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    The EU Clinical Trials Register currently displays   40165   clinical trials with a EudraCT protocol, of which   6574   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
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    EudraCT Number:2009-010980-18
    Sponsor's Protocol Code Number:APL-B-019-08
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2009-05-19
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2009-010980-18
    A.3Full title of the trial
    Efficacité et Tolérance de la Plitidepsine chez les patients souffrant d’un liposarcome dédifférencié (DLPS) avancé, non opérable ou métastatique, en rechute/réfractaire : Une étude exploratoire multicentrique de phase II.
    A.4.1Sponsor's protocol code numberAPL-B-019-08
    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, S.A.
    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.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 (plitidepsin)
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level PT
    E.1.2Classification code 10024627
    E.1.2Term Liposarcoma
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the antitumor activity of plitidepsin in terms of progression-free survival rate at three months (PFS3).
    E.2.2Secondary objectives of the trial
    • Response rate as per the Response Evaluation Criteria in Solid Tumors (RECIST).
    • Correlation of clinical benefit (as per RECIST: complete response [CR] + partial response [PR] + stable disease [SD] ≥ 3 months) according to c-Jun N-terminal (JUN)-kinase (JNK) immunohistochemistry (IHC) expression status.
    • Progression-free survival (PFS) and progression-free survival rate at six months (PFS6).
    • Overall survival (OS).
    • Safety evaluation in this patient population.
    • Pharmacogenomic (PGx) analysis of :
    ������ Potential biomarkers of sensitivity or resistance to plitidepsin and predictive markers of treatment outcome from pre-treatment available paraffin-embedded tumor tissue samples, and
    ������ Changes of gene expression profile (GEP) in peripheral white blood cells (PWBC) before and after plitidepsin exposure and in fresh/frozen tissue samples (when available) in consenting patients.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenomic study objectives:
    -Potential biomarkers of sensitivity or resistance to plitidepsin and predictive markers of treatment outcome from pre-treatment available paraffin-embedded tumor tissue samples, and
    -Changes of gene expression profile (GEP) in peripheral white blood cells (PWBC) before and after plitidepsin exposure and in fresh/frozen tissue samples (when available) in consenting patients.
    E.3Principal inclusion criteria
    1. Histologically confirmed DLPS.
    2. Metastatic or unresectable locally advanced disease with progression or relapse after standard therapy (at least one prior anthracycline-containing chemotherapy regimen).
    3. Age ≥ 18 years.
    4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
    5. Documented disease progression (as per RECIST) before study entry.
    6. Measurable disease according to RECIST outside any previously irradiated field.
    7. Adequate hematological, renal, metabolic and hepatic function.
    a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.2 x 109/l, and platelet count ≥ 100 x 109/l.
    b. Alkaline phosphatase(AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 x upper limit of normality (ULN) (≤5 in case of extensive skeletal involvement for AP exclusively).
    c. Total bilirubin ≤ 1.5 x ULN. d. Albumin > 25 g/l.
    e. Calculated creatinine clearance (CrCl) ≥ 40 ml/min (according to Cockroft and Gault formula).
    f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
    8. Troponin I ≤ ULN.
    9. No prior or concurrent malignant disease except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma.
    10. Life expectancy > 3 months.
    11. At least three weeks since last chemotherapy (six weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy.
    12. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0).
    13. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple gated acquisition (MUGA) within normal limits.
    14. 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. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier.
    15. Voluntarily signed and dated written informed consents prior to any study specific procedure.
    E.4Principal exclusion criteria
    1. Previous treatment with plitidepsin.
    2. Pathological diagnosis different from DLPS.
    3. More than three prior lines of therapy for advanced disease.
    4. Concomitant diseases/conditions:
    a. History or presence of unstable angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease.
    b. Previous mediastinal radiotherapy.
    c. Previous treatment with anthracyclines at cumulative doses in excess of 450 mg/m2 doxorubicin equivalent.
    d. Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade > 1.
    e. Active uncontrolled infection.
    f. Myopathy or persistent CPK elevations > 2.5 x ULN in two different determinations performed with one week apart.
    g. Limitation of the patient’s ability to comply with the treatment or to follow-up the protocol.
    h. Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
    5. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases.
    6. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding. 7. Treatment with any investigational product within the period ≤ 5 half-lives prior to the first infusion of plitidepsin.
    8. Tumor tissue sample not available for pathological review and/or JNK immunochemistry testing.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint:
    PFS3, defined as the percentage of patients remaining alive and progression free at three months (i.e., Week 12 ± 1) after the first infusion as per RECIST.
    Secondary endpoints:
    • Overall response rate (ORR), defined as the percentage of patients with CR or PR response according to RECIST
    • PFS, defined as the time between the date of the first infusion and the date of disease progression defined as per RECIST or death of any cause.
    • PFS6, defined as the percentage of patients remaining alive and progression free at six months from first infusion as per RECIST.
    • Clinical benefit, defined as the percentage of patients with CR, PR or SD according to RECIST. Correlation of clinical benefit and the JNK status of the patients, as assessed by IHC, will be performed.
    • OS, defined as the time from first infusion to death (of any cause).
    -Safety profile:
    • Treatment safety (AEs, SAEs and laboratory abnormalities) graded according to the NCI-CTCAE version 3.0 (25).
    • PGx 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 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 Yes
    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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E. 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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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 Information not present in EudraCT
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 Information not present in EudraCT
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 37
    F.4.2.2In the whole clinical trial 37
    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 Decision2009-06-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-06-15
    P. End of Trial
    P.End of Trial StatusOngoing
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