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    Summary
    EudraCT Number:2009-016138-29
    Sponsor's Protocol Code Number:APL-C-001-09
    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:2010-05-21
    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 number2009-016138-29
    A.3Full title of the trial
    Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma
    A.3.2Name or abbreviated title of the trial where available
    ADMYRE: Aplidin - Dexamethasone in RElapsed/Refractory MYeloma
    A.4.1Sponsor's protocol code numberAPL-C-001-09
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/04/245
    D.3 Description of the IMP
    D.3.1Product nameAplidin
    D.3.4Pharmaceutical form Powder and solvent for solution 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.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.2.1.1.1Trade name Fortecortin 4 mg Tabletten
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNDexamethasone
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 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
    Relapsed/refractory multiple myeloma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM).
    E.2.2Secondary objectives of the trial
    - To evaluate tumor response according to the International Myeloma Working Group (IMWG) criteria. - To assess duration of response (DR) and overall survival (OS). - To assess efficacy in patients who undergo crossover from dexamethasone alone to plitidepsin and dexamethasone combination. - To characterize and compare the safety profile on both arms in this population. - To characterize the pharmacokinetics (PK) and pharmacokinetic /pharmacodynamic (PK/PD) relationship.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age >/= 18 years. 2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) </= 2 (see Appendix 2). 3. Life expectancy >/=3 months. 4. Patients previously diagnosed with multiple myeloma based on IMWG diagnostic criteria (see Appendix 4). 5. Patients must have relapsed or relapsed and refractory multiple myeloma (MM) (Appendix 5) after at least three but not more than six prior therapeutic regimens for MM, including induction therapy and stem cell transplant in candidate patients, which will be considered as only one regimen. 6. Patients must have received previous bortezomib-containing and lenalidomide-containing regimens (or thalidomide where lenalidomide is not available), unless unable to tolerate either of them. 7. Patients must have measurable disease defined as: a) For secretory MM: any quantifiable serum monoclonal protein value and, where applicable, urine light-chain excretion >/= 200 mg/24 hours. b) For oligo- or non-secretory MM: presence of soft tissue (not bone) plasmacytomas, as determined by clinical examination or applicable radiographs [i.e., magnetic resonance imaging (MRI), computed tomography (CT)-scan], and/or by the presence of abnormal serum free light chains (sFLC): involved FLC level >/= 10 mg/dl provided the serum FLC ratio is abnormal. 8. At least two-week washout period since the end of last therapy(six weeks if previous nitrosoureas-containing regimen), given recovery to grade </= 1 from any non-hematological related adverse event (AE) derived from previous treatment (excluding alopecia). 9. Adequate bone marrow (BM), renal, hepatic, and metabolic function (assessed </= 7 days before inclusion in the study): a) Absolute neutrophil count (ANC) >/= 1.0 x 10^9/l (>/= 0.5 x 10^9/l if due to extensive and documented BM involvement by >/= 50% of plasma cells in BM biopsy). - Screening of ANC should be independent of granulocyte- and granulocyte/macrophage-colony stimulating factor (G-CSF and GM-CSF) support for at least one week and of pegylated G-CSF for at least two weeks. b) Platelet count >/= 50 x 10^9/l (>/= 25 x 10^9/l if due to extensive and documented BM disease involvement). c) Hemoglobin >/= 8.5 g/dl. - Patients may receive red blood cells (RBC) and/or erythropoietin (EPO), and/or platelets transfusions in accordance with institutional guidelines. d) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 3.0 x the upper limit of normal (ULN). e) Direct bilirubin </= 1.0 x ULN. f) Calculated creatinine clearance (CrCl) >/= 30 ml/minute (by means of Cockcroft and Gault´s formula) (see Appendix 3). g) Creatine phosphokinase (CPK) </= 2.5 x ULN. h) Albumin >/= 2.5 g/dl. 10. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) above the lower limit of normal (LLN). 11. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. 12. Voluntarily signed and dated written informed consent prior to any specific study procedure
    E.4Principal exclusion criteria
    1. Concomitant diseases/conditions: a) History or presence of angina, myocardial infarction, clinically relevant valvular heart disease, cardiac amyloidosis or congestive heart failure within the last 12 months. b) Symptomatic arrhythmia (excluding anemia-related sinusal tachycardia grade </= 2) or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade >/= 2. c) Active uncontrolled infection or recent history of acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose. d) Morphological or cytological features of myelodysplasia and/or post-chemotherapy aplasia on BM assessment. e) 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). f) Known human immunodeficiency virus (HIV) infection (HIV testing is not required unless infection is clinically suspected). g) Known active hepatitis B or C virus (HBV or HCV) infection. h) Limitation of the patient`s ability to comply with the treatment or follow-up requirements. i) Any other major illness that, in the Investigator`s judgment, will substantially increase the risk associated with the patient`s participation in this study. j) Peripheral neuropathy > grade 2. 2. Women who are pregnant or breast feeding. 3. Concomitant medications that include corticosteroids,chemotherapy, or other therapy that is or may be active against MM,within two weeks prior to Cycle 1 Day 1. Concurrent corticosteroids are allowed, provided they are administered at an equivalent prednisone dose of </= 10 mg daily, as premedication for blood products only. 4. Known history of peptic ulcer and/or major upper gastrointestinal bleeding episode occurring during last year before study entry and/or related to prior steroid-based therapy. 5. Relevant history of mood-disturbances changes associated with previous steroid-based therapy. 6. Disease-related symptomatic hypercalcemia despite optimal medical therapy. 7. Known hypersensitivity to any involved study drug or any of its formulation components.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy: • PFS, according to IRC assessment, as per intention-to-treat (ITT) analysis.
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over 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.8.3 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In 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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 125
    F.4.2.2In the whole clinical trial 250
    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 Decision2010-05-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-05-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-11-20
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