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    Summary
    EudraCT Number:2011-001474-25
    Sponsor's Protocol Code Number:SVM9122
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2011-09-20
    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 number2011-001474-25
    A.3Full title of the trial
    A single-centre, single arm, open-label, exploratory trial of Interleukin-2 administered subcutaneously as neo-adjuvant treatment prior to sentinel lymph node biopsy(SLNB)/complete lymph node dissection (CLND) in subjects with stage III malignant melanoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Subcutaneous administration of Interleukin-2 prior to surgical intervention in case of sonographically and cytologically involved sentinel node
    A.3.2Name or abbreviated title of the trial where available
    IL-2 s.c. in sentinel node positive Melanoma patients
    A.4.1Sponsor's protocol code numberSVM9122
    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 SponsorKlinik für Dermatologie, Venerologie und Allergologie; Charité - Universitätsmedizin Berlin
    B.1.3.4CountryGermany
    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 supportAG Voit (Research fund, administered by Prof. Christiane Voit)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité - Universitätsmedizin Berlin
    B.5.2Functional name of contact pointHauttumorcentrum
    B.5.3 Address:
    B.5.3.1Street AddressCharitéplatz 1
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code10117
    B.5.3.4CountryGermany
    B.5.4Telephone number0049(0)30450-518075
    B.5.5Fax number0049(0)30450-518967
    B.5.6E-mailschaefer-hesterberg@charite.de
    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 Proleukin
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    The trial is planned in a neo-adjuvant setting for a 4-weeks period in Melanoma patients with stage III. The stage is to be discovered by ultrasound and veriefied by fine needle punctere and cytology.
    E.1.1.1Medical condition in easily understood language
    Involvement/metastasis of the draining lymph node/s with cells of the malignant melanoma (skin cancer).
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the complete response rate of the SLNB/CLND specimens, as assessed by histopathology in subjects with stage III malignant melanoma measured after 4 weeks of local neo-adjuvant treatment with IL-2.
    E.2.2Secondary objectives of the trial
    *To describe immune modulating effects of IL-2 within the tumour draining lymph nodes and peripheral blood:
    -- morphological and functional changes of lymph nodes assessed by ultrasound
    --Comparing fine needle aspirates in the affected lymph nodes before and after IL-2 treatment (qRT-PCR) of a selected panel of genes specific for T cells, B cells, NK cells as well as various cytokines, effector molecules, chemokines and receptors
    --relative frequency of cells staining for markers of T cells, B cells, NK cells and dendritic cells in the resected lymph nodes as measured by immuno-histo chemistry (IHC) staining
    --Relative frequency of absolute numbers of blood cells (incl. T cell subtypes and B cells) as measured by flow cytometry of peripheral mononuclear blood cells (PBMC)
    --Describing levels of soluble CD25 and other serum markers
    **To describe the safety of local neo-adjuvant subcutaneous IL-2 administration
    ***To estimating relapse free survival
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria
    1. Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject.)
    2. Confirmed (by histology of the primary and FNAC/cytology of the involved lymph node) stage III malignant melanoma according to the American Joint Committee on Cancer (AJCC 2009) within the following classification:
    a. T1-4b
    b. N1-3 (assessed by high resolution ultrasound and FNAC)
    c. M0
    3. At least one lymph node with only partially malignant involvement as assessed by ultrasound
    4. 18 years of age or above
    5. ECOG performance status of 0 or 1
    6. Hematology:
    a. White blood cell (WBC) ≥ 2.5 x 109/L
    b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    c. Platelet count ≥ 100 x 109/L
    d. Hemoglobin ≥ 100 g/L
    7. Serum-creatinine ≤ 1.8 mg/dL
    8. Liver function:
    a. ALT and Alkaline Phosphatase ≤ 2.5 x upper limit of normal (ULN)
    b. LDH ≤ 2 x ULN
    E.4Principal exclusion criteria
    Exclusion criteria
    1. Known or suspected allergy to trial product(s) or related products
    2. Any contraindication as listed in the product label for IL-2 (Proleukin®, Aldesleukin)
    3. Previous participation in this trial. (Participation is defined as screening)
    4. Any signs of stage IV disease according to AJCC 2009 as assessed by routine radiographic staging5. Prior wide excision of the primary lesion, which in the opinion of the investigator may alter lymphatic flow to the sentinel lymph nodes
    6. Bulky lymph nodes metastases, which in the opinion of the investigator may completely obstruct lymphatic flow to the regional lymph nodes, as assessed by ultrasound
    7. Clinically significant infection in the area of the primary tumour
    8. Documented positive serologic testing for hepatitis B or C
    9. History of or active presence of auto-immune diseases (except vitiligo and treated pernicious anemia)
    10. History of any other active malignancy incl. ocular malignant melanoma (except basal cell carcinoma of the skin and cervical cancer in situ) within 5 years of enrolment
    11. Cardiac disease within the last 12 months defined as:
    a) decompensated heart failure (New York Heart Association (NYHA) class III or IV)
    b) unstable angina pectoris
    c) serious arrhythmias
    d) myocardial infarction
    12. Concurrent treatment with systemic corticosteroids or other immunosuppressive drugs (topical or inhaled corticosteroid treatment is permitted)
    13. Known chronic infectious disease including human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) related illness
    14. Any significant systemic disease which according to the Investigator could compromise the safety of the subject or interfere with the trial objectives
    15. Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures are implants, injectables, combined oral contraceptives, hormonal IUD, barrier methods, sexual abstinence or vasectomised partner)
    16. The receipt of any investigational drug within 3 months prior to this trial
    17. Location of the primary lesion where multiple injections of s.c. IL-2 are not feasible
    E.5 End points
    E.5.1Primary end point(s)
    Complete pathological response rate defined as the fraction of subjects observed with complete absence of metastatic deposits in the SLNB/CLND specimens after a 4-week neo-adjuvant IL-2 administration as assessed according to the EORTC Melanoma Group protocol for SLN examination
    E.5.1.1Timepoint(s) of evaluation of this end point
    Following 4 weeks of neo-adjuvant treatment with IL-2
    E.5.2Secondary end point(s)
    •Ultra-sonographic assessments of the relevant lymph nodes
    •Signs of malignant deposits in lymph node specimens
    •Gene expression detected in the FNA by qRT-PCR of relevant genes
    •Immunohistochemical assessment of lymph node specimens
    •Assessment of various proteins detected in serum, including soluble CD25
    •Relapse free survival
    •Incidence and severity of adverse events observed during the trial
    E.5.2.1Timepoint(s) of evaluation of this end point
    Ultrasonography (weeks 1, 2, 3 and 4);
    Signs of malignant deposits (week 4);
    Gene expression in FNA (week 0 and 4);
    IHC (week 4); serum markers (week 1, 2, 3, 4, 5 and 8);
    adverse events (week 1, 2, 3, 4, 5 and 8);
    relapse free survival (up to year 4 after trial)
    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 No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 Information not present in EudraCT
    E.8.1.1Randomised No
    E.8.1.2Open Information not present in EudraCT
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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 No
    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: Initially, 10 subjects will be enrolled in the first stage of the trial.
    --If less than 3 subjects obtain a complete response, no further subjects will be enrolled in the trial.
    End of trial is after completion of neo-adjuvant treatment and a 4 week after-care phase of 10-20 subjects. Furthermore, subjects will be followed for up to 4 years for the assessment of relapse free survival and DMFS.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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 years1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state20
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 20
    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)
    After the final visit, there will be no restrictions for the subjects to receive other treatments according to the clinical judgment of the Investigator. However, all subjects will be followed for up to 4 years after the Final visit or until progression of the disease in order to assess the relapse free survival (RFS). The schedule for follow-up for assessment of RFS will be according to local practice at Charite
    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 Decision2012-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-09-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-12-31
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