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    Summary
    EudraCT Number:2014-004597-42
    Sponsor's Protocol Code Number:BIRMA
    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:2016-03-16
    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 number2014-004597-42
    A.3Full title of the trial
    LGX818 in combination with MEK162 in refractory or relapsed multiple myeloma patients with BRAFV600E
    or BRAFV600K mutation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    LGX818 in combination with MEK162 in refractory or relapsed multiple myeloma patients with BRAFV600E
    or BRAFV600K Mutation
    A.3.2Name or abbreviated title of the trial where available
    BIRMA
    A.4.1Sponsor's protocol code numberBIRMA
    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 SponsorUniversität Heidelberg vertreten durch die kaufmännische Direktorin
    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 supportArray BioPharma
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Heidelberg
    B.5.2Functional name of contact pointInternal Medicine V
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 410
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number+496221564781
    B.5.5Fax number+496221561957
    B.5.6E-mailmarc.raab@med.uni-heidelberg.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 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 nameencorafenib
    D.3.2Product code LGX818
    D.3.4Pharmaceutical form Capsule, hard
    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 INNENCORAFENIB
    D.3.9.2Current sponsor codeLGX818
    D.3.9.4EV Substance CodeSUB177218
    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 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 Mektovi
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 namebinimetinib
    D.3.2Product code MEK162
    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 INNBINIMETINIB
    D.3.9.1CAS number 601143-89-9
    D.3.9.2Current sponsor codeMEK162
    D.3.9.4EV Substance CodeSUB179942
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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: 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 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 nameencorafenib
    D.3.2Product code LGX818
    D.3.4Pharmaceutical form Capsule, hard
    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 INNENCORAFENIB
    D.3.9.2Current sponsor codeLGX818
    D.3.9.4EV Substance CodeSUB177218
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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
    Relapsed or refractory Multiple Myeloma
    E.1.1.1Medical condition in easily understood language
    Relapsed or refractory Multiple Myeloma
    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 HLT
    E.1.2Classification code 10028229
    E.1.2Term Multiple myelomas
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • The primary objective of this study is to demonstrate the therapeutic efficacy of LGX818/MEK162 to decrease myeloma tumour burden
    E.2.2Secondary objectives of the trial
    • To provide information on survival related parameters for patients being treated with LGX818/MEK162
    • To further characterize responses after treatment with LGX818/MEK162
    • To evaluate the adverse events profile of LGX818/MEK162 in this indication (with respect to related adverse events of CTCAE grade 1 and 2 and all adverse events of grade 3 and 4 and SAEs)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patient has provided a signed study Informed Consent Form prior to any studyspecific procedure and is able to comply with protocol requirements
    2.Patients with multiple myeloma,relapsed or refractory after failure of two or more lines of systemic treatments. All patients must have received at least one immunomodulatory drug (IMiD) and a proteasome inhibitor.
    Multiple myeloma requiring systemic therapy must have been confirmed in the medical history of the patients with criteria established by the International Myeloma Working Group (IMWG) (Rajkumar V et al. Lancet International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet 2014; 15: 538-548)
    3.Written confirmation of BRAFV600Emutation or BRAFV600K mutation in in the majority of myeloma cells, defined by positive IHC staining with mutations specific antibody of ≥ 50% in the respective biopsy and confirmed by DNA sequencing of the respective codon.
    4.Measurable disease, as defined as:
    • Measurable levels of myeloma paraprotein in serum (≥ 0.5 g/dL) or
    • urine (≥ 0.2 g/24 hours) or
    • FLC of involved light chain > 100mg/l and abnormal FLC-ratio
    5.Age ≥18
    6.WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by co-morbid conditions) (see Appendix III)
    7.Negative pregnancy test within 72 hours of inclusion (women of childbearing potential)
    8. For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy (see also exclusion criteria).
    9.All patients must agree to abstain from donating blood while on study
    10.Adequate cardiac function:
    • left ventricular ejection fraction (LVEF) ≥ 50% as determined by a echocardiogram
    • QTc interval ≤ 450 ms
    11.Ability of subject to take oral medications
    12.Ability of subject to understand character and individual consequences of clinical trial


    E.4Principal exclusion criteria
    1.Patient with prior treatment with MEK and/or RAF inhibitors
    2.Systemic AL amyloidosis (except for patients with AL amyloidosis of the skin or the bone marrow)
    3.Patients with meningeosis or central nervous system lesion(s) caused by multiple myeloma. However, patients treated with stereotactic radiotherapy or surgery are eligible if patient remained without evidence of CNS disease progression ≥ 4 weeks.
    4.History or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO
    5.History of retinal degenerative disease
    6.Plasma cell leukaemia which requires the presence of 20% of plasma cell in peripheral blood leukocytes and at least 2/nl.
    7.Patient has received radiotherapy (including therapeutic radioisotopes) ≤ 21 days, if not restricted to a single osteolytic lesion, or has not recovered from side effects of such therapy.
    8.Patient has had major surgery within 21 days prior to starting study drug or has not recovered from major side effects of the surgery.
    9.Patient is concurrently using other approved antineoplastic or any investigational agents in the last 14 days prior to start of treatment.
    10.Impaired cardiovascular function or clinical significant cardiovarscular disease including any of the following: Symptomatic chronic heart failure, history or current evidence of clinically
    significant cardiac arrhythmia and/or conduction abnormality <6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia;
    a.LVEF < 50% as determined by ECHO, or uncontrolled hypertension despite medical treatment (please refer to WHO ISH guidelines)
    b.Clinically significant resting bradycardia, unstable angina pectoris ≤ 3 months prior to starting study drug, history of acute coronary syndromes <6 months prior to screening
    c.QTcF > 450 msec
    d.patients with acute diffuse infiltrative pulmonary and pericardial disease
    11.Significant hepatic dysfunction (serum bilirubin ≥ 2 mg/dl or ASAT and/or ALAT ≥ 2.5 times normal level)
    12.Active hepatitis B, and/or active hepatitis C infection
    13.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/MEK162
    14.Gilbert´s Syndrom
    15.Patients who have neuromuscular disorders that are associated with elevated CK
    16.Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment
    17.Patients known to be HIV-positive
    18.Patients with active, uncontrolled infections
    19.Patient is receiving chronic treatment with systemic steroids or another immuno-suppressive agent at start of study treatment.
    20.Patient has consumed Seville oranges, grapefruit, grapefruit hybrids, pomelos and exotic citrus fruits (as well as their juices) during the last 7 days prior to start of treatment.
    21.Second malignancy within the past 3 years except:
    a. Adequately treated basal cell or squamous cell skin cancer
    b. Adequately treated carcinoma in situ of the cervix,
    c. Prostate Cancer not requiring systemic treatment or under anti-hormonal treatment and PSA-level below upper level of normal range.
    d. Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins),
    e. solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry
    f. Similar condition with an expectation of > 95 % 5-year disease free survival
    22.Patients with any of the following laboratory values at Screening/Baseline.
    a. Absolute neutrophil count (ANC) <1,000/mm3 [1.0 x 109/L] without Growth factor support in the last 7 days
    b. Platelets ≤ 50000/mm3 [50 x 109/L]
    c. Hemoglobin < 8.0 g/ dl
    d. Serum creatinine >2 x ULN or calculated or directly measured CrCl ≤ 45 ml/min;
    23. Clinically significant autoimmune haemolytic anaemia with positive Coombs test or immune thrombocytopenia
    24. Patient is a woman of child-bearing potential, UNLESS they are using a double barrier method for birth control throughout the trial.
    25. Sexually active males unless they agree to use a condom during intercourse while taking the drug. This practice should be continued for another 12 weeks after stopping treatment.
    26. Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study.
    27. Patients taking non-topical medication known to be a strong inhibitor of CYP3A4. However patients who either discontinue their treatment or switch to another medication at least three days prior to registration are eligible.
    28. Participation in other clinical trials within 1 month prior to enrolment except patients for supportive care studies and vaccination studies. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.

    E.5 End points
    E.5.1Primary end point(s)
    • The first primary endpoint is best ORR during treatment.
    E.5.2Secondary end point(s)
    • Progression-free survival
    • Overall survival
    • Time-to-progression (TTP)
    • Duration of response (DOR)
    • Disease-free survival (DFS)
    • Time-to best-objective response
    • Time-to-objective Response
    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 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.8.2.4Number of treatment arms in the trial1
    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 concerned5
    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 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
    The study is considered completed 3 months after all patients have experienced a progressive disease event. This includes progressive disease during study treatment as well as after discontinuation of the study drug for toxicity or other reasons.
    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 months0
    E.8.9.1In the Member State concerned 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) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state15
    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)
    Standard of care after disease Progression, further treatment will be done according to the responsible physicians discretion and clinical routine
    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 Decision2016-04-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-26
    P. End of Trial
    P.End of Trial StatusOngoing
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