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    The EU Clinical Trials Register currently displays   37236   clinical trials with a EudraCT protocol, of which   6125   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2004-001117-34
    Sponsor's Protocol Code Number:APL-B-013-02
    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:2009-02-20
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2004-001117-34
    A.3Full title of the trial
    A Phase II Multicenter,Open-Label, Clinical And Pharmacokinetic Study Of Aplidin As A 1-Hour Weekly IV Infusion, In Patients With Relapsed Or Refractory aggressive non-Hodgkin’s Lymphoma.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAPL-B-013-02
    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.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 Concentrate 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.3.9.1CAS 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 Yes
    D. medicinal product typedepsipetide 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
    Aggressive non-Hodgkin’s Lymphoma.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level HLGT
    E.1.2Classification code 10025321
    E.1.2Term Lymphomas non-Hodgkin's T-cell
    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 anti-tumour activity of Aplidin given as a 1-hour weekly IV infusion, in patients with aggressive non-Hodgkin’s Lymphoma, relapsing or refractory to a prior therapy.
    E.2.2Secondary objectives of the trial
    To further investigate the safety profile of Aplidin given as 1-hour weekly IV infusion in this patient population. To obtain additional pharmacokinetic information for Aplidin given as 1-hour weekly IV infusion in patients with aggressive non-Hodgkin’s Lymphoma.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    ALTRI SOTTOSTUDI: Farmacogenomica

    E.3Principal inclusion criteria
    1. Written informed consent obtained before starting any study-specific procedure. 2. Histologically confirmed aggressive lymphomas, including the following: 2.1 B-Cell neoplasms. 2.1.1 Precursor B-cell neoplasm Precursor B-lymphoblastic lymphoma 2.1.2 Mature (peripheral) B-cell neoplasms 1 Follicular lymphoma (histologic conversion) 2 Mantle-cell lymphoma (diffuse pattern or blastic variant) 3 Diffuse large B-cell lymphoma 4 Mediastinal large B-cell lymphoma 5 Burkitt’s lymphoma/Burkitt cell leukemia 2.2 T-cell and NK-cell neoplasms 2.2.1 Precursor T-cell neoplasm Precursor T-lymphoblastic lymphoma 2.2.2 Mature (peripheral) T-cell neoplasms Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia (HTLV1) Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type Peripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, T/null cell, primary systemic type 3. Patient requires treatment because NHL relapses following a response to standard chemotherapy or high dose chemotherapy + stem cell transplantation , or NHL is refractory (i.e. failure to achieve al least CR, PR or SD) to its more recent chemotherapy. 4. Prior autologous and/or allogeneic stem cell transplantation is allowed. In case of allogeneic hematopoietic stem cell transplantation (HSCT), patient has to be off immunosuppressive agents before he can enrolled. 5. Disease is measurable: existence of a bidimensional lesion greater than 2 cm in its longer diameter or malignant lymphocytosis greater than 5 x 10^9/L. Any other procedure for measurable disease in particular cases, could be allowed upon Pharma Mar’s approval. 6. Recovery from any non-hematological toxicity derived from previous treatments. The presence of alopecia and NCI-CTC grade < 2 symptomatic peripheral neuropathy is allowed. 7. Age >/= 18 years. 8. Performance status (ECOG) </= 2 (Appendix 2) 9. Adequate renal, hepatic, and bone marrow function (assessed </= 14 days before inclusion in the study): Neutrophil count >/= 1.5 x 10^9/L Platelet count >/= 100 x 10^9/L Haemoglobin >/= 8.0 g/dL Creatinine clearance >/= 40 ml/min (calculated from the Cockcroft and Gault formula, Appendix 3) Serum bilirubin </= 1.5 mg/dL and alkaline phosphatase </= 2.5 x ULN (</= 5 x ULN in case of extensive bone involvement) AST, ALT </= 2.5 x ULN (</= 5 x ULN in case of liver involvement). Albumin >/= 25 g/L. Lower haematological values due to bone marrow infiltration could be accepted upon Pharma Mar’s approval after clinical discussion between Pharma Mar and the Investigator. 10. Left ventricular ejection fraction within normal limits.
    E.4Principal exclusion criteria
    1. Prior therapy with Aplidin. 2. Concomitant therapy with any anti-lymphoproliferative agent, including glucocorticoids at a daily dose greater than 10 mg prednisone or equivalent, except when they were indicated for symptom control and disease progression was documented while on esteroids. 3. Acute lymphoblastic leukemia. 4. CNS lymphoma. 5. HIV-associated lymphoma. 6. Prior gene therapy with viral vectors. 7. More than three previous lines of systemic biological agents or chemotherapies. (Bone marrow or stem cell transplantation as consolidation therapy of a previous response is understood as one line of chemotherapy). 8. Wash-out periods since the end of the precedent therapy less than: 6 weeks for nitroso-urea or high dose chemotherapy. 3 weeks for other chemotherapies or biological agents. 4 weeks for radiation or radionuclide therapy (6 weeks in case of prior extensive external beam radiation (more than 25% of bone marrow distribution). 4 weeks for major prior surgery. 30 days for any investigational product. 4 weeks for immunosuppressive therapy after allogeneic hematopoietic stem cell transplantation. 9. Pregnant or lactating women. 10. Men and women of reproductive potential who are not using effective contraceptive methods (one or more of the following): Complete abstinence from intercourse from 2 weeks prior to administration of the study drug, throughout the study, and for at least 6 months after completion or premature discontinuation from the study to account for elimination of the investigational drug; or, Patient or patient’s partner physical sterilization; or, One of the following, for female patients or female partner of male patients: Implants of levonorgestrel; or, Injectable progestogen; or, Oral contraceptive (combined or progestogen only; subject taking oral contraceptives should have been on a stable regimen for at least 2 months prior to screening),or, Any intrauterine device (IUD) with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criterion); or, Double barrier method (2 physical barriers or 1 physical barrier plus spermicide); or, Any other method with published data showing that the lowest expected failure rate for that method is less than 1% per year. 11. History of another neoplastic disease. The exceptions are: Non-melanoma skin cancer Carcinoma in situ of any site Any other cancer curatively treated and no evidence of disease for at least 10 years. 12. Known cerebral or leptomeningeal involvement. 13. Other relevant diseases or adverse clinical conditions: History or presence of unstable angina, myocardial infarction, valvular heart disease or congestive heart failure. Previous mediastinal radiotherapy. Uncontrolled arterial hypertension despite optimal medical therapy. Previous treatment with doxorubicin at cumulative doses in excess of 400 mg/m2. Symptomatic arrhythmia requiring treatment. Abnormal ECG (see Appendix 6). History of significant neurological or psychiatric disorders Active infection; infection by HIV, HBV or HCV o Myopathy or any clinical situation that causes significant and persistent elevation of CK (>2.5 ULN in two different determinations performed with one week appart) Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis) Uncontrolled endocrine diseases (e.g. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months). 14. Treatment with any investigational product in the 30 days period before inclusion in the study. 15. Known hypersensitivity to Aplidin, mannitol, cremophor EL, or ethanol 16. Limitation of the patient’s ability to comply with the treatment or follow-up protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate (CR/CRu+PR)
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Sopravvivenza, tossicita`
    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. 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 Yes
    E. trial design description
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    6 mesi dopo l’ultima visita di trattamento per l’ultimo paziente in terapia (Follow-up massimo per lo studio)
    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 months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months4
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 56
    F.4.2.2In the whole clinical trial 58
    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 Decision2008-11-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-09-29
    P. End of Trial
    P.End of Trial StatusCompleted
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