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    Summary
    EudraCT Number:2004-001118-15
    Sponsor's Protocol Code Number:APL-B-005-02
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-03-31
    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 number2004-001118-15
    A.3Full title of the trial
    Phase II multicenter,open-label, clinical and pharmacokinetic study of Aplidin® as a 3-hour infusion every 2 weeks, in patients with advanced or metastatic transitional cell carcinoma of the urothelium, relapsing or progressing after first line chemotherapy
    A.4.1Sponsor's protocol code numberAPL-B-005-02
    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 SponsorPharma Mar, S.A
    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.3.9.2Current sponsor codeAPLD
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCyoctodepsin
    D.3.9.2Current sponsor codeAPLD
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    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
    More than 90% of bladder carcinomas are transitional cell carcinomas (TCC) derived from the uroepithelium. About 6% to 8% are squamous cell carcinomas, and 2% are adenocarcinomas. Adenocarcinomas may be either of urachal origin or of nonurachal origin; the latter type is generally thought to arise from metaplasia of chronically irritated transitional epithelium.
    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® administered as a 3 h iv infusion every 2 weeks, in patients with advanced or metastatic transitional cell carcinoma of the urothelium, relapsing or progressing after first line chemotherapy.
    E.2.2Secondary objectives of the trial
    Evaluation of Pharmacokinetics of this schedule of Aplidin® in this patient population.
    To further investigate the safety profile of Aplidin® given as 3-hour IV infusion every 2 weeks in this patient population.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. Written informed consent obtained from the patient before starting any study-specific procedure. If any patient is unable to give consent, it may be obtained from the patient’s legal representative if in accordance with local laws and regulations.
    2. Transitional cell carcinoma of the urothelium of the bladder, urether or renal pelvis, with the following characteristics:
    · Confirmed pathological diagnosis.
    · Advanced (locally advanced or metastatic) and / or non-resectable disease (surgical exeresis does not eradicate all the macroscopic disease).
    · With documented objective progression according to the RECIST criteria within 6 months prior to registration.
    · Presence of at least one measurable lesion (RECIST). In case of a single measurable lesion, pathological proof of malignancy is mandatory.
    3. One previous line of systemic chemotherapy. All prior therapies should have been finished at least 3 weeks before patient registration.
    4. Prior radiotherapy: a minimum of 4 weeks (8 weeks in case of extensive prior radiotherapy) must have elapsed between the end of the prior radiotherapy and entry into the protocol. Previously irradiated lesions may not be used as indicator lesions unless a new lesion has occurred in a previously irradiated area.
    5. Recovery from any 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
    8. Life expectancy > 3 months.
    9. Adequate renal, hepatic, and bone marrow function (assessed < 14 days before inclusion in the study):
    · Neutrophil count ³ 1.5 x 109/L
    · Platelet count ³ 100 x 109/L
    · Haemoglobin ³ 10 g/dL
    · Creatinine clearance ³ 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 metastases)
    · AST, ALT < 2.5 x ULN (< 5 x ULN in case of liver metastasis).
    · Albumin > 25 g/L
    10. Left ventricular ejection fraction within normal limits.
    E.4Principal exclusion criteria
    1. Prior therapy with Aplidin®.
    2. More than one line of prior systemic chemotherapy.
    3. Pregnant or lactating women; men and women of reproductive potential who are not using effective contraceptive methods.
    If subject is female, she is eligible to enter and participate in this study if she is of:
    a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant); or,
    b. child-bearing potential, has a negative pregnancy test (urine or serum) at screen, and agrees to one of the following:
    · Complete abstinence from intercourse from 2 weeks prior to administration of the study drug, throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the investigational drug (a minimum of 5 plasma half-lifes); or,
    · Female sterilization; or,
    · Sterilization of male partner; or,
    · Implants of levonorgestrel; or,
    · Injectable progestogen; or,
    · Oral contraceptive (combined or progestogen only); 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.
    Subject taking oral contraceptives should have been on a stable regimen for at least 2 months prior to screening

    4. 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.
    5. Known symptomatic cerebral or leptomeningeal involvement.
    6. Other relevant diseases or adverse clinical conditions:
    · Congestive heart failure or angina pectoris, myocardial infarction within 12 months before inclusion in the study.
    · Uncontrolled arterial hypertension (i.e. current arterial diastolic blood pressure over 100 mmHg)
    · 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).
    · Cardiac ventricular arrhythmia.
    · History of significant neurological or psychiatric disorders
    · Active infection.
    · 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)
    · Limitation of the patient’s ability to comply with the treatment or follow-up protocol.
    · 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)
    7. Treatment with any investigational product in the 30 days period before inclusion in the study.
    8. Known hypersensitivity to Aplidin®, mannitol, cremophor EL, or ethanol
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective tumor response (CR or PR) according to RECIST
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Information not present in EudraCT
    E.6.2Prophylaxis Information not present in EudraCT
    E.6.3Therapy Information not present in EudraCT
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence Information not present in EudraCT
    E.6.9Dose response Information not present in EudraCT
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic Information not present in EudraCT
    E.6.12Pharmacoeconomic Information not present in EudraCT
    E.6.13Others Information not present in EudraCT
    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 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) No
    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.8.5The 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
    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 months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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 2005-03-31. 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.3.3.6.1Details of subjects incapable of giving consent
    using effective contraceptive methods
    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 32
    F.4.2.2In the whole clinical trial 32
    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 Opinion2004-07-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-03-20
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