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    Summary
    EudraCT Number:2004-005276-16
    Sponsor's Protocol Code Number:ET743-OVA-301
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-08-10
    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 ConcernedGermany - BfArM
    A.2EudraCT number2004-005276-16
    A.3Full title of the trial
    An open-label multicenter randomized Phase 3 study comparing the combination of DOXIL®/CAELYX® and YONDELIS® with DOXIL®/CAELYX® alone in subjects with advanced relapsed ovarian cancer.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberET743-OVA-301
    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 Yes
    D.2.1.1.1Trade name Yondelis
    D.2.1.1.2Name of the Marketing Authorisation holderPharmaMar S.A.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/03/171
    D.3 Description of the IMP
    D.3.1Product nameYONDELIS (trabectedin)
    D.3.2Product code ET-743; R279741; RWJ-680581
    D.3.4Pharmaceutical form Powder for 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.3.8INN - Proposed INNtrabectedin
    D.3.9.1CAS number 114899-77-3
    D.3.9.2Current sponsor codeET-743
    D.3.9.3Other descriptive nameEcteinascidin 743
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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.IMP: 2
    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 Yes
    D.2.1.1.1Trade name Yondelis
    D.2.1.1.2Name of the Marketing Authorisation holderPharmaMar S.A
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/03/171
    D.3 Description of the IMP
    D.3.1Product nameYONDELIS (trabectedin)
    D.3.2Product code ET-743; R279741; RWJ-680581
    D.3.4Pharmaceutical form Powder for 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.3.8INN - Proposed INNtrabectedin
    D.3.9.1CAS number 114899-77-3
    D.3.9.2Current sponsor codeET-743
    D.3.9.3Other descriptive nameEcteinascidin 743
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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.IMP: 3
    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 Caelyx 2 mg/ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderSchering-Plough
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCAELYX
    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.3.8INN - Proposed INNdoxorubicin hydrochloride
    D.3.9.1CAS number 25316-40-9
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.0
    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
    Advanced relapsed ovarian cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10033130
    E.1.2Term Ovarian cancer NOS
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to demonstrate that the combination of YONDELIS + DOXIL improves progression-free survival (PFS) compared with DOXIL alone in the management of ovarian cancer in second-line therapy.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to compare overall survival (OS), demonstrate an increase of overall response rate (ORR), and to compare the safety profiles of the combination therapy and monotherapy with DOXIL alone. The pharmacokinetics of DOXIL and YONDELIS in each treatment arm will be characterized.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenomics

    Exploratory evaluation of subject pharmacogenomic profiles and hypothesis-generating evaluation of the relationship between circulating tumor cells (CTCs), response to therapy, disease progression, and OS. This will include evaluation of genotypes and gene expression markers that may be related to the metabolism of, the response to or the susceptibility to toxicity of YONDELIS. A subset of the available pharmacogenomic data (training and confirmation sets of subject data) will be used to identify candidate targets. The remaining subset of the data will be used for confirming the impact of the target. These evaluations will be done at selected sites that are able to do the testing in subjects willing and consenting to participate. The exploratory and hypothesisgenerating data will be analyzed and reported separately from the clinical study.
    E.3Principal inclusion criteria
    • Female, age 18 or older
    • Histologically proven epithelial ovarian cancer, epithelial fallopian tube cancer, or primary peritoneal cancer
    • Prior treatment with only 1 chemotherapy regimen, including adjuvant therapy, which must be platinum-based and may include sequential maintenance therapy or second look debulking surgery (no gaps in administration of initial therapy may occur other than a delay no longer than 2 months for treatment toxicity).
    • Eastern Cooperative Oncology Group performance status is equal to or less than 2
    • Estimated life expectancy of at least 3 months
    • Recurrence or progression after 6 full cycles of a complete 6 cycle initial treatment regimen or 6 months after the beginning (first dose) of the initial treatment line of platinum-based chemotherapy for ovarian cancer to include
    − Subjects with platinum-resistant disease (platinum-free interval from the end of first-line treatment less than 6 months)
    − Subjects with platinum-sensitive disease (platinum-free interval from the end of first-line treatment equal to or more than 6 months) who are not expected to benefit from or who are ineligible for or who are not willing to receive retreatment with platinum-based chemotherapy
    • Measurable disease that can be evaluated by RECIST guidelines for response or progression or both and documented by radiographic methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scan. Date of radiological evidence is the documented date of progression
    • Must be able to receive dexamethasone or its equivalent
    • Adequate organ function as evidenced by the following peripheral blood
    counts or serum chemistry values within 7 days before randomization:
    hemoglobin ≥9 g/dL
    absolute neutrophil count (ANC) ≥1,500/µL, and
    platelet count ≥100,000/µL
    serum creatinine ≤1.5 mg/dL (≤132.6 µmol/L) or creatinine clearance ≥60 mL/min
    creatine phosphokinase (CPK) ≤upper limit of normal (ULN)
    • Hepatic function variables
    Total bilirubin ≤1.5 ULN, direct bilirubin ≤ULN
    Total alkaline phosphatase (ALP) ≤1.5 ULN, or if >1.5 ULN, then ALP liver fraction or 5’ nucleotidase must be ≤ULN
    AST and ALT must be ≤2.5 × ULN
    • Left ventricular ejection fraction (LVEF) by baseline multigated acquisition (MUGA) scan or 2-d echocardiogram must be within normal limits for the institution (see Section 6.2.2)
    • Adequately recovered from the acute toxicity from any prior treatment
    • Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
    • At investigative sites that are participating in the optional CellSearch, pharmacogenomic, or protein testing portion of this protocol, the subject (or their legally acceptable representative) must sign the informed consent forms for CellSearch enumeration alone, or for additional pharmacogenomic testing, utilizing CellSearch, additional blood or paraffin samples or serum for DNA, mRNA, and protein expression analysis. These informed consent documents will indicate whether or not
    the subject wishes to participate in these parts of the study. Participation in the pharmacogenomics and CellSearch aspects of this study is not mandatory.
    E.4Principal exclusion criteria
    • Subjects treated with more than 1 prior chemotherapy regimen (including adjuvant therapy)
    • Refractory disease, defined as disease progression within 6 months of the beginning (first dose) of the initial line of platinum-based chemotherapy for ovarian cancer
    • Isolated rise in CA-125 without documented radiological evidence of disease progression
    • Prior exposure to anthracyclines for ovarian cancer or to YONDELIS or hypersensitivity to the pharmacologically active substance or to any of the excipients
    • Subjects unwilling or unable to have a central venous catheter, which is required if randomly assigned to treatment with YONDELIS + DOXIL
    • Subjects of child bearing potential not employing adequate contraception, which may include prescription contraceptives (oral, injection, or patch), intrauterine device, double-barrier method or male partner sterilization (not applicable to subjects that are surgically sterile) or subjects who are lactating.
    • Less than 4 weeks from radiation or experimental therapy, less than 2 weeks from last dose of hormonal therapy, or less than 3 weeks from prior chemotherapy or biological therapy.
    • History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 5 years or more
    • Known hypersensitivity to doxorubicin or to excipients in the formulations of either DOXIL or YONDELIS.
    • Known clinically relevant central nervous system metastasis
    • Active viral hepatitis or history of liver disease
    • Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure (Attachment 1), uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities.
    • Any other unstable medical conditions, such as:
    − Uncontrolled diabetes
    − Psychiatric disorder (including dementias) that prevents compliance with protocol
    − Uncontrolled seizures
    − Acute deep vein thrombosis requiring intravenous or subcutaneous therapeutic anticoagulant therapy (chronic coumadin or prophylactic subcutaneous heparin allowed)
    − Active infection.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint, PFS, is defined as the time between the date of randomization and the date of disease progression or death. This analysis will utilize the determination of progression date documented by central review (Section 11.4.5). Subjects who complete the study without disease progression will continue to have tumor assessments every 8 weeks and will be censored at the last tumor assessment before the end of the study.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Information not present in EudraCT
    E.6.8Bioequivalence Information not present in EudraCT
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life relationship between circulating tumor cells (CTCs) and efficacy
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Information not present in EudraCT
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Information not present in EudraCT
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    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 Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Combination of Yondelis with comparator (Caelyx) against comparator alone
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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 No
    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 state69
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 308
    F.4.2.2In the whole clinical trial 650
    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 Decision2006-01-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-12-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-11-12
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