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    Summary
    EudraCT Number:2008-008922-55
    Sponsor's Protocol Code Number:GEIS20
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2010-03-04
    Trial 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 ConcernedPortugal - INFARMED
    A.2EudraCT number2008-008922-55
    A.3Full title of the trial
    RANDOMIZED, OPEN, MULTICENTER, PROSPECTIVE, PHASE II CLINICAL TRIAL OF DOXORUBICIN vs. TRABECTEDIN PLUS DOXORUBICIN IN THE FIRST LINE TREATMENT OF PATIENTS WITH ADVANCED NON OPERABLE AND/OR METASTATIC SOFT TISSUE SARCOMAS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NOT APPLICABLE
    A.4.1Sponsor's protocol code numberGEIS20
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGrupo Español de Investigación en Sarcomas
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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.2.5The 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 nameTrabectedin
    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 INNTRABECTEDIN
    D.3.9.1CAS number 114899-77-3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 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.2.5The 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 nameDoxorubicin
    D.3.2Product code Doxorubicin
    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.3.9.2Current sponsor codeadriamycin
    D.3.9.3Other descriptive namedoxorubicin
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.4
    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 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.2.5The 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 nameDoxorubicin
    D.3.2Product code Doxorubicin
    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.3.9.2Current sponsor codeADRIAMICYN
    D.3.9.3Other descriptive nameDOXORUBICIN
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.4
    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
    NON OPERABLE AND/OR METASTATIC SOFT TISSUE SARCOMAS
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    E.1.2Level HLGT
    E.1.2Classification code 10041299
    E.1.2Term Soft tissue sarcomas
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of the combination of trabectedin and doxorubicin in comparison with doxorubicin alone in patients with advanced non operable and/or metastatic Soft Tissue Sarcomas (STS). To this end, progression free survival will be compared between both groups of treatment.
    E.2.2Secondary objectives of the trial
    - To determine activity by means of RECIST objective responses in both study arms, trabectedin/doxorubicin combination and the control arm.
    - To determine the tumor control (response rates plus stabilizations) in both arms of treatment.
    - Overall survival.
    - To determine activity by tissue changes applying the Choi criteria to STS (see radiological review sub study).
    - To determine toxicity of trabectedin/doxorubicin combination and the control arm.
    - To determine protein and mRNA expression of genes possibly involved in a potential profile of more favorable response or resistance to study drugs and to analyze the prognostic impact of them on predefined efficacy parameters (see translational sub study).
    - To evaluate genomic instability, as well as protein expression that could influence response/resistance to the study drugs and make a correlation with efficacy endpoints.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    I) Protein expression study:
    Identify and quantify by TMA (see procedure) from paraffin-embedded STS tumor tissue predictive factors of response to treatment with doxorubicin plus/minus trabectedin.
    II) Microsatellite instability analysis:
    -Evaluate the incidence of genetic instability in tumors from patients included in the trial, taking into account 18 MSI and EMAST markers.
    -Analyze the protein expression of the main proteins involved in DNA repair machinery: MLH1, MSH2, MSH6 y PMS2 associated with MDMSI; and p53, associated with EMAST.
    - Correlate genetic instability with response to doxorubicin and doxorubicin plus trabectedin.
    -Correlate genetic instability and PFS.
    III) DNA repair genes analysis:
    - Validate the molecular sensitivity signature (low BRCA1, high XPG or ERCC1 expression) obtained in the retrospective study of advanced sarcoma patients treated with trabectedin monotherapy. In this case, the correlation of these markers with clinical response to the combined treatment with doxorubicin-trabectedin will be studied, using as a control patients treated with doxorubicin alone.
    - Analyze the XPG Asp1104Hi polymorphism in blood samples (genotype) and in tumor samples (somatic mutations) to establish their correlation with response to trabectedin.
    - Correlate the molecular and genetic signature with PFS.
    E.3Principal inclusion criteria
    The patient must sign voluntarily the informed consent
    Aged between 18 and 70.

    - Pathological diagnosis of non operable and/or metastatic soft tissue sarcoma.

    - The following histological subtypes can be included:

    • Undifferentiated pleomorphic sarcoma (previously, malignant fibrous histiocytoma)
    • Leiomyosarcoma
    • Angiosarcoma/ epithelial hemangioendothelioma
    • Liposarcoma and its variants (well differentiated, dedifferentiated, myxoid/round cells, pleomorphic)
    • Synovial sarcoma
    • Fibrosarcoma and its variants ( epithelial fibrosarcoma/low grade fibromyxoid sarcoma)
    • Hemangiopericytoma/solitary fibroid tumor
    • Neurogenic sarcoma (Malignant peripheral nerve sheath tumor (MPNST))
    • Mixofibrosarcoma
    • Epithelioid Sarcoma
    • Unclassified sarcoma (spindle cell/epithelioid/pleomorphic/myxoid)

    - Measurable disease, according to RECIST criteria

    - Performance status 0-1 (ECOG).

    - Adequate bone marrow function (hemoglobin > 10 g/dL, leukocytes ≥ 3.000/mm3, neutrophils ≥ 1.500/mm3, platelets ≥ 100.000/mm3). Patients with plasma creatinine ≤ 1,6 mg/dL, transaminases ≤ 2.5 times the UNL, total bilirubin ≤ UNL, CPK ≤ 2.5 times UNL, alkaline phosphatase ≤ 2.5 times the UNL are acceptable. If the increase of alkaline phosphatase is > 2.5 times the UNL, then the alkaline phosphatase liver fraction and/or 5’ nucleotidase and/or GGT must be ≤ UNL.

    - Men or women of child bearing potential should be using an effective method of contraception before entry into the study and throughout the same and for 6 months after ending the study. Women of childbearing potential must have a negative urine pregnancy test before study entry.

    - Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.

    - It should be performed HBV and HCV serologies prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators' discretion the preventive treatment with lamivudine. If the patient is HCV+ it could be included in the study if there are no changes in transaminases values at investigators' discretion.
    E.4Principal exclusion criteria
    Patients presenting with any of the following criteria cannot be included in the study:

    - Previous chemotherapy treatment.

    - Previous radiotherapy involving the only localization(s) of measurable tumoral disease.

    - Performance status ≥ 2 (ECOG).

    - CNS metastases.

    - Plasma bilirubin > UNL.

    - Creatinine > 1.6 mg/dL.

    - History of other neoplastic disease with the exception of basalioma or in situ cervical cancer adequately treated.

    - Significant cardiovascular disease (for example, dyspnea > 2 NYHA)

    - Significant systemic diseases grade 3 or higher on the NCI-CTC version 3.0 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity.

    - Uncontrolled bacterial, mycotic or viral infections.

    - Known positive test for infection by human immunodeficiency virus (HIV)
    - Women who are pregnant or breast-feeding

    - Psychological, familial, social or geographic circumstances that limit the patient’s ability to comply with the protocol or informed consent.

    - Patients participating in another clinical trial or receiving any other investigational product.
    Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.

    - The following histologic subtypes are excluded:
    - Rhabdomyosarcoma
    -Ewing’s family of tumors
    - Desmoplastic small round cell tumor
    - Clear cell sarcoma
    - Alveolar sarcoma
    E.5 End points
    E.5.1Primary end point(s)
    PFS: Progression free survival
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) No
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA27
    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 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
    The study will be considered closed from a normative point of view after the data on overall survival is sufficiently prepared for its initial publication. The follow-up observations of the patients included in the trial can be maintained indefinitely.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Man of childbearing potential using contraception
    F.4 Planned number of subjects to be included
    F.4.1In the member state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 182
    F.4.2.2In the whole clinical trial 182
    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 Decision2010-09-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-08-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-04-12
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