concomitant systemic disorders that would compromise the safety of the patient or limit the patient’s ability to complete or comply with the study, including: a)Uncontrolled medical illness that the Investigator feels will compromise the patient’s tolerance to the study medication. b)Uncontrolled or unstable angina, myocardial infarction, cerebrovascular accident, valvular heart disease or congestive heart failure (New York Heart Association Classification 3 or 4), within 12 months prior to initiation of study drug. c)Pulmonary embolism within three months prior to initiation of study drug. d)Uncontrolled arterial hypertension (>/= 160/110 mmHg) despite optimal medical therapy. e)Previous treatment with doxorubicin at cumulative doses >/= 450 mg/m2. f)Symptomatic arrhythmia (excluding anemia-related sinusal tachycardia grade </= 2), or prolongation of the QTc (Bazzett`s, QTcB) interval to >450 msec for men or >470 msec for women at pre-study screening, unless attributable to pre-existing bundle branch block. 14.Known hypersensitivity to the study drug or any of its formulation components (e.g., Cremophor). 15.Treatment with any investigational product in the 30 days before inclusion in the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this trial is the treatment success rate, with success defined as confirmed disease response. A confirmed response is deemed to be an objective status of complete response (CR), partial response (PR), or clinical improvement (CI), according to the IWG-MRT consensus criteria (i.e., on two consecutive evaluations performed at least eight weeks apart).
    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 No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned1
    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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    La conclusione dello studio e` prevista 4 settimane dopo l`interruzione del trattamento dell`ultimo paziente in trattamento
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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.1.1.1In 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.1.3Elderly (>=65 years) Yes
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 13
    F.4.2.2In the whole clinical trial 45
    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 Decision2010-09-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-09-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-03-04
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