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    Summary
    EudraCT Number:2010-021946-22
    Sponsor's Protocol Code Number:DeCOG–MM-PAL11
    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:2010-10-08
    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 - PEI
    A.2EudraCT number2010-021946-22
    A.3Full title of the trial
    THE IPI – MULTIBASKET TRIAL IN ADVANCED OCULAR MELANOMA:
    PROSPECTIVE CLINICAL PHASE II MULTIBASKET STUDY IN OCULAR MELANOMA PATIENTS WITH ADVANCED DISEASE
    A.4.1Sponsor's protocol code numberDeCOG–MM-PAL11
    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 Hospital 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.4.2CountryGermany
    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 No
    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 nameMDX-010/Ipilimumab
    D.3.4Pharmaceutical form
    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.3.9.1CAS number 477202-00-9
    D.3.9.3Other descriptive nameIPILIMUMAB
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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) 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 Yes
    D.3.11.13.1Other medicinal product typeRecombinant protein
    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
    Histologically proven uveal melanoma
    Measurable disease according to RECIST in unresectable stage III-IV
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10025671
    E.1.2Term Malignant melanoma stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10068117
    E.1.2Term Metastatic ocular melanoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    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 further characterize efficacy of second line ipilimumab monotherapy 3mg/kg given according to the MDX010-20 protocol in a broad range of pretreated metastatic ocular melanoma patients with or without prior systemic treatment seen in daily clinical practice:
    • Overall survival rate at 12 months defined as the rate of patients alive 12 months after the date from the first study treatment for complete study population
    E.2.2Secondary objectives of the trial
    To explore safety and additional efficacy parameters of the ipilimumab treatment in certain subgroups: (cutaneous versus uveal versus mucosal melanoma; LDH < 2 ULN versus LDH  2 ULN; status brain metastases versus no brain metastases in medical history;b-raf mutation positive versus b-raf mutation negative)
    Secondary objectives are
    • Safety / toxicity according to the CTC Criteria (Version 4.0)
    • Efficacy according to immune-related response criteria (ir-RC) at any time during treatment
    • Efficacy according RECIST criteria
    • Progression free survival rate at 6 months
    • Overall survival
    • To explore clinical efficacy of ipilimumab in relation to b-raf mutation status, brain metastases and LDH
    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 Programm
    Since ipilimumab is a T-cell potentiator it will most likely exert its effects on lymphocytes and other immune cells. Early clinical data suggest a correlation between early increase in ALC with clinical benefit after ipilimumab treatment (Yang et al., 2010; Ku et al., 2010). Furthermore, targeted therapy using agents such as PLX4032 are dependent in its efficacy on the presence of specific b-raf mutations. Based on requested blood samples and tumour tissue the following side studies are planned.
    Soluble Factors in Patients´ Serum
    Analysis of various soluble factors such as LDH, S-100, IL-8, IL-6; TNF, sFas, bFGF, S-100, VEGF using Multiplex protein technologies in sera of all patients before start of treatment and time point of first evaluation (week 12). In context, 20 ml venous blood will be collected once at the beginning of the study and thereafter at week 12, respectively. Levels will be compared with response and outcome.
    In context of this study, 2 ml EDTA “full blood” for HLA-typing and single nucleotide polymorphism (SNP) analysis will be collected once at the beginning of the study or any other time point of the study. Full blood can be stored without further processing at -70°C.
    Formalin Fixed Paraffin Embedded (FFPE) tissue is requested once from every patient. FFPEs blocks from histologically confirmed cutaneous melanoma such as primary tumor or subsequent metastases such as lymph node etc. will be eligable. Collecting samples of fresh tissue is optional. This tissue will be store at -70°C.
    DNA will be extracted and tissue micro arrays (TMAs) will be constructed to investigate tumor microenvironment and tumor infiltrating immune cells
    E.3Principal inclusion criteria
    Inclusion Criteria
    Patients meeting all of the following criteria will be considered for admission to the trial:
    1. Histologically proven ocular melanoma
    2. Measurable disease according to RECIST in unresectable stage III-IV
    3. Minimum age of 18 years,
    4. Able and willing to give valid written inform consent
    5. Patients with or without prior systemic treatment for advanced malignant melanoma are eligble .
    6. In case of systemic pre-treatment, an interval of at least 28 days since treatment with chemotherapy, biochemotherapy, surgery, radiation, or immunotherapy is mandatory as well as recovery from any clinically significant toxicity experienced during treatment is recommended. Prior treatment must be completed by the time of ipilimumab administration. Palliative radiation therapy outside of the brain or therapeutic radiation to the brain after the patient’s condition is stabilized and systemic steroids required for the management of symptoms due to brain metastases is decreased to the lowest fixed dose possible and does not require the 28-day waiting period. Patient must have recovered from any acute toxicity associated with prior therapy.
    7. Expected survival of at least six months
    8. ECOG Performance Status 0, 1 or 2.
    9. Within the last 2 weeks prior to study day 1 the following laboratory parameters, which should be within the ranges specified:

    Lab Parameter
    Range
    White blood cells (WBC)  2500/mm3 (≥ 1 2.5 x 109/L)
    Absolute neutrophil count (ANC)  1000/mm3 (≥ 1.0 x 109/L)
    Platelets  75.000/mm3 (≥ 75 x 109/L)
    Hemoglobin  9 g/dL ( 90 g/L; may be transfused)
    Creatinine  2.0 x ULN
    Bilirubine total  2.0 x ULN (excepted patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
    ALT, AST  2.5 x ULN for patients without liver metastasis,
     5 x ULN for patients with liver metastases
    10. No childbearing potential or negative pregnancy test of women of childbearing potential performed within 7 days prior to the start of treatment.
    Women of childbearing potential (WOCP) must be using an effective method of contraception (Pearl-Index < 1, e.g. 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, spermicides]) 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.
    No men of fathering potential or men of fathering potential must be using an effective method of contraception to avoid conception 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.
    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. Post-menopause is defined as:
    • Amenorrhea  12 consecutive months without another cause, or
    • For women with irregular menstrual periods and taking 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) at Baseline within 7 days before the start of ipilimumab and at week 12.
    E.4Principal exclusion criteria
    Exclusion Criteria
    Patients will be excluded from the study for any of the following reasons:
    1. The patient requires concomitant therapy with any of the following: IL 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; any other systemic therapy for cancer including any other experimental treatment.
    2. The patient requires chronic use of systemic corticosteroids. Systemic steroids for management of symptoms due to brain mets should be avoided if possible or subject should be stable on the lowest clinically effective dose. Topical or inhalational steroids are permitted.
    3. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment.
    4. Active autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Diseasse, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener’s Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis).
    5. Symptomatic CNS metastases (Remark: Asymptomatic stable, untreated or pretreated central nervous system (CNS) metastasis are allowed)
    6. Family history of congenital or hereditary immunodeficiency.
    7. 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 immunodeficient condition.
    8. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
    9. Lack of availability for clinical follow-up assessments.
    10. The patient has concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.
    11. Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders.
    12. Patients with serious intercurrent illness, requiring hospitalization.
    13. For female patients: the patient is pregnant or lactating. Women of childbearing potential: Refusal or inability to use effective means of contraception
    14. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
    15. Subjects with melanoma who have another active, concurrent, malignant disease are not eligible for this trial, with the exception of adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix.
    16. Previous treatment with ipilimumab
    E.5 End points
    E.5.1Primary end point(s)
    Primary Objective
    To further characterize efficacy of ipilimumab monotherapy 3mg/kg given according to the MDX010-20 protocol in a broad range of metastatic ocular melanoma patients with or without systemic pretreatment seen in daily clinical practice
    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 Information not present in EudraCT
    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 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 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.8.3 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 concerned25
    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 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
    A Safety Data Monitoring Committee (SDMC) will be responsible for reviewing all Grade 3-4 irAE on a regular basis.
    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
    E.8.9.2In all countries concerned by the trial years2
    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) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    Further patient treatment will be at the discretion of the Investigator. All patients in re-induction phase when their study period is ending, will be offered free ipilimumab to complete the re-induction treatment. Off-study patients eligible for a re-induction may be treated with ipilimumab if deemed appropriate by the treating physician, either using commercial drug if licensed in Germany or via the Early Access Program if the Marketing Authorization is not granted yet.
    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 Decision2011-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-01-11
    P. End of Trial
    P.End of Trial StatusCompleted
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