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    Summary
    EudraCT Number:2013-000773-71
    Sponsor's Protocol Code Number:vem+IL-2v1.0
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-07-12
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2013-000773-71
    A.3Full title of the trial
    A multicenter phase II study evaluating the efficacy and tolerability of vemurafenib in combination with Pegylated Interferon and Interleukin-2 in patients with BRAF-mutated metastatic melanoma
    Et multicenter fase II studie af effekten og tolerabiliteten af vemurafenib kombineret med Pegyleret Interferon og Interleukin-2 til patienter med BRAF-muteret metastatisk melanom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter phase II study evaluating the effect and tolerability of vemurafenib in combination with Pegylated Interferon and Interleukin-2 in patients with metastatic melanoma positive for the BRAF-mutation
    En multicenter fase II undersøgelse af vemurafenib i kombination med Pegyleret Interferon og Interleukin-2 til patienter med BRAF-muteret metastatisk malignt melanom
    A.3.2Name or abbreviated title of the trial where available
    vem+IL-2
    A.4.1Sponsor's protocol code numbervem+IL-2v1.0
    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 SponsorDepartment of Oncology, Aarhus University Hospital
    B.1.3.4CountryDenmark
    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 supportAarhus University Hospital
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportOdense University Hospital
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportCopenhagen University Hospital at Herlev uøniversity Hospital
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportF.HOFFMANN-LA ROCHE LTD
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartment of Oncology, Aarhus University Hospital
    B.5.2Functional name of contact pointHenrik Schmidt
    B.5.3 Address:
    B.5.3.1Street AddressNorrebrogade 44
    B.5.3.2Town/ cityAarhus
    B.5.3.3Post code8000
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4578461682
    B.5.5Fax number+4578462530
    B.5.6E-mailhenrschm@rm.dk
    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 Zelboraf
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 nameZelboraf
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNvemurafenib
    D.3.9.1CAS number 918504-65-1
    D.3.9.3Other descriptive nameVEMURAFENIB
    D.3.9.4EV Substance CodeSUB32161
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number240
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 Proleukin
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharmaceuticals UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNaldesleukin
    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 IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number18000000
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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 PegIntron
    D.2.1.1.2Name of the Marketing Authorisation holderMerck, Sharp and Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 Concentrate and solvent for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpeginterferon alfa-2b
    D.3.9.3Other descriptive namePEGINTERFERON ALFA-2B
    D.3.9.4EV Substance CodeSUB12549MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Metastatic melanoma
    Metastatisk malignt melanom
    E.1.1.1Medical condition in easily understood language
    Disseminated malignant melanoma
    Udbredt modermærkekræft
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10027481
    E.1.2Term Metastatic melanoma
    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
    To evaluate 6 month progression free-survival (PFS) rate of vemurafenib in combination with interleukin-2 (IL-2) and pegylated interferon (IFN) in patients with BRAF-mutated metastatic melanoma
    At evaluere progressions fri overleve (PFS) efter 6 måneder blandt patienter med BRAF-muteret metastatisk malignt melanom ved behandling med vemurafenib i kombination med interleukin-2 (IL-2) og pegyleret interferon (IFN)
    E.2.2Secondary objectives of the trial
    •To evaluate the safety and tolerability of vemurafenib in combination with IL-2/IFN
    •To evaluate 1-year survival rate (OS)
    •To evaluate overall response rates as defined by RECIST v.1.1
    •To evaluate the number of long-term survivors by estimating the 5-year survival rate
    •To evaluate predictive and prognostic biomarkers for response and survival
    •Evaluere sikkerheden og tolerabiliteten ved behandling med vemurafenib i kombination med IL-2/IFN
    •Evaluere 1-års overlevelses raten
    •Evaluere respons raten i henhold til RECIST v.1.1
    •Evaluere andelen af langtids overlevere ved at estimere 5-års overlevelsen
    •Evaluere prediktive og prognostiske biomarkører for respons og overlevelse

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Histologically verified unresectable stage III or stage IV melanoma with documented BRAF V600 mutation determined by the cobas® 4800 BRAF mutation test
    •Age between 18 and 70
    •ECOG performance status (PS) 0-2
    •Patients must have measurable target lesions disease as defined by RECIST v1.1
    •Prior medical treatment for metastatic melanoma is allowed, except previous treatment with BRAF-inhibitor and IL-2 based immunotherapy
    •Adequate cardiac function (less or equal to NYHA II). In the case of previous myocardial infarction echocardiography or MUGA-scan must be performed and left ventricle ejection fraction must be found normal
    •Adequate hematologic, renal and liver function as defined by laboratory values performed within 2 weeks of enrolment:
    o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    o Platelet count ≥ 100 x 109/L
    o Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or - creatinine clearance (CrCl) > 50 mL/hr by Cockroft–Gault formula
    o Alanine aminotransferase (ALAT) ≤ 2.5 times ULN (≤ 5 times ULN if considered due to liver metastasis)
    o Serum bilirubin ≤ 1.5 times ULN
    o Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN if considered due to liver metastasis)
    •Patients must have absence of any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of the study drugs hazardous or obscure the interpretation of adverse events
    •Fertile men and women must be using an effective method of contraception during treatment and for at least one month after completion of treatment
    •Women of child-bearing potential (WOCBP) must have a negative pregnancy test (HCG-urinalysis) before trial entry
    •Signed informed consent must be obtained prior to performing any study-related procedures. Testing for the V600 BRAF-mutation is considered as a standard procedure
    E.4Principal exclusion criteria
    •Any known severe and symptomatic autoimmune diseases that upon the opinion of the Investigators may conflict with the administration of the study medication.
    •Cerebral metastases. Patients that have been radically treated (neurosurgery or stereotactic radiotherapy) for a solitary cerebral metastasis may be included if MRI of the brain performed at least one month after treatment is without evidence of disease activity
    •Patients must not be dependent on systemic treatment with corticosteroids or other immunosuppressing agents
    •Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that may compromise adequate absorption. Patients must be able to swallow tablets
    •Uncontrolled infectious disease (requiring treatment with intravenous antibiotics)
    •Second malignancy in the past 5 years with the exception of surgically cured carcinoma in situ of the cervix or basal and squamous cell carcinoma of the skin.
    •QTc-interval > 500 ms
    •Any psychological, familial, sociological or geographical condition that upon the opinion of the investigators may affect the compliance with the protocol and follow-up schedule
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS)
    Progressions fri overlevelse (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months after the inclusion of the last patient
    6 måneder efter inklusionen af den sidste patient
    E.5.2Secondary end point(s)
    1. Grade and number of adverse events
    2. Overall survival after 1 year
    3. Overall survival after 5 years
    4.Evaluation of possible prognostic and predictive biomarkers
    1. Opgørelse af bivirkninger (grad og hyppighed)
    2. Overlevelsen efter 1 år
    3. Overlevelsen efter 5 år
    3.Evaluere potentielle prognostiske og prediktive biomarkører
    E.5.2.1Timepoint(s) of evaluation of this end point
    The primary analysis of efficacy and safety parameters will be performed when all 50 patients enrolled in the study have either died, withdrawn consent or have been followed for at least 6 months.
    The final analysis of this study will be performed when all patients enrolled have either died, withdrawn consent, are lost to follow up or have been followed up for up to 5 years.
    Den primære analyse vil blive foretaget når samtlige inkluderede patienter enten er døde,har tilbagetrukket samtykke eller er fulgt i mindst 6 måneder.
    Den endelige analyse vil blive foretaget når samtlige inkluderede patienter enten er døde,har tilbagetrukket samtykke eller er fulgt i op til 5 år.
    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 No
    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 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.8.3 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 concerned3
    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 study will end when all patients enrolled have developed progressive disease (as per RECIST v1.1), died, withdrawn consent, are lost to follow up, start another anti-cancer therapy, the end of follow-up or the study is terminated by the Sponsor.
    Patients will be followed for up to 10 years.
    Studiet afsluttes når alle patienter inkluderet har fået konstateret sygdoms progression (defineret i henhold til RECIST v1.1), er døde, har tilbagetrukket deres samtykke, manglende follow-up, påbegynt anden anti-cancer behandling, follow-up er over eller studiet er afsluttet af Sponsor.Patienterne vil blive fulgt i op til 10 år.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    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: 40
    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 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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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)
    Not different from normal treatment of this group of patients
    Samme behandling som andre patienter med udbredt modermærkekræft
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation GCP-Unit, Institute of Clinical Medicine
    G.4.3.4Network Country Denmark
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-19
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-02-20
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