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    Summary
    EudraCT Number:2017-000768-13
    Sponsor's Protocol Code Number:TUD-CoBRIM-067
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-08-14
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-000768-13
    A.3Full title of the trial
    An open-label phase II multicenter study of vemurafenib (Zelboraf®) plus cobimetinib (Cotellic®) after radiosurgery in patients with active BRAF-V600-mutant melanoma brain metastases
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open-label phase II multicenter study of vemurafenib (Zelboraf®) plus cobimetinib (Cotellic®) after radiosurgery in patients with active BRAF-V600-mutant melanoma brain metastases
    Multizentrische Phase II-Studie zu Vemurafenib plus Cobimetinib nach Strahlenchirurgie bei Melanom-Patienten mit BRAF-V600-Mutation und aktiven Hirnmetastasen
    A.3.2Name or abbreviated title of the trial where available
    RadioCoBRIM
    RadioCoBRIM
    A.4.1Sponsor's protocol code numberTUD-CoBRIM-067
    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 SponsorTechnische Universität Dresden
    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 supportRoche Pharma AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTechnische Universität Dresden
    B.5.2Functional name of contact pointKKS Dresden / Julia Kalinka
    B.5.3 Address:
    B.5.3.1Street AddressFetscherstraße 74
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01307
    B.5.3.4CountryGermany
    B.5.4Telephone number004935145819632
    B.5.5Fax number00493514585799
    B.5.6E-mailRadioCoBRIM.KKS@uniklinikum-dresden.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 Pharma AG
    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 nameZelboraf
    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 Yes
    D.2.1.1.1Trade name Cotellic
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Pharma AG
    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 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-Hemifumarat
    D.3.9.3Other descriptive nameCOBIMETINIB HEMIFUMARATE
    D.3.9.4EV Substance CodeSUB168371
    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 active BRAF-V600-mutant melanoma brain metastases
    E.1.1.1Medical condition in easily understood language
    Histologically confirmed metastatic melanoma carrying BRAF V600-mutation
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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 investigate the Best overall response rate (BORR) in the brain by combination of vemurafenib plus cobimetinib after radiosurgery in patients with melanoma brain metastases
    E.2.2Secondary objectives of the trial
    • Extracranial BORR
    • BORR calculated for the whole body tumor sites
    • Intracranial duration of response
    • Extracranial duration of response
    • Progression-free survival (PFS)
    • Overall survival (OS)
    • Safety
    • Radiomics features predictive of long-term local control of brain metastases
    • Radiomics features predicting treatment-related toxicity, e.g. radionecrosis, hemorrhage, edema.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Immunomonitoring to provide novel insights into the immune modulatory capacity of the combination therapy of vemurafenib and cobimetinib; blood samples will be taken to study a panel of immunomodulatory cells and molecules (e.g. cytokines)
    E.3Principal inclusion criteria
    • Signed informed consent
    • Female and male patients ≥ 18 years of age
    • Histologically confirmed metastatic melanoma (stage IV, per AJCC staging), carrying BRAF V600-mutation
    • Performed SRS 14 ±7 days before baseline using a harmonized protocol in patients with at least one measurable intracranial target lesion for which the following criteria are met:
    o Previously untreated (Lesions in previously irradiated area should not be selected)
    o Largest diameter of ≥ 0.5 but ≤ 4 cm as determined by contrast-enhanced MRI
    o ≤ 10 brain metastases
    • ECOG performance status 0 - 2
    • Life expectancy ≥ 12 weeks
    • Adequate bone marrow function as indicated by the following:
    o ANC ≥ 1500/µL
    o Platelets ≥ 100,000/µL
    o Hemoglobin ≥ 9 g/dL
    • Adequate renal function, as indicated by creatinine ≤ 1.5 x ULN
    • Adequate liver function, as indicated by bilirubin < 1.5 x ULN and AST and ALT < 3 x ULN (documented liver metastases: AST and ALT < 5 x ULN)
    • INR in normal range
    • Able to swallow pills
    E.4Principal exclusion criteria
    • Symptomatic brain metastases requiring immediate local interventions such as neurosurgery or radiosurgery
    • Leptomeningeal disease (also synchronous with brain metastases)
    • Prior therapy with BRAF or MEK inhibitors within 12 weeks prior to baseline visit (prior therapies for metastatic melanoma including chemo-, cytokine-, immuno-, biological and vaccine-therapy will be allowed). A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.
    • Prior whole brain irradiation (Patients with prior local therapy of brain metastases are eligible)
    • Patients receiving therapeutic steroids are not stable on corticosteroids 2 weeks before SRS
    • Active and uncontrolled infection
    • Known HIV infection, or active HBV or HCV infection
    o Active HBV infection (chronic and acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening (past or resolved HBV infection, defined as negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible)
    o Active HCV infection, defined as positive HCV antibody test and positive HCV RNA test at screening
    • Intracranial radiation therapy within 14 days prior to SRS
    • Extracranial radiation therapy within the last 14 days prior to baseline visit
    • Treatment with strong CYP3A4/5 inhibitors (e.g. ketoconazole) and inducers (e.g. phenytoin, carbamazepine). (anticonvulsant levetiracetam is allowed; patient should be stable on levetiracetam for 2 weeks)
    • Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia.
    • Conditions that will interfere significantly with the absorption of drugs (e.g. Colitis ulcerosa)
    • Inability to undergo MRI secondary to:
    o Metal
    o Claustrophobia
    o Gadolinium contrast allergy
    • Previous malignancies active within the last 3 years, with the exception of locally curable cancers that have been treated to complete remission or untreated stage I chronic lymphoid leukemia.
    • Unwillingness or inability to comply with study and follow-up procedures
    • Known hypersensitivity to any of the excipients of cobimetinib and vemurafinib
    • The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
    o St. John’s wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
    o Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)
    • Patient is included in another interventional trial
    • Use of any investigational or non-registered product within 4 weeks prior to baseline visit
    • Pregnant or lactating women
    • History, risk factor or retinal pathology that increases the risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology that is considered a risk factor for RVO or CSR, or a history of retinal detachment, central serous chorioretinopathy or retinal vein thrombosis. The risk factors for RVO are listed below:
    o Uncontrolled glaucoma with intraocular pressures > 21 mm Hg,
    o Serum cholesterol ≥ Grade 2 (≥ 7.75 mmol/L),
    o Hypertriglyceridemia ≥ Grade 2 (≥ 3.42 mmol/L),
    Hyperglycemia (fasting) ≥ Grade 2 (≥ 8.9 mmol/L).
    • History of clinically significant cardiac dysfunction including:
    o Myocardial infarction,
    o Severe/unstable angina pectoris,
    o Symptomatic congestive heart failure (NYHA stage ≥ 2),
    o cerebrovascular accident or transient ischemic attack within the previous 6 months
    o History of congenital long QT syndrome or mean QTcF > 450 msec or uncorrectable electrolyte abnormalities
    o Hypertension > Grade 2 not controlled by medications
    o Left ventricular ejection fraction (LVEF) < 50%
    o Uncontrolled arrhythmias
    E.5 End points
    E.5.1Primary end point(s)
    Best overall response rate in the brain within two years, defined as the rate of patients with complete response (CR) or partial response (PR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    within 2 years of therapy with vemurafenib and cobimetinib, every 6 weeks
    E.5.2Secondary end point(s)
    • Extracranial BORR
    • BORR calculated for the whole body tumor sites
    • Intracranial duration and kind of response
    • Extracranial duration and kind of response
    • Progression-free survival
    • Overall survival
    Safety:
    • Total adverse events
    • Serious adverse events
    • ≥ Grade 3 adverse events
    • Adverse events of special interest
    • Adverse events leading to treatment discontinuation
    Further Variables:
    • Radiomics features predictive of long-term local control of brain metastases
    • Radiomics features predicting treatment-related toxicity, e.g. radionecrosis, hemorrhage, edema.
    E.5.2.1Timepoint(s) of evaluation of this end point
    within 2 years of therapy with vemurafenib and cobimetinib, every 3 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 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
    End of Study Visit (2 years after start of treatment )
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 state32
    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)
    After the end of the study, the local investigator will be responsible for ensuring that consideration has been given for the post-study care of the subject’s medical condition. Due to the brain metastases disease, the patient will be offered a further experimental therapy as no standard treatment is approved at this time.
    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 Decision2017-11-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-21
    P. End of Trial
    P.End of Trial StatusOngoing
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