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    Summary
    EudraCT Number:2010-019033-98
    Sponsor's Protocol Code Number:BMS-TUE-01
    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:2011-08-31
    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 number2010-019033-98
    A.3Full title of the trial
    A phase II study to evaluate safety and efficacy of combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with metastatic melanoma
    A.3.2Name or abbreviated title of the trial where available
    i i i Study
    A.4.1Sponsor's protocol code numberBMS-TUE-01
    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 Clinical Center of Tuebingen
    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 support
    B.4.2Country
    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 Yes
    D.2.1.1.1Trade name YERVOY®
    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 nameIpilimumab
    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.3.9.3Other descriptive nameIpilimumab
    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 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) Yes
    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.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 YERVOY®
    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 nameIpilimumab
    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.3.9.3Other 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) 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) Yes
    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.IMP: 3
    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® S
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma GmbH
    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.3.1Product namePROLEUKIN® S
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntratumoral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 110942-02-4
    D.3.9.3Other descriptive nameALDESLEUKIN
    D.3.9.4EV Substance CodeSUB05303MIG
    D.3.10 Strength
    D.3.10.1Concentration unit million IU million international units
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number22
    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) Yes
    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
    Stage IV Melanoma
    E.1.1.1Medical condition in easily understood language
    histologically confirmed metastatic melanoma, stage IV,
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    efficacy of the combined treatment with ipilimumab and intratumoral IL-2 based on the Disease Control Rate according to immune-related Response Criteria (irDCR) at week 12
    E.2.2Secondary objectives of the trial
    • Tolerability according to NCI-CTCAE-Criteria (version 4)
    • Overall response rate (sum of irPR and irCR) at week 12 according to irRC
    • Overall survival after 12 months
    • Best overall responsei rate according to irRC (irBORR).
    • Overall Response Rate at week 12 and Best Overall Response Rate according to modified mWHO criteria
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Investigation of tumor-infiltrating lymphocytes, Peripheral blood mononuclear cells (PBMC) subsets, melanoma-specific T cells during treatment
    • Response rate of injected metastases only at week 12.
    • Rate of patients with substantial increase of anti-melanoma T cells in peripheral blood during treatment
    • Changes in T cell subsets during treatment
    • Changes in subsets of tumor-infiltrating lymphocytes during treatment
    E.3Principal inclusion criteria
    • Willing and able to give written informed consent;
    • Histological diagnosis of malignant melanoma;
    • Stage IV melanoma;
    • At least one injectable lesions > 5 mm (longest diameter) or at least 5 injectable lesions < 5 mm.
    • Measurable disease. Note: lesions, which are designated for direct IL -2 injections, must not be considered in the evaluation of measurability;
    • Men and women,  18 years of age;
    • Patient must have demonstrated 1 of the following in response to at least 1 cycle of 1 or more systemic regimens:
    1) relapse following an objective response (PR/CR);
    2) failed to demonstrate an objective response (PR/CR); or
    3) inability to tolerate treatment due to unacceptable toxicity
    • At least 4 weeks since treatment (chemotherapy, biochemotherapy, surgery, radiation, immunotherapy, etc.) for melanoma and recovered from any clinically significant toxicity experienced during treatment;
    • Life expectancy ≥3 months;
    • ECOG performance status of 0 or 1;
    • Women 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 before the start of ipilimumab;
    • No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C;
    • Required values for initial laboratory tests:
    1. WBC  2000/µL
    2. ANC  1000/µL
    3. Platelets  75000/µL
    4. Hemoglobin  9 g/dL ( 8 g/dL; may be transfused)
    5. Creatinine  2.0 x ULN
    6. AST/ALT  2.5 x ULN (  5 times x ULN for patients with liver metastases)
    7. Bilirubin  2.0 x ULN, (except patients with Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
    • Men of fathering potential must be using an adequate 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.
    E.4Principal exclusion criteria
    • Any other prior malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix;
    • Ocular melanoma; mucosal melanoma
    • Either untreated or symptomatic central nervous system (CNS) metastases (patients with brain metastases who are identified at screening may be rescreened after the lesion(s) have been appropriately treated);
    • Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome). Patients with vitiligo may be included.
    • 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.
    • Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
    • A history of prior systemic treatment with ipilimumab, CD137 agonist, CTLA 4 inhibitor, CTLA-4 agonist or IL-2 in stage IV melanoma.
    • Concomitant or less than 4 weeks off therapy with any of the following: interferon; other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; chronic use of systemic corticosteroids.
    • Women of childbearing potential (WOCBP), defined in Section 5.3, who:
    1. are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 26 weeks after cessation of study drug, or
    2. have a positive pregnancy test at baseline, or
    3. are pregnant or breastfeeding.
    • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious) illness.
    E.5 End points
    E.5.1Primary end point(s)
    Immune related Disease control rate (irDCR): sum of patients with an overall response irCR or irPR or irSD divided by the total number of patients, who are evaluable of efficacy. 95% confidence intervals will be provided.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at week 12
    E.5.2Secondary end point(s)
    Immune related Overall response rate at week 12 (irORR): sum of patients with an overall response irPR or irCR, divided by the total number of patients, who are evaluable of efficacy. 95% confidence intervals will be provided.
    Immune related Best overall response rate (irBORR): number of patients whose irBOR is CR or PR divided by the total number of patients, who are evaluable of efficacy. 95% confidence intervals will be provided.
    Response rate with regards to injected metastases only at week 12: sum of patients with CRinj or PRinj divided by the total number of patients with either CRinj, PRinj, SDinj or PDinj. 95% confidence intervals will be provided.
    Overall survival after 12 months: The calculation of the overall survival rate after 12 months (12 months after the first dose) will comprise all patients, who received at least one dose of study drug(s). It will be calculated using the Kaplan-Meier method. An event is defined as death from malignant melanoma. All other patients will be censored at the time point of his/her last follow-up within the context of this protocol. 95% confidence intervals for the estimated survival rate will be provided.
    Overall response rate at week 12 according to mWHO criteria: sum of patients with an overall response PR or CR according to mWHO criteria, divided by the total number of patients, who are evaluable of efficacy. 95% confidence intervals will be provided.
    Best overall response rate according to mWHO criteria: number of patients whose Best Overall Response is CR or PR according to mWHO criteria divided by the total number of patients, who are evaluable of efficacy. 95% confidence intervals will be provided.
    Clinical safety data will be analyzed by descriptive statistics for all patients, who received at least one dose of any investigational product within this protocol and attended at least once after dosing for adverse event assessment.
    The endpoints of optional translational side studies (rate of patients with substantial increase of anti-melanoma T cells in peripheral blood during treatment, changes in T cell subsets during treatment and changes in subsets of tumor-infiltrating lymphocytes) are exploratory and will only be analyzed by descriptive statistics.
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 12 and after 12 months after the first dose per patient
    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 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 concerned4
    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
    12 months after the first dose of the last patient enrolled into this study
    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: 21
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state41
    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 Decision2011-10-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-10-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-23
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