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    Summary
    EudraCT Number:2004-002692-16
    Sponsor's Protocol Code Number:APL-B-012-02
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2005-03-30
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2004-002692-16
    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 Indolent Non-Hodgkin’s Lymphoid Neoplasms.
    A.4.1Sponsor's protocol code numberAPL-B-012-02
    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 SponsorPharmaMar SA unipersonal
    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 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 nameAplidin
    D.3.2Product code APLD
    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 INNCyoctodepsin
    D.3.9.1CAS number 137219-37-5
    D.3.9.2Current sponsor codeAPLD
    D.3.9.3Other descriptive nameAplidine
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.3Concentration number0.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCyoctodepsin
    D.3.9.1CAS number 137219-37-5
    D.3.9.2Current sponsor codeAPLD
    D.3.9.3Other descriptive nameAplidin
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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
    Non-Hodgkin’s Lymphomas (NHLs) relapsing or refractory
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    · To assess the anti-tumor activity of Aplidin® given as a 1-hour weekly IV infusion, in patients with Indolent non-Hodgkin’s Lymphoid neoplasm, 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 indolent non-Hodgkin’s Lymphoid neoplasm (NHL).
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. Written informed consent obtained before starting any study-specific procedure..
    2. Histologically confirmed indolent lymphoid neoplasms, including the following:
    2.1. Mature (peripheral) B-cell neoplasms
    · B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
    · B-cell prolymphocytic leukemia
    · Lymphoplasmacytic lymphoma
    · Splenic marginal zone B-cell lymphoma (1/2 villous lymphocytes)
    · Hairy cell leukemia
    · Extranodal marginal zone B-cell lymphoma of MALT type
    · Nodal marginal zone B-cell lymphoma (1/2 monocytoid B cells)
    · Follicular lymphoma (except large cell)
    · Mantle-cell lymphoma (except diffuse pattern or blastoid variant)
    2.2 Mature (peripheral) T-cell neoplasms
    · T-cell prolymphocytic leukemia
    · T-cell granular lymphocytic leukemia
    · Mycosis fungoides/Sezary syndrome
    3. The lymphoproliferative malignancy either relapses following a response to standard or high-dose chemotherapy , or is refractory to previous chemotherapy and there is a clinical need to start a new chemotherapy.
    3.1. Relapsed disease is defined as development of any of the following after a prior response of at least 6 months duration:
    · Lymphadenopathy
    · Splenomegaly
    · Malignant lymphocytosis greater than 5000 x 109/L
    · Infiltration of the bone marrow with malignant lymphocytes
    3.2. Refractory disease
    · No partial response (PR) to prior therapy OR
    · Complete response or PR of less than 6 months duration
    4. Disease is measurable: existence of a bidimensional lesion greater than 2 cm in its longer diameter or malignant lymphocytosis greater than 5000 x 109/L
    5. Recovery from any non-hematological toxicity derived from previous treatments. The presence of alopecia and NCI-CTC grade < 2 symptomatic peripheral neuropathy is allowed.
    6. Age > 18 years.
    7. Performance status (ECOG) < 2 (Appendix 4)
    8. Adequate renal, hepatic, and bone marrow function (assessed < 14 days before inclusion in the study):
    8.1. Neutrophil count ³ 1.5 x 109/L
    8.2. Platelet count ³ 100 x 109/L
    8.3. Haemoglobin ³ 8.0 g/dL
    8.4. Creatinine clearance ³ 40 ml/min (calculated from the Cockcroft and Gault formula, Appendix 5)
    8.5. Serum bilirubin * 1.5 mg/dL and alkaline phosphatase * 2.5 x ULN (< 5 x ULN in case of extensive bone metastases)
    8.6. AST, ALT < 2.5 x ULN (< 5 x ULN in case of liver metastasis).
    8.7. Albumin > 25 g/L
    9. 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. Aggressive histological conversion.
    4. HIV-associated lymphoma
    5. CNS lymphoma
    6. More than five previous lines of systemic biological agents or chemotherapies.
    7. Prior gene therapy with viral vectors.
    8. Wash-out periods since the end of the precedent therapy less than:
    8.1. 6 weeks for nitroso-urea or high dose chemotherapy
    8.2. 4 weeks for other chemotherapies or biological agents
    8.3. 4 weeks for radiation or radionuclide therapy (6 weeks in case of prior extensive external beam radiation (more than 25% of bone marrow distribution).
    8.4. 4 weeks for major prior surgery
    8.5. 30 days for any investigational product
    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):
    10.1. 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,
    10.2. Patient or patient’s partner physical sterilization; or,
    10.3. 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:
    11.1. Non-melanoma skin cancer
    11.2. Carcinoma in situ of any site
    11.3. Any other cancer curatively treated and no evidence of disease for at least 10 years.
    12. Known symptomatic cerebral or leptomeningeal involvement.
    13. Other relevant diseases or adverse clinical conditions:
    13.1. Congestive heart failure or angina pectoris, myocardial infarction within 12 months before inclusion in the study.
    13.2. Uncontrolled arterial hypertension (i.e. current arterial diastolic blood pressure over 100 mmHg).
    13.3. Uncontrolled cardiac supraventricular arrhythmias (i.e. requiring a change in medication within the last 3 months or a hospital admission within the past 6 months).
    13.4. Cardiac ventricular arrhythmia.
    13.5. History of significant neurological or psychiatric disorders
    13.6. Active infection; infection by HIV, HBV or HCV
    13.7. 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)
    13.8. Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis)
    13.9. 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/nPR)
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    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) Information not present in EudraCT
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    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 Information not present in EudraCT
    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 follow up period will be closed 2 years after the last-treatment visit of the last patient
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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 Information not present in EudraCT
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-03-30. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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 Decision2004-10-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2004-06-24
    P. End of Trial
    P.End of Trial StatusOngoing
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