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    EudraCT Number:2009-016631-35
    Sponsor's Protocol Code Number:NCT-2009-11-02-53
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-05-31
    Trial results
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2009-016631-35
    A.3Full title of the trial
    Phase II Trial of Ipilimumab in Patients with advanced melanoma and spontaneous preexisting immune response to NY-ESO-1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ipilimumab bei Patienten mit fortgeschrittenem Malignem Melanom und vorbestehender spontaner Immunantwort gegen NY-ESO-1,
    eine Phase II Studie
    A.3.2Name or abbreviated title of the trial where available
    CTLA-4 NY-ESO-1
    A.4.1Sponsor's protocol code numberNCT-2009-11-02-53
    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 SponsorUniversitätsklinikum Heidelberg
    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.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNCT Heidelberg
    B.5.2Functional name of contact pointPrincipal Investigator
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 460
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.4Telephone number++496221567229
    B.5.5Fax number++496221567225
    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. name Yervoy
    D. 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 nameBMS-734016/MDX-010/Ipilimumab
    D.3.2Product code BMS-734016
    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.3.9.1CAS number 477202-00-9
    D.3.9.2Current sponsor codeBMS-734016
    D.3.9.3Other descriptive nameIPILIMUMAB
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    D. medicinal product typerecombinant, human monoclonal antibody produced in genetically engineered CHO cells
    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
    patients with advanced melanoma and spontaneous preexisting immune response to NY-ESO-1.
    E.1.1.1Medical condition in easily understood language
    Patienten mit fortgeschrittenem Malignem Melanom und
    vorbestehender spontaner Immunantwort gegen NY-ESO-1,
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level HLT
    E.1.2Classification code 10027156
    E.1.2Term Skin melanomas (excl ocular)
    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
    Immune-related Disease Control Rate irDCR (irCR, irPR, irSD) according to the immune-related response criteria (see Appendix 1) in patients with spontaneous preexisting NY-ESO-1 immune response treated with ipilimumab.
    E.2.2Secondary objectives of the trial
    Immune-related median progression-free survival (PFS) in patients with spontaneous preexisting immune response to NY-ESO-1 treated with ipilimumab

    Overall survival (OS) rate at 12 months after the first study treatment in patients with spontaneous preexisting immune response to NY-ESO-1 treated with ipilimumab

    Safety / toxicity according to the CTC Criteria (Version 4.0)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
     Signed Written Informed Consent must be obtained before performing
    protocol-related procedures that are not part of standard patient care.
     Target Population
    Histologic diagnosis of malignant melanoma; unresectable Stage III
    melanoma or Stage IV melanoma; Measurable/evaluable disease (as per
    mWHO criteria), within 28 days before first dose of study drug;
     Preexisting spontaneous immune response to NY-ESO-1, defined by
    positive results in ELISA above a prespecified cut-off value. (see
    Appendix 7).
    Cut-off calculation: Sera from 50 healthy donors are measured in
    triplicates against the GST-NY-ESO-1 fusion protein and the mean as
    well as the standard deviation are determined.
     The cut-off represents the mean of the means of all measured
    samples plus 3 times the standard deviation of the mean of the
    means. .
     Previously treated or untreated metastatic melanoma. The previous
    treatment must have been finished at least 28 days before the first
    ipilimumab administration. Patients must have recovered from any acute
    toxicity associated with prior therapy
     Life expectancy of ≥ 16 weeks;
     Eastern Cooperative Oncology Group (ECOG) performance status of 0
    or 1;
     Have the complete set of baseline (i.e., screening) digital images of
    lesions and radiographic images, including, but not limited to: chest,
    abdomen, pelvis, and other soft tissue scans. All images must be of
    adequate quality;
     Men and women, ages 18 and above.
     Ability of subject to understand character and individual consequences
    of the clinical trial
     Required values for initial laboratory tests:
    • WBC ≥ 2000/μL
    • ANC ≥ 1000/μL
    • Platelets ≥ 100 x 103/μL
    • Hemoglobin ≥ 9 g/dL (may be transfused)
    • Creatinine ≤ 2 x ULN
    • AST/ALT ≤ 2.5 x ULN for subjects without liver metastasis≤ 5 x ULN for
    subjects with liver metastasis
    • Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert’s Syndrome who must
    have a total bilirubin less than 3.0 mg/dL).

    Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study [and for up to 26 weeks after the last dose of investigational product] in such a manner that the risk of pregnancy is minimized.
    Suggested precautions should be used to minimize the risk of pregnancy for at least 1 month before dosing, and while women are on study and for up to 26 weeks after last dose of study drug; 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 postmenopausal.
    Post menopause is defined as
    • Amenorrhea ≥ 12 consecutive months without another cause, or
    • For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL. Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.

    WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.

    Men must be willing and able to use an acceptable method of birth control for up to 26 weeks after the last dose of investigational product, if their sexual partners are WOCBP.
    E.4Principal exclusion criteria
    Women who are pregnant or breastfeeding

    Target Disease Exceptions

    Brain Metastasis, unless previously treated, off steroids for at least 4 weeks and considered to be stable (eg, no progression of the treated lesion);

    Primary ocular or mucosal melanoma

    Prior malignancy active within the previous 5 years except for locally curable cancers that have been adequately treated, such as basal or squamous cell skin cancer.

    Medical History and Concurrent Diseases

    Autoimmune disease: subjects with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease are excluded from this study as are subjects with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive
    sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]). Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome) are excluded from this study

    Any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.

    Previous participation with a NY-ESO 1 derived vaccination study.

    Laboratory Test Findings

    Inadequate hematologic function defined by an absolute neutrophil count (ANC) < 1,000/mm3, a platelet count < 100,000/mm3, or a hemoglobin level < 9 g/dL;

    Inadequate hepatic function defined by a total bilirubin level > 2.0 x ULN except subjects with Gilbert’s Syndrome, who must have a total bilirubin < 3.0 ULN. AST and ALT levels ≥ 2.5 times the ULN, or ≥ 5 times the ULN if liver metastases are present;

    Inadequate renal function defined by a serum creatinine level ≥ 2.0 times the ULN, or inadequate creatinine clearance defined as less than 50 mL/min;

    Positive tests for HIV, Hepatitis B, and Hepatitis C. If positive results are not indicative of true active or chronic infection, the patient can enter the study after discussion and agreement with the investigator and the Medical Monitor.

    Prohibited Treatments and/or Therapies

    Chronic use of immunosuppressants and/or systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses). However, use of corticosteroids are allowed for treating irAEs, or adrenal insufficiencies;

    Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 4 weeks prior to or after any dose of ipilimumab);

    Prior treatment with a CD137 agonist, ipilimumab or other CTLA-4 inhibitor.

    Further Exclusion Criteria

    Prisoners or subjects who are involuntarily incarcerated

    Participation in other clinical trials or observation period of competing trials, respectively during the last 30 days before the first application of the investigational agent .
    Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. No exceptions will be granted.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the immune-related Disease Controle Rate (irDCR) as defined in Section 2.1.) For patients without irDCR evaluation at the end of treatment (or within the observation period in case of discontinuation of the planned treatment) it is assumed that no irDCR is achieved.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at week 12, 24, 36, 48
    E.5.2Secondary end point(s)
    -Disease Control Rate (CR, PR, SD) according to RESIST Criteria
    -Progression free survival (PFS)
    -Overall survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS: after 12 months
    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. 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 No
    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) 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.8.5The 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
    The estimated duration of the study is 24 months including patient enrollment.
    Last patient out: June 2014
    Trial report completed: June 2015

    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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.1.3Elderly (>=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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    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)
    Patients with sustained clinical benefit and whithout any irAEs requiring discontinuation of therapy might switch to commercially available drug according to the discretion of the treating physician.
    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 Decision2010-08-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-09-13
    P. End of Trial
    P.End of Trial StatusCompleted
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