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    Summary
    EudraCT Number:2015-002760-16
    Sponsor's Protocol Code Number:IB2015-04
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-09-04
    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 ConcernedFrance - ANSM
    A.2EudraCT number2015-002760-16
    A.3Full title of the trial
    Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly trabectedin combined with Metronomic Cyclophosphamide in Patients with Advanced Pretreated Soft-tissue Sarcomas. A Phase I/II study from the French Sarcoma Group.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly trabectedin combined with Metronomic Cyclophosphamide in Patients with Advanced Pretreated Soft-tissue Sarcomas. A Phase I/II study from the French Sarcoma Group.
    A.3.2Name or abbreviated title of the trial where available
    Protocol TARMIC
    A.4.1Sponsor's protocol code numberIB2015-04
    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 SponsorINSTITUT BERGONIE
    B.1.3.4CountryFrance
    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 supportPharma Mar S.A.
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportInstitut Bergonié
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINSTITUT BERGONIE
    B.5.2Functional name of contact pointPauline BEAUFRERE
    B.5.3 Address:
    B.5.3.1Street Address229 cours de l'Argonne
    B.5.3.2Town/ cityBORDEAUX Cedex
    B.5.3.3Post code33076
    B.5.3.4CountryFrance
    B.5.4Telephone number+33(0)556333270
    B.5.5Fax number+33(0)556333330
    B.5.6E-mailp.beaufrere@bordeaux.unicancer.fr
    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 ENDOXAN
    D.2.1.1.2Name of the Marketing Authorisation holderBAXTER SAS
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 holderPHARMA MAR S.A.
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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.3.9.4EV Substance CodeSUB20756
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    Adult patients with unresectable locally advanced or metastatic soft-tissue
    sarcoma.
    E.1.1.1Medical condition in easily understood language
    Adult patients with unresectable locally advanced or metastatic soft-tissue
    sarcoma.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10039494
    E.1.2Term Sarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I:
    To establish the recommended phase II dose (RP2D), the maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28), the safety profile, and the dose limiting toxicities (DLT) of trabectedin given in combination with cyclophosphamide (CP).

    Phase II:
    To evaluate the antitumor activity of trabectedin in association with CP in terms of non-progression at 6 months (complete or partial responses or stable disease more than 24 weeks, as per RECIST v1.1 criteria) after centralized radiological review, in patients with advanced STS who already failed anthracycline-containing chemotherapy (CT).
    E.2.2Secondary objectives of the trial
    Phase I:
    · To evaluate preliminary signs of antitumor activity of trabectedin given in combination with CP in terms of objective response under treatment (as per RECIST v1.1 criteria), 6-month non-progression, 1-year progression-free survival (PFS) and 1-year overall survival (OS).
    · To describe the pharmacokinetics (PK) of trabectedin given in combination with CP.
    · Biomarker study: To perform pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers in blood at baseline and different study time points).

    Phase II:
    · To evaluate the antitumor activity of trabectedin in association with CP in terms of objective response under treatment (as per RECIST v1.1 criteria), 1- year progression free survival (PFS) and 1-year overall survival (OS).
    · To evaluate the toxicity of trabectedin in association with CP (NCI-CTC v4).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic, pharmacodynamic and biomarkers studies
    E.3Principal inclusion criteria
    1. Patients with soft-tissue sarcoma histologically confirmed by central review (Pr. Coindre team), except in case of diagnosis was already confirmed by the RRePS Network,
    2. Metastatic or unresectable locally advanced disease,
    3. Age ≥ 18 years,
    4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2,
    5. Life expectancy > 3 months,
    6. Measurable disease according to RECIST v1.1 outside any previously irradiated field,
    7. For patients included in phase II study, progressive disease according to RECIST v1.1 criteria diagnosed on the basis of two CT scan or MRI obtained at an interval less than 6 months in the period of 12 months prior to inclusion and confirmed by central review,
    8. Previous use of Anthracyclines,
    9. Have provided tissue from an archival tissue sample,
    10. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
    11. Adequate hematological, renal, metabolic and hepatic function: a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l, and platelet count ≥ 100 x 109/l
    b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive liver involvement) and alkaline phosphatase (AP) ≤ 2.5 x ULN
    c. Total bilirubin ≤ ULN.
    d. Albumin ≥ 25 g/l
    e. Serum Creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft formula).
    f. Creatine Phosphokinase (CPK) ≤ 2.5 x ULN
    12. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier,
    13. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
    14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0),
    15. Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code),
    16. Voluntarily signed and dated written informed consent prior to any study specific procedure.
    E.4Principal exclusion criteria
    1. Previous treatment with Trabectedin,
    2. Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] HIV1, HIV2, hepatitis B or hepatitis C infections,
    3. History of chronic alcohol use and/or cirrhosis,
    4. The following unstable cardiac conditions are not allowed:
    - Congestive heart failure
    - Angina pectoris
    - Myocardial infarction within 1 year before registration
    - Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mmHg despite optimal medical therapy
    - Arrhythmias clinically significant
    5. Patients unable to receive corticotherapy,
    6. Known central nervous system malignancy (CNS),
    7. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
    8. Participation to a study involving a medical or therapeutic intervention in the last 30 days,
    9. Previous enrolment in the present study,
    10. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
    11. Known hypersensitivity to any involved study drug or any of its formulation components.
    12. Recent vaccination (in the last 2 weeks before inclusion) for yellow fever.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I trial:
    · Toxicity graded using the common toxicity criteria from the NCI v4.0
    · Incidence rate of DLT at each dose level on cycle 1

    Phase II trial:
    · 6-month non-progression as defined above for the phase I escalation study
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I trial:
    - Toxicity is assessed as long as patient is under treatment
    - Incidence rate of DLT is assessed during the first 28 days of treatment, for each patient

    Phase II trial:
    - 6-months non-progression is assessed 6 months after the beginning of treatment
    E.5.2Secondary end point(s)
    Phase I trial:
    · 6-month non-progression defined as CR, PR or stable disease more than 24 weeks according to RECIST v1.1 criteria.
    · 1-year Overall Survival (OS) defined as the time from study treatment initiation to death (of any cause).
    · 1-year Progression-Free Survival (PFS) defined as the time from study treatment initiation to disease progression (defined as per RECIST v1.1) or death (of any cause), whichever occurs first.
    · PK measurements expressed as the AUC, the half-life of trabectedin, CP and concentration peak.
    · Pharmacodynamic study:
    Blood: Serum/plasma cytokines levels (INFγ, TNFα, IL2,4,6,10) by ELISA ; Serum/plasma VEGF and TPS-1 levels by ELISA, monocytes, Treg, CD4+, CD8+ and DR lymphocytes subpopulations monitoring, CD4+/CD8+ ratio (Flow Cytometry),
    Tumor: Fresh pre-treatment and on-treatment tumor biopsies will be collected to assess pharmacodynamics changes of TAM infiltration and additional tumor markers. Frozen biopsy samples will be analyzed for:
    - Hematoxylin and eosin staining (H&E).
    - Immunohistochemistry (IHC) assessments include, but are not limited to the following markers: CSF-1R, CD68/CD163, CD68/MHC class II, CD31 (microvessel density), Ki67 and other exploratory markers. The analysis will be prioritized based on the amount of material available.

    Phase II trial:
    Toxicity, objective response under treatment, 1-year OS and 1-year PFS defined above for the phase I escalation study except for the PD study which is optional in this phase II trial.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I trial:
    -Objective response under treatment: from treatment initiation until the end of treatment
    -6-months non-progression: 6 months after the beginning of treatment
    -1-year OS and 1-year PFS: 1 year after treatment initiation
    -AUC, half-life of trabectedine, CP and trabectedine concentration peak: from samples collected on Days 1 and 15 of cycle 1
    -Blood samples markers levels (pharmacodynamics study): from samples collected at baseline, and on Days 1 of cycles 1 and 2
    -Tumor markers: from tumor biopsies obtained at baseline and at Cycle 1 day 28

    Phase II trial:
    -Toxicity: as long as patient is under treatment
    -Objective response under treatment: as patient is under treatment
    -1-year OS and 1-year PFS: 1 year after treatment initiation
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers study
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation
    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.8.1.7.1Other trial design description
    dose level
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    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 No
    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
    LVLS
    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 months
    E.8.9.1In the Member State concerned days
    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.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 11
    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 state71
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    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 Decision2015-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-30
    P. End of Trial
    P.End of Trial StatusOngoing
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