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    Summary
    EudraCT Number:2013-001546-34
    Sponsor's Protocol Code Number:EADO_VC_NEO_1
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-11-06
    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 ConcernedAustria - BASG
    A.2EudraCT number2013-001546-34
    A.3Full title of the trial
    Neoadjuvant treatment with the combination of
    vemurafenib and cobimetinib (GDC-0973) in limited metastasis of malignant melanoma (AJCC stage IIIC/IV) and integrated biomarker study: a single armed phase II EADO trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Neoadjuvant treatment with the combination of
    vemurafenib and cobimetinib (GDC-0973) in limited metastasis of malignant melanoma (AJCC stage IIIC/IV) and integrated biomarker study: a single armed phase II EADO trial
    A.3.2Name or abbreviated title of the trial where available
    NEO-VC
    A.4.1Sponsor's protocol code numberEADO_VC_NEO_1
    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 Tübingen
    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 supportHoffmann-La Roche
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Tübingen
    B.5.2Functional name of contact pointDepartment of Dermatology
    B.5.3 Address:
    B.5.3.1Street AddressLiebermeisterstrasse 25
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number+4970712987110
    B.5.5Fax number+497071295187
    B.5.6E-mailclaus.garbe@med.uni-tuebingen.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 Zelboraf
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 nameVemurafenib
    D.3.4Pharmaceutical form Film-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 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 nameCobimetinib
    D.3.4Pharmaceutical form Film-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 INNCOBIMETINIB
    D.3.9.3Other descriptive nameCOBIMETINIB
    D.3.9.4EV Substance CodeSUB122319
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.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 metastatic melanoma, stage IIIC or IV (American Joint Committee on Cancer 2010) with hardly resectable/unresectable limited metastasis positive for the BRAF V600 mutation, which are expected to become resectable (R0) due to tumor shrinkage under vemurafenib + cobi-metinib.
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic melanoma with hardly resectable/unresectable limited metastasis
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    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 17.1
    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
    Percent of patients who actually become resectable and are resected
    E.2.2Secondary objectives of the trial
    Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment.
    Overall survival time after resection, in the group who actually underwent complete resection.
    Rate of objective responses.
    Tolerability.
    Overall survival and progression free survival time in the total study population.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Detection of biomarkers for response to vemurafenib + cobimetinib by analysis of baseline metastatic tumor tissues/ blood samples and comparing metastatic tu-mor tissues pretreatment and post treatment.
    Differences in gene expression, oncogenic muta-tion/copy number alteration profiles, and oncogenic signaling pathway status in baseline metastatic tumor-tissues/ blood samples and metastatic tumor tissues before/after neoadjuvant study treatment (at time of resection).
    E.3Principal inclusion criteria
    1. Adult patients, ≥ 18 years of age
    2. Willing and able to give informed consent
    3. Metastatic melanoma, stage IIIC or IV (American Joint Committee on Cancer 2010)
    4. ECOG 0-1
    5. MAP-kinase pathway inhibitor treatment-naïve
    6. Positive for BRAF V600 mutation, preferentially to be shown from metastatic tumor tissue
    7. Decision of eligibility for neoadjuvant combined vemurafenib and cobimetinib treatment by interdisci-plinary tumor board. Patient with limited numbers of metastases and few organ systems involved should be selected, making surgical resection after neoad-juvant treatment probable.
    8. Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST V1.1) criteria
    9. Adequate hematologic and organ function as defined by:
    • ANC ≥ 1.5 × 109/L
    • Platelets ≥ 100 × 109/L
    • Hemoglobin ≥ 9 g/dL
    • Albumin ≥ 2.5 g/dL
    • Bilirubin ≤ 1.5 × the upper limit of normal (ULN)
    • AST, ALT, and alkaline phosphatase ≤ 3 × ULN,
    except patients with documented liver metasta-ses:
    AST and/or ALT ≤ 5 × ULN
    • Patients with documented liver or bone metasta-ses: alkaline phosphatase ≤ 5 × ULN
    • Serum creatinine ≤ 1.5 × ULN
    10. For fertile men: effective contraception during treat-ment and for 6 months after completion in such a manner that the risk of pregnancy is minimized
    11. For women of childbearing potential, negative preg-nancy test performed within 28 days prior study en-rolment, preferably as close to the first dose as pos-sible, and agrees to use adequate contraception from pregnancy test onwards, through the dosing period, and for at least 6 months after the last dose of investigational product as:
    • complete abstinence from sexual intercourse
    • oral contraceptive, either combined or progesto-gen alone
    • injectable progestogen
    • implants of levonorgestrel
    • estrogenic vaginal ring
    • percutaneous contraceptive patches
    • intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year
    • male partner sterilization (vasectomy with docu-mentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject
    • double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
    E.4Principal exclusion criteria
    1. Candidates for direct surgery: patients with single site easily resectable metastasis
    2. Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment
    3. Active central nervous system metastases ex-cept metastases after complete resection or ste-reotactic irradiation and stable status for at least 3 months
    4. History of carcinomatous meningitis
    5. Severe cardiovascular disease within 6 months prior to study drug administration
    6. History or evidence of cardiovascular risk includ-ing any of the following
    • LVEF < 50% or < LLN, whichever is lower
    • a QTc interval ≥ 450 ms
    • evidence of clinically significant uncontrolled arrhythmias
    7. History or evidence of retinal vein occlusion
    8. Previous malignancy within 5 years prior to study, except for basal or squamous cell carci-noma of the skin, melanoma in-situ, or carcino-ma in-situ of the cervix
    9. Psychological, familial, sociological, or geograph-ical conditions that do not permit compliance with the protocol
    10. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
    11. Legal incapacity or limited legal capacity
    12. Subjects housed in an institution on official or le-gal orders
    13. Participation in another clinical study with exper-imental therapy within the 30 days before start of treatment
    14. Pregnancy or lactation period
    15. Concomitant use of study therapy and drugs with a potential for QT prolongation (see database www.qtdrugs.org)
    16. Known immediate or delayed hypersensitivity re-action or idiosyncrasy to cobimetinib and/or vemurafenib and/or to any of its excipients
    17. Patients with diseases that affect liver function, such as viral hepatitis
    18. Patients receiving medications known to increase the risk of peripheral edema

    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the percentage of patients becoming operable after the combined treatment within 18 weeks.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after the combined treatment within 18 weeks
    E.5.2Secondary end point(s)
    Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment.
    Overall survival time after resection, in the group who actually underwent complete resection
    Rate of objective responses
    Tolerability
    Overall survival and progression free survival time in the total study population
    E.5.2.1Timepoint(s) of evaluation of this end point
    Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment.
    Overall survival time after resection, in the group who actually underwent complete resection: day of death or end of study
    Rate of objective responses: every 6 weeks
    Tolerability: during the whole study
    Overall survival and progression free survival time in the total study population: study enrolement until the day of progression/death
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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
    LVLS
    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 months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    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: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 110
    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)
    No further treatment will be applied within the scope of the protocol as soon as it was decided to permanently discontinue study treatment, e.g. due to progressive disease or unacceptable toxicity. Thereafter, further patient treatment will then be performed according to the updated national and international guidelines at the discretion of the Investigator.
    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 Decision2014-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-11
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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