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    Summary
    EudraCT Number:2010-023412-13
    Sponsor's Protocol Code Number:CMEK162X2201
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-02-14
    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 number2010-023412-13
    A.3Full title of the trial
    A Phase II, open-label study to assess the safety and efficacy of oral MEK162 in adults with locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600 or NRAS mutations
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study evaluating the safety and efficacy of an investigational compound (MEK162) in adult patients with a specific type of advanced cutaneous malignant melanoma
    A.4.1Sponsor's protocol code numberCMEK162X2201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01320085
    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 SponsorArray BioPharma Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportArray BioPharma Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationArray BioPharma Inc.
    B.5.2Functional name of contact pointAbdu Nessralla III
    B.5.3 Address:
    B.5.3.1Street Address100 Cambridge park Drive
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02140
    B.5.3.4CountryUnited States
    B.5.4Telephone number+13038675712
    B.5.5Fax number+13033861310
    B.5.6E-mailabdu.nessralla@arraybiopharma.com
    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 nameMEK162
    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.3.9.1CAS number 606143-89-9
    D.3.9.2Current sponsor codeMEK162
    D.3.9.3Other descriptive nameARRY-438162
    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.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
    locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600 or NRAS mutations
    E.1.1.1Medical condition in easily understood language
    specific molecular subtypes of locally advanced or metastatic malignant cutaneous melanoma
    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 PT
    E.1.2Classification code 10027480
    E.1.2Term Metastatic malignant melanoma
    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
    • To estimate the objective response rates (ORRs) of MEK162 when administered orally as 45mg bid, to adult patients with advanced, unresectable cutaneous malignant melanoma, i) harboring BRAFV600 or ii) harboring NRAS mutations and iii) when administered orally as 60mg bid, to adult patients with advanced, unresectable cutaneous malignant melanoma, harboring BRAFV600 mutations
    E.2.2Secondary objectives of the trial
    To assess the effect of oral MEK162 on time-related efficacy
    parameters (progression free survival (PFS) and duration of response)
    • To further assess the effect of MEK162 on other time related efficacy
    parameters
    • To characterize the safety and tolerability of oral MEK162
    • To assess the effects of MEK162 on MEK/MAPK signaling (PD changes
    of molecular status of pERK, and DUSP6)
    • To measure plasma concentrations of MEK162 and the
    pharmacologically active metabolite, AR00426032
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study have to meet all of the following criteria:
    1. Male or female patients age ≥ 18 years
    2. Histologically confirmed diagnosis of locally advanced or metastatic cutaneous melanoma AJCC Stage IIIB to IV, not potentially curable with surgery (Appendix 1)
    3. Must have documented presence of somatic BRAFV600 or NRAS mutation in tumor tissue.
    4. All patients enrolled should provide sufficient fresh or archival tumor sample at baseline to enable central confirmation of BRAF or NRAS mutations and the additional analyses described in the protocol
    5. Evidence of measurable tumor disease as per RECIST (Appendix 2), defined as at least one lesion that can accurately be measured in at least one dimension as ≥ 20 mm by conventional radiological technique or ≥ 10 mm with spiral CT-scan. Cutaneous lesions must have clearly defined margins and measure ≥ 5 mm in at least one diameter and be documented by color photography. Target lesions should not be selected in previously irradiated fields unless there is clear evidence of progression in such lesions.
    6. WHO performance status of 0-2.
    7. Adequate organ function and laboratory parameters as defined in the protocol
    8. Recovery from all reversible adverse events of previous anti-cancer therapies to baseline or to Grade ≤ 1, except for alopecia and Grade <2 sensory PNP
    9. LVEF ≥ 50% as determined by MUGA scan or TTE
    10. Patient is deemed by the Investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up) and be within geographical proximity to make the required study visits
    11. Negative serum β-HCG test (female patients of childbearing potential only) within 72 hrs prior to first dose
    12. Written informed consent obtained prior to any screening procedures.
    E.4Principal exclusion criteria
    Patients eligible for this study must not meet any of the following criteria at screening:
    1. History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or ophthalmopathy visible at screening that would be considered a risk factor for CSR or RVO
    2. Patients with CNS metastasis unless previously treated with surgery, whole-brain radiation or stereotactic radiosurgery and the disease has been stable for at least 2 months without steroid use or on a stable dose of steroids for at least 1 month prior to the first dose of MEK162
    3. Prior therapy with a MEK- inhibitor
    4. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
    • History/evidence of acute coronary syndromes (including MI, unstable angina, CABG, coronary angioplasty, or stenting) <6 months prior to screening
    • Symptomatic CHF, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality
    • Uncontrolled arterial hypertension, defined as BP > 140/100 mmHg (average of 3 consecutive readings)
    5. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection
    6. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures , e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.
    7. Patients who have received prior systemic anti-cancer treatment within the following time frames:
    • Patients who have received cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study drugs
    • Patients who have received biologic therapy (e.g., antibodies) within 4 weeks prior to starting study drug
    • Patients who have been treated with continuous or intermittent small molecule therapeutics within ≤ 5 t1/2 of the agent, or ≤ 4 weeks prior to starting study drug where half life is unknown
    • Patients who have received any other investigational agents within a period of time that is less than the cycle length used for that treatment or ≤ 4 weeks (whichever is shorter) prior to starting study drugs
    • Treatment with prior radiotherapy within 28 days of the first dose of study drug; however, if the radiation portal covered ≤ 10% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
    8. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such procedure
    9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL)
    10. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are:
    • women whose sexual orientation precludes intercourse with a male partner
    • women whose partners have been sterilized by vasectomy or other means
    • using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices (IUDs); periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable). Reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation
    Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
    11. 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.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Response Rate [ORR] (Complete Responses [CR] and Partial Responses [PR]) according to RECIST
    E.5.1.1Timepoint(s) of evaluation of this end point
    at baseline and at the end of every 2nd cycle/every 8 weeks until progression (as per RECIST)
    E.5.2Secondary end point(s)
    - PFS according to RECIST
    - Safety: Adverse drug reactions and serious adverse drug reactions,
    changes in hematology and chemistry values, vital signs, ECGs and
    XML File Identifier: gbyKsLCd6VlTxxVmO697Eib9RH0=
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    assessment of physical and ocular examinations graded according to the
    NCI CTCAE v4.0
    - OS, duration of response, time to response
    E.5.2.1Timepoint(s) of evaluation of this end point
    - PFS: at the end of every 2nd cycle/every 8 weeks until progression (as
    per RECIST)
    - Safety: throughout all cycles
    - 18 months
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA9
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    Italy
    Netherlands
    Switzerland
    United States
    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
    End of study will be when (at least) 80% of the patients in the study
    have died, or 24 months after last patient first visit, whichever occurs
    earlier.
    As of protocol version 5, due to several patients continuing to receive
    treatment, the end of the study will occur when the last patient
    completes the 30-day safety follow-up visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial 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: 85
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 85
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 170
    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 Decision2011-04-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-28
    P. End of Trial
    P.End of Trial StatusCompleted
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