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    Summary
    EudraCT Number:2013-000043-78
    Sponsor's Protocol Code Number:CA184-205
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-01-07
    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 ConcernedGermany - PEI
    A.2EudraCT number2013-000043-78
    A.3Full title of the trial
    Prospective randomized trial of an adjuvant therapy of completely resected Merkel Cell Carcinoma (MCC) with immune checkpoint blocking antibodies (Nivolumab, Opdivo®; Ipilimumab, Yervoy®) versus observation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparison of therapy of Merkel Cell Carcinoma (MCC) with Ipilimumab (Yervoy®) or Nivolumab (Opdivo®) versus observation only
    A.3.2Name or abbreviated title of the trial where available
    ADMEC-O
    A.4.1Sponsor's protocol code numberCA184-205
    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 SponsorUniversity of Essen
    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 supportBristol-Myers Squibb
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Essen
    B.5.2Functional name of contact pointDepartement of Dermatology
    B.5.3 Address:
    B.5.3.1Street AddressHufelandstr. 55
    B.5.3.2Town/ cityEssen
    B.5.3.3Post codeD-45122
    B.5.3.4CountryGermany
    B.5.4Telephone number+492017234342
    B.5.5Fax number+492017235935
    B.5.6E-maildirk.schadendorf@uk-essen.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 Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form 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 INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    completely resected Merkel cell carcinoma
    E.1.1.1Medical condition in easily understood language
    Merkel cell carcinoma after surgical removal of the tumor
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064025
    E.1.2Term Merkel cell carcinoma
    E.1.2System Organ Class 100000004864
    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 efficacy of adjuvant nivolumab monotherapy in completely resected MCC patients; i.e. the primary endpoint is disease-free survival (DFS) in arm A at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization compared to DFS in arm B .
    E.2.2Secondary objectives of the trial
    To assess safety and additional efficacy parameters of the nivolumab treatment in MCC, as well as to characterize potential biomarkers; secondary endpoints are:
    (i) Adverse events according to CTCAE, Version 4.0 criteria, that are definitely, probably, or possibly related to the administration of nivolumab
    (ii) Overall survival rate at 12 months, defined as the number of patients surviving at 12 months after randomization divided by the total number of patients randomized.
    (iii) DFS rate at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization divided by the total number of patients randomized
    Explorative Objectives:
    (iv) Disease-free and overall survival and
    (v) Identification and validation of prognostic/predictive biomarkers
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Translational Research Program.
    The biology and the immunology of MCC are only partially understood, thus it appears mandatory to implement a comprehensive translational research program in order to establish the means to identify the group of patients most likely to benefit from therapy. This translational research program will focus on the immune monitoring of the MCC patients treated in the phase II trial, as well as aim at the discovery of predictive and/or surrogate biomarkers for a successful immune therapy of MCC. The randomized design of the study allows distinguishing predictive from prognostic biomarkers. To reach this goal, sampling for translational research studies (tumor tissue, peripheral blood mononuclear cells (PBMC), plasma, serum) will be done as described in the study protocol.
    These studies include:
    - Prognostic/predictive value of the presence of tumor infiltrating lymphocytes in MCC lesions prior to therapy
    - Expression of immune modulatory molecules in the tumor
    - Presence of immune modulatory cells in the tumor
    - Association with MCPyV
    - Detection of circulating free MCC-specific DNS/microRNA in plasma and serum
    E.3Principal inclusion criteria
    1. The patient is willing and able to give written informed consent.
    2. Central histological confirmation of diagnosis of Merkel cell carcinoma (MCC).
    3. All MCC manifestations have been completely resected by surgery within 12 weeks before enrolment.
    4. No currently present metastases (as confirmed by standard imaging studies (e.g. suggested by S2k guidelines).
    5. No previous systemic therapy for MCC.
    6. Required values for initial laboratory tests:
    - WBC ≥ 2000/uL
    - ANC ≥ 1000/uL
    - Platelets ≥ 75 x 103/uL
    - Hemoglobin ≥ 8 g/dL (≥ 80 g/L)
    - Creatinine ≤ 2.0 x ULN
    - AST/ALT ≤ 2.5 x ULN
    - Total Bilirubin ≤ 2.0 x ULN (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
    7. ECOG performance status of 0 or 1.
    8. No active or chronic infection with HIV, Hepatitis B or C.
    9. Men and women, ≥ 18 years of age.
    10. Women of childbearing potential (WOCBP) must be using an adequate method of contraception (Pearl-Index < 1) to avoid pregnancy during treatment phase and for additional 5 months after the last dose of nivolumab, in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of nivolumab.
    11. Men of fathering potential must be using an adequate method of contraception to avoid conception during treatment phase and for additional 7 months after the last dose of nivolumab) in such a manner that the risk of pregnancy is minimized.
    E.4Principal exclusion criteria
    1. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease, are excluded from this study, as are patients with a history of symptomatic disease requiring systemic steroids (e.g., rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus, autoimmune vasculitis); autoimmune motor neuropathy.
    2. Other serious illnesses, e.g., serious infections requiring i.v. antibiotics.
    3. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immune deficient condition.
    4. 4. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of nivolumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
    5. Any non-oncology vaccine therapy for up to 1 month before or after any dose of nivolumab.
    6. A history of prior or current treatment with a T cell potentiating agent (e.g. IL-2, interferon, anti-CTLA-4, anti-CD137, anti-PD1, anti-PD-L1, or anti-OX40 antibody).
    7. Chronic use of immunosuppressive agents or systemic corticosteroids.
    8. Women of childbearing potential (WOCBP), defined above in Section 5.1, who:
    • are unwilling or unable to use an acceptable method of contraception to avoid pregnancy during treatment phase and for additional 5 months after the last dose of investigational product
    • have a positive pregnancy test at baseline
    • are pregnant or breastfeeding.
    9. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
    10. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.
    11. Men of reproductive potential unwilling to use an adequate method to avoid pregnancy during treatment phase and for additional 7 months after the last dose of investigational product.
    12. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment.
    E.5 End points
    E.5.1Primary end point(s)
    the primary endpoint is disease-free survival (DFS) in arm A at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization compared to DFS in arm B .
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 12 month after randomization
    E.5.2Secondary end point(s)
    (i) Adverse events according to CTCAE, Version 4.0 criteria, that are definitely, probably, or possibly related to the administration of nivolumab
    (ii) Overall survival rate at 12 months, defined as the number of patients surviving at 12 months after randomization divided by the total number of patients randomized.
    (iii) DFS rate at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization divided by the total number of patients randomized
    Explorative Objectives:
    (iv) Disease-free and overall survival and
    (v) Identification and validation of prognostic/predictive biomarkers
    E.5.2.1Timepoint(s) of evaluation of this end point
    at 12 month after randomization
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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 No
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned20
    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
    2 years post LPFV (last patient first visit). First visit of the patient is defined as date of first infusion (treatment arm) or date of randomization (observation arm)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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.1.2.1Number of subjects for this age range: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 155
    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 state190
    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 finishing or discontinuing the participation in the trial patients will be treated according to the current german guidelines for treatment of MCC-patients.
    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 Decision2014-04-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-19
    P. End of Trial
    P.End of Trial StatusOngoing
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