<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01726738</url>
  </required_header>
  <id_info>
    <org_study_id>LCCC 1128</org_study_id>
    <nct_id>NCT01726738</nct_id>
  </id_info>
  <brief_title>LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations</brief_title>
  <official_title>LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UNC Lineberger Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>UNC Lineberger Comprehensive Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma&#xD;
      is designed to explore the mechanisms by which tumors acquire resistance to the combination&#xD;
      of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at&#xD;
      baseline and at progression.If a subject is removed from the study for one of a variety of&#xD;
      reasons including, but not limited to, an inability to tolerate the combination of dabrafenib&#xD;
      and trametinib, a need to receive other therapy or completion of 3-years of study treatment&#xD;
      without progression, and the subject later receives, as part of his/her standard of care, the&#xD;
      combination of dabrafenib and trametinib and progresses on the standard of care regimen, then&#xD;
      the subject may be contacted by the treating physician to be put back on to the LCCC 1128&#xD;
      protocol and have a progression biopsy at this progression time point. Markers of resistance&#xD;
      will be explored by performing near kinome-wide profiling on tumor samples, and in patients&#xD;
      who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA&#xD;
      sequencing technology. Overall response rate and duration to this combination will also be&#xD;
      assessed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The present phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV&#xD;
      melanoma is designed to explore the mechanisms by which tumors acquire resistance to the&#xD;
      combination of BRAF and MEK inhibition. Overall response rate and duration to this&#xD;
      combination will also be assessed.&#xD;
&#xD;
      Tissue will be collected at baseline and at progression (clinical or radiological). Patients&#xD;
      may remain on treatment after progression (at the discretion of the investigator) as long as&#xD;
      they are still experiencing clinical benefit. We anticipate that up to 50% of patients may&#xD;
      continue on therapy post-progression for 2-8 weeks.&#xD;
&#xD;
      BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination with the MEK&#xD;
      inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this&#xD;
      combination, and to determine the recommended phase 2 doses (RP2D) for each agent. Expansion&#xD;
      cohorts at the RP2D for these drugs in combination were included in the phase I to&#xD;
      characterize the safety in more detail, and to explore the efficacy of this combination. The&#xD;
      combination was well tolerated as described in section 1.5, with decreased frequency of rash&#xD;
      compared to either agent alone and with just 1 report of cutaneous SCC.&#xD;
&#xD;
      This proposed study will utilize the RP2D determined in the Phase I/II study: trametinib 2mg&#xD;
      QD and dabrafenib 150 mg BID. Despite a very promising overall response rate of 81%, these&#xD;
      patients will also likely go on to develop resistance as a result of new resistance&#xD;
      mutations, and given the cooperative signaling network of kinases that sense inhibition of&#xD;
      key nodal kinases and induce compensatory responses that offset pharmacological intervention.&#xD;
      The study objectives are as follows: Objectives Primary Objective To identify kinases that&#xD;
      are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK&#xD;
      (trametinib) inhibitors, and to determine a kinome signature predictive of resistance to&#xD;
      BRAF/MEK inhibition in stage III/IV melanoma Secondary Objectives To explore whether&#xD;
      resistance to BRAF and MEK inhibition is associated with new functional mutations in the&#xD;
      approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of&#xD;
      the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll&#xD;
      in LCCC1108, with particular focus on one of five established resistance genes (BRAF, NRAS,&#xD;
      MEK1, MAP3K8 or COT, and PTEN) To determine the overall response rate (ORR: complete response&#xD;
      + partial response) as measured via RECISTv1.1 To estimate the duration of ORR as measured&#xD;
      via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1 To&#xD;
      estimate the rate of overall survival (OS) at 1 year from day 1 of treatment&#xD;
&#xD;
      Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression&#xD;
      from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) coupled with&#xD;
      mass spectrometry.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 4, 2013</start_date>
  <completion_date type="Actual">September 17, 2020</completion_date>
  <primary_completion_date type="Actual">November 3, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Kinase Expression</measure>
    <time_frame>Baseline and One year post treatment</time_frame>
    <description>The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry (MS) and reported as a sum of the Log 2 Fold Change between baseline and one year post treatment across all patients</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Kinome Signature Predictive of Resistance</measure>
    <time_frame>One year post treatment</time_frame>
    <description>Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes</measure>
    <time_frame>One year</time_frame>
    <description>The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using Next Generation (NextGen) DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) or Cancer Osaka Thyroid (COT), and PTEN).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>One year post treatment</time_frame>
    <description>To determine the disease overall response rate (ORR: complete response (CR) + partial response (PR)/total number of patients) as measured radiographically via Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. CR is defined as the disappearance of all target lesions; PR is a &gt;=30% decrease in the sum of the longest diameter of target lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Overall Response</measure>
    <time_frame>One year post treatment</time_frame>
    <description>Duration of overall response is defined as the time from documentation of response (Complete or Partial) to time of disease progression or death. Response was measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. Complete Response is defined as the disappearance of all target lesions; Partial Response as a &gt;=30% decrease in the sum of the longest diameter of target lesions, and Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>One year post treatment</time_frame>
    <description>PFS is defined as the time from Day 1 of protocol treatment to the date of progression as measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or to the date of death. Per RECIST, Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Overall Survival (OS) at 12 Months</measure>
    <time_frame>One year post treatment</time_frame>
    <description>The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Stage III Melanoma</condition>
  <condition>Stage IV Melanoma</condition>
  <condition>Unresectable Melanoma</condition>
  <condition>BRAF Mutant Melanoma</condition>
  <arm_group>
    <arm_group_label>BRAF (dabrafenib) and MEK (trametinib) inhibitors</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BRAF inhibitor dabrafenib and MEK inhibitor trametinib</intervention_name>
    <description>Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
    <arm_group_label>BRAF (dabrafenib) and MEK (trametinib) inhibitors</arm_group_label>
    <other_name>BRAF Inhibitor Dabrafenib GSK2118436</other_name>
    <other_name>MEK Inhibitor Trametinib GSK1120212</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Main Study Inclusion Criteria:&#xD;
&#xD;
        Subject must meet all of the inclusion criteria to participate in this study:&#xD;
&#xD;
        Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF&#xD;
        mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2&#xD;
&#xD;
        Normal organ function as defined by the following:&#xD;
&#xD;
          -  Absolute neutrophil count &gt;1.2 × 109/L&#xD;
&#xD;
          -  Hemoglobin &gt;9 g/dL, platelets &gt;75 × 109/L&#xD;
&#xD;
          -  PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may&#xD;
             enroll with INR established within the therapeutic range prior to D1 of treatment)&#xD;
&#xD;
          -  Albumin &gt;2.5 g/dL&#xD;
&#xD;
          -  Total bilirubin &lt;1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease&#xD;
             will not be excluded)&#xD;
&#xD;
          -  AST and ALT &lt; 2.5× ULN&#xD;
&#xD;
          -  CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities&#xD;
             except alopecia and lab values as outlined in the criterion above must be less than or&#xD;
             equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only&#xD;
             Females of child-bearing potential: willing to use two forms of effective&#xD;
             contraception, and to continue use for 16 weeks post last dose of study medication.&#xD;
             Effective contraception is defined as any medically recommended method (or combination&#xD;
             of methods) as per standard of care, including abstinence. Females of non-childbearing&#xD;
             potential are those who are postmenopausal (defined as greater than 1 year without&#xD;
             menses with appropriate clinical profile, e.g., age appropriate: &gt;45 years in the&#xD;
             absence of hormone replacement therapy (HRT). In questionable cases, the subject must&#xD;
             have a follicle stimulating hormone (FSH) value &gt;40 mIU/mL and an estradiol value&#xD;
             &lt;40pg/mL (&lt;140 pmol/L); or who have had a bilateral tubal ligation or tubal occlusion,&#xD;
             bilateral oophorectomy, or hysterectomy. Men with a female partner of childbearing&#xD;
             potential must have either had a prior vasectomy or agree to use effective&#xD;
             contraception as described from D1 of treatment, throughout the treatment period, and&#xD;
             for 16 weeks after the last dose of study treatment. If a subject becomes pregnant&#xD;
             during the treatment period of the study, the study treatments should be stopped&#xD;
             immediately.&#xD;
&#xD;
        In women of child-bearing potential, negative serum pregnancy test within 48 hours prior to&#xD;
        day 1 of study treatment and agree to use effective contraception. Effective contraception&#xD;
        is defined as: (a) an intrauterine device with a documented failure rate of less than 1%&#xD;
        per year. (b) male partner sterilization prior to the female subject's entry, and this male&#xD;
        is the sole sexual partner for that female. (c) complete abstinence from sexual intercourse&#xD;
        for 14 days prior to enrollment throughout study treatment, and for at least 4 months after&#xD;
        the last dose of study treatment. Abstinence is only acceptable when in line with the&#xD;
        preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar ovulation,&#xD;
        symptothermal, post-ovulation methods, etc) and withdrawal are not acceptable methods of&#xD;
        contraception. (d) double- barrier contraception: condom and occlusive cap (diaphragm or&#xD;
        cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). Note:&#xD;
        hormonal based methods (e.g. oral contraceptives) are not permitted.&#xD;
&#xD;
        Female subjects who are lactating must discontinue nursing prior to the first dose of study&#xD;
        treatment and must refrain from nursing throughout the treatment period and for 4 months&#xD;
        following the last dose of study treatment Measurable disease as defined by RECIST v1.1&#xD;
        Able to swallow and retain oral medication Left ventricular ejection fraction by ECHO ≥&#xD;
        institutional lower limit of normal&#xD;
&#xD;
        Main Study Exclusion Criteria:&#xD;
&#xD;
        Any subject meeting any of the following exclusion criteria at baseline will be ineligible&#xD;
        for study participation:&#xD;
&#xD;
        Patients with a history of a prior malignancy are excluded unless they have been disease&#xD;
        free for 3 or more years or unless they have a completely resected non-melanoma skin&#xD;
        cancer, and/or subjects with indolent second malignancies.&#xD;
&#xD;
        History of malignancy with confirmed activating RAS mutation at any time. Note: Prospective&#xD;
        RAS testing is not required. However, if the results of previous RAS testing are known,&#xD;
        they must be used in assessing eligibility.&#xD;
&#xD;
        Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib&#xD;
        (GSK2118436), vemurafenib, and LX281/BMS-908662) or a MEK inhibitor (including but not&#xD;
        limited to trametinib (GSK1120212), AZD6244, and RDEA119); NOTE: There is no limit to the&#xD;
        number of other prior therapies, and patients may be previously untreated.&#xD;
&#xD;
        Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
        chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).&#xD;
&#xD;
        Active GI or intracranial hemorrhage&#xD;
&#xD;
        History or evidence of cardiovascular risk including any of the following:&#xD;
&#xD;
          -  QTc ≥ 480 msec;&#xD;
&#xD;
          -  History or evidence of current clinically significant uncontrolled arrhythmias;&#xD;
&#xD;
             o Exception: Subjects with controlled atrial fibrillation for &gt;30 days prior to D1 of&#xD;
             study treatment are eligible.&#xD;
&#xD;
          -  History of acute coronary syndromes (including myocardial infarction and unstable&#xD;
             angina), coronary angioplasty, or stenting within 6 months prior to study entry;&#xD;
&#xD;
          -  Patients with history of hypertension should have hypertension adequately controlled&#xD;
             (BP&lt;140/90) with appropriate anti-hypertensive therapy or diet prior to study entry;&#xD;
&#xD;
          -  Patients with intra-cardiac defibrillators or permanent pacemakers;&#xD;
&#xD;
          -  Known cardiac metastases;&#xD;
&#xD;
          -  Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects&#xD;
             with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on&#xD;
             study). Subjects with moderate valvular thickening should not be entered on study.&#xD;
&#xD;
        History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency&#xD;
&#xD;
        Brain metastases are excluded unless:&#xD;
&#xD;
          -  All known lesions were previously treated with surgery or stereotactic surgery&#xD;
             (whole-brain radiation is not allowed unless given after definitive treatment with&#xD;
             surgery or stereotactic surgery), AND&#xD;
&#xD;
          -  Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in&#xD;
             lesion size) for ≥ 12 weeks prior to D1 of study treatment (stability must be&#xD;
             confirmed with two consecutive magnetic resonance image (MRI) or computed tomography&#xD;
             (CT) scans with contrast, AND&#xD;
&#xD;
          -  Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to D1 of study&#xD;
             treatment, AND&#xD;
&#xD;
          -  Treatment with any CYP enzyme inducing anticonvulsants occurred &lt; 4 weeks prior to D1&#xD;
             of study treatment&#xD;
&#xD;
        NOTE: if study subject has history of brain metastasis, but currently has no evidence of&#xD;
        disease in brain (NED), confirmation by two consecutive scans separated by ≥6 weeks prior&#xD;
        to D1 of treatment is required.&#xD;
&#xD;
        Pulmonary embolism on active therapy History of interstitial lung disease or pneumonitis&#xD;
        Known HIV, Hepatitis B or C infection (with the exception of chronic or cleared HBV and HCV&#xD;
        infection which will be allowed provided the following tests are done at screening: viral&#xD;
        hepatitis serology, Hepatitis B surface antigen and Hepatitis B core antibody (IgM) and/or&#xD;
        Hepatitis C RNA) Currently active GI disease, or prior surgery that may affect ability to&#xD;
        absorb oral medications&#xD;
&#xD;
        History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment&#xD;
        epithelial detachment (RPED):&#xD;
&#xD;
          -  Predisposing factors to RVO or RPED (e.g. uncontrolled glaucoma or ocular&#xD;
             hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus,&#xD;
             or history of hyperviscosity or hypercoagulability syndromes)&#xD;
&#xD;
          -  Visible retinal pathology as assessed by ophthalmic exam that is considered a risk&#xD;
             factor for RVO or CSR such as:&#xD;
&#xD;
               -  Evidence of new optic disc cupping&#xD;
&#xD;
               -  Evidence of new visual field defects&#xD;
&#xD;
               -  Intraocular pressure &gt; 21 mm Hg Currently receiving cancer therapy (chemotherapy,&#xD;
                  radiotherapy, immunotherapy, or biologic therapy) NOTE: palliative radiation&#xD;
                  therapy is permitted for non-target lesions that are either new or present at&#xD;
                  baseline provided total dose does not exceed 30 Gy. However, radiation skin&#xD;
                  injury has been reported with concurrent use of dabrafenib and radiation. To&#xD;
                  reduce this risk, it is recommended that dabrafenib be held for seven days before&#xD;
                  and two days after radiation in subjects receiving dabrafenib in combination with&#xD;
                  trametinib when palliative radiation is prescribed.&#xD;
&#xD;
        Use of other prohibited medications within 5 half-lives or 14 days prior to the first dose&#xD;
        of study drugs or requires any of these medications while receiving medication on this&#xD;
        study Pregnant or lactating female&#xD;
&#xD;
        Inclusion Criteria for Off-Study Subjects to Receive Progression Biopsy&#xD;
&#xD;
        Currently progressing on Trametinib/Deabrafenib Combination Therapy&#xD;
&#xD;
        Willing to undergo biopsy for research purposes only.&#xD;
&#xD;
        Tumor amenable to research biopsy.&#xD;
&#xD;
        Signed written informed consent to have a progression biopsy performed on the LCCC 1128&#xD;
        protocol.&#xD;
&#xD;
        Previously enrolled on the LCCC 1128 study and did not have a progression biopsy previously&#xD;
        performed while on study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carrie Lee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UNC Lineberger Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lineberger Comprehensive Cancer Center, University of North Carolina</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.unclineberger.org</url>
    <description>Lineberger Comprehensive Cancer Center, UNC Chapel Hill, NC</description>
  </link>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>November 8, 2012</study_first_submitted>
  <study_first_submitted_qc>November 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 15, 2012</study_first_posted>
  <results_first_submitted>June 26, 2020</results_first_submitted>
  <results_first_submitted_qc>September 3, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">September 7, 2020</results_first_posted>
  <last_update_submitted>November 3, 2020</last_update_submitted>
  <last_update_submitted_qc>November 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 23, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Melanoma</keyword>
  <keyword>Stage III</keyword>
  <keyword>Stage IV</keyword>
  <keyword>Unresectable</keyword>
  <keyword>BRAF Mutant</keyword>
  <keyword>Dabrafenib</keyword>
  <keyword>Trametinib</keyword>
  <keyword>Kinome</keyword>
  <keyword>Resistance</keyword>
  <keyword>Sequencing</keyword>
  <keyword>Mutations</keyword>
  <keyword>Kinases</keyword>
  <keyword>Mechanism</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trametinib</mesh_term>
    <mesh_term>Dabrafenib</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 22, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/38/NCT01726738/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>A total of 17 participants were recruited from University of North Carolina Hospitals (Chapel Hill, NC) between January 2013 and July 2016</recruitment_details>
      <pre_assignment_details>In addition to the 17 patients who were enrolled and participated in the trial, 6 additional patients consented, but were found to be ineligible and 1 additional patient withdrew consent prior to starting the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
          <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the Recommend Phase 2 Dose (RP2D) determined in the Phase I/II study (BRF113220): trametinib 2mg once a day (QD) and dabrafenib 150 mg twice a day (BID) on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
          <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="17"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54" lower_limit="36" upper_limit="74"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Kinase Expression</title>
        <description>The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry (MS) and reported as a sum of the Log 2 Fold Change between baseline and one year post treatment across all patients</description>
        <time_frame>Baseline and One year post treatment</time_frame>
        <population>Progression samples were not available for 7 participants; 3 additional participants did not have samples that were evaluable by MIB/MS</population>
        <group_list>
          <group group_id="O1">
            <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
            <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Kinase Expression</title>
          <description>The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry (MS) and reported as a sum of the Log 2 Fold Change between baseline and one year post treatment across all patients</description>
          <population>Progression samples were not available for 7 participants; 3 additional participants did not have samples that were evaluable by MIB/MS</population>
          <units>Sum Log 2 Fold Change Kinase Expression</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>RIPK2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-20.87259"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PTK6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-19.64376"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BRAF</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-16.41738"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CDK1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.5401"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PAK4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.31239"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LIMK1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.38811"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>EIF2AK2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.51229"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AURKA</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.87395"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PI4K2B</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.66173"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PKMYT1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-11.3527"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MAP4K3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.8909"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>WEE1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.61838"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEC</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.15407"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CSNK1D</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.57122"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>EPHA4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.5134"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AURKB</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.70255"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ZAK</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.14964"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LIMK2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.86008"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ADCK4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-8.56373"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NME4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.34905"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Kinome Signature Predictive of Resistance</title>
        <description>Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.</description>
        <time_frame>One year post treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
            <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
          </group>
        </group_list>
        <measure>
          <title>Kinome Signature Predictive of Resistance</title>
          <description>Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.</description>
          <units>predictive kinase signatures</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes</title>
        <description>The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using Next Generation (NextGen) DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) or Cancer Osaka Thyroid (COT), and PTEN).</description>
        <time_frame>One year</time_frame>
        <population>Progression samples were not available for 7 participants; 3 additional participants did not have samples that were evaluable by MIB/MS</population>
        <group_list>
          <group group_id="O1">
            <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
            <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
          </group>
        </group_list>
        <measure>
          <title>BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes</title>
          <description>The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using Next Generation (NextGen) DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) or Cancer Osaka Thyroid (COT), and PTEN).</description>
          <population>Progression samples were not available for 7 participants; 3 additional participants did not have samples that were evaluable by MIB/MS</population>
          <units>Functional mutation predictors</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate (ORR)</title>
        <description>To determine the disease overall response rate (ORR: complete response (CR) + partial response (PR)/total number of patients) as measured radiographically via Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. CR is defined as the disappearance of all target lesions; PR is a &gt;=30% decrease in the sum of the longest diameter of target lesions</description>
        <time_frame>One year post treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
            <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR)</title>
          <description>To determine the disease overall response rate (ORR: complete response (CR) + partial response (PR)/total number of patients) as measured radiographically via Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. CR is defined as the disappearance of all target lesions; PR is a &gt;=30% decrease in the sum of the longest diameter of target lesions</description>
          <units>percentage of patients with response</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="76" lower_limit="50" upper_limit="93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Overall Response</title>
        <description>Duration of overall response is defined as the time from documentation of response (Complete or Partial) to time of disease progression or death. Response was measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. Complete Response is defined as the disappearance of all target lesions; Partial Response as a &gt;=30% decrease in the sum of the longest diameter of target lesions, and Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.</description>
        <time_frame>One year post treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
            <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Overall Response</title>
          <description>Duration of overall response is defined as the time from documentation of response (Complete or Partial) to time of disease progression or death. Response was measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. Complete Response is defined as the disappearance of all target lesions; Partial Response as a &gt;=30% decrease in the sum of the longest diameter of target lesions, and Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.</description>
          <units>Months</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13" lower_limit="1.4" upper_limit="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>PFS is defined as the time from Day 1 of protocol treatment to the date of progression as measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or to the date of death. Per RECIST, Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.</description>
        <time_frame>One year post treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
            <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS)</title>
          <description>PFS is defined as the time from Day 1 of protocol treatment to the date of progression as measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or to the date of death. Per RECIST, Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.</description>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17" lower_limit="4.1" upper_limit="25.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Overall Survival (OS) at 12 Months</title>
        <description>The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment</description>
        <time_frame>One year post treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
            <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Overall Survival (OS) at 12 Months</title>
          <description>The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment</description>
          <units>percentage of patients alive at 1 year</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="70" lower_limit="42" upper_limit="86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From start of treatment through 30 days after end of treatment</time_frame>
      <group_list>
        <group group_id="E1">
          <title>BRAF (Dabrafenib) and MEK (Trametinib) Inhibitors</title>
          <description>BRAF inhibitor dabrafenib and MEK inhibitor trametinib: Patients received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle is defined as 3 weeks in duration. Cycles were repeated until disease progression (clinical or radiological). Patients could remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Endocrine Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Gastrointestinal Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Flu Like Symptoms</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>General Disorders And Administration Site Conditions - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Multi-Organ Failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Treatment Related Secondary Malignancy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Intracranial Hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory Failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash Maculo-Papular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Skin And Subcutaneous Tissue Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Endocrine Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Cataract</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Eye Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Eye Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Floaters</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Watering Eyes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Dry Mouth</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Gastroesophageal Reflux Disease</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Gastrointestinal Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Stomach Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Edema Face</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Edema Limbs</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Flu Like Symptoms</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Gait Disturbance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>General Disorders And Administration Site Conditions - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Generalized Muscle Weakness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Non-Cardiac Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic Reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Gum Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Infections And Infestations - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Papulopustular Rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Tooth Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Vaginal Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Wound Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Alkaline Phosphatase Increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Blood Bilirubin Increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Cpk Increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Creatinine Increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Ejection Fraction Decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Ggt Increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Lipase Increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Lymphocyte Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Lymphocyte Count Increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Neutrophil Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Platelet Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Weight Gain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Weight Loss</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>White Blood Cell Decreased</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Flank Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Musculoskeletal And Connective Tissue Disorder - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Neck Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Pain In Extremity</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps) -</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Tumor Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Intracranial Hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Memory Impairment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Peripheral Sensory Neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Sinus Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Libido Decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Personality Change</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Psychiatric Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic Kidney Disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Urinary Incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Urinary Tract Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Dysmenorrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Reproductive System And Breast Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Vaginal Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic Rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Nasal Congestion</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Postnasal Drip</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Respiratory Failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Respiratory, Thoracic And Mediastinal Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Sore Throat</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Upper Respiratory Infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Dry Skin</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Erythema Multiforme</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Nail Loss</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Pain Of Skin</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Palmar-Plantar Erythrodysesthesia Syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Photosensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Rash Acneiform</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Rash Maculo-Papular</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Skin And Subcutaneous Tissue Disorders - Other, Specify</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Skin Induration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hot Flashes</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Robin Johnson</name_or_title>
      <organization>University of North Carolina Lineberger Comprehensive Cancer Center</organization>
      <phone>919-966-1125</phone>
      <email>robin_v_johnson@med.unc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01726738
org study id: LCCC 1128
nct id: NCT01726738
lead sponsor: 
collaborator: 
has dmc: Yes
This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma
      is designed to explore the mechanisms by which tumors acquire resistance to the combination
      of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at
      baseline and at progression.If a subject is removed from the study for one of a variety of
      reasons including, but not limited to, an inability to tolerate the combination of dabrafenib
      and trametinib, a need to receive other therapy or completion of 3-years of study treatment
      without progression, and the subject later receives, as part of his/her standard of care, the
      combination of dabrafenib and trametinib and progresses on the standard of care regimen, then
      the subject may be contacted by the treating physician to be put back on to the LCCC 1128
      protocol and have a progression biopsy at this progression time point. Markers of resistance
      will be explored by performing near kinome-wide profiling on tumor samples, and in patients
      who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA
      sequencing technology. Overall response rate and duration to this combination will also be
      assessed.
The present phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV
      melanoma is designed to explore the mechanisms by which tumors acquire resistance to the
      combination of BRAF and MEK inhibition. Overall response rate and duration to this
      combination will also be assessed.

      Tissue will be collected at baseline and at progression (clinical or radiological). Patients
      may remain on treatment after progression (at the discretion of the investigator) as long as
      they are still experiencing clinical benefit. We anticipate that up to 50% of patients may
      continue on therapy post-progression for 2-8 weeks.

      BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination with the MEK
      inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this
      combination, and to determine the recommended phase 2 doses (RP2D) for each agent. Expansion
      cohorts at the RP2D for these drugs in combination were included in the phase I to
      characterize the safety in more detail, and to explore the efficacy of this combination. The
      combination was well tolerated as described in section 1.5, with decreased frequency of rash
      compared to either agent alone and with just 1 report of cutaneous SCC.

      This proposed study will utilize the RP2D determined in the Phase I/II study: trametinib 2mg
      QD and dabrafenib 150 mg BID. Despite a very promising overall response rate of 81%, these
      patients will also likely go on to develop resistance as a result of new resistance
      mutations, and given the cooperative signaling network of kinases that sense inhibition of
      key nodal kinases and induce compensatory responses that offset pharmacological intervention.
      The study objectives are as follows: Objectives Primary Objective To identify kinases that
      are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK
      (trametinib) inhibitors, and to determine a kinome signature predictive of resistance to
      BRAF/MEK inhibition in stage III/IV melanoma Secondary Objectives To explore whether
      resistance to BRAF and MEK inhibition is associated with new functional mutations in the
      approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of
      the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll
      in LCCC1108, with particular focus on one of five established resistance genes (BRAF, NRAS,
      MEK1, MAP3K8 or COT, and PTEN) To determine the overall response rate (ORR: complete response
      + partial response) as measured via RECISTv1.1 To estimate the duration of ORR as measured
      via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1 To
      estimate the rate of overall survival (OS) at 1 year from day 1 of treatment

      Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression
      from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) coupled with
      mass spectrometry.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Kinase Expression
time frame: Baseline and One year post treatment
description: The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry (MS) and reported as a sum of the Log 2 Fold Change between baseline and one year post treatment across all patients
measure: Kinome Signature Predictive of Resistance
time frame: One year post treatment
description: Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.
measure: BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes
time frame: One year
description: The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using Next Generation (NextGen) DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) or Cancer Osaka Thyroid (COT), and PTEN).
measure: Overall Response Rate (ORR)
time frame: One year post treatment
description: To determine the disease overall response rate (ORR: complete response (CR) + partial response (PR)/total number of patients) as measured radiographically via Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. CR is defined as the disappearance of all target lesions; PR is a >=30% decrease in the sum of the longest diameter of target lesions
measure: Duration of Overall Response
time frame: One year post treatment
description: Duration of overall response is defined as the time from documentation of response (Complete or Partial) to time of disease progression or death. Response was measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions. Complete Response is defined as the disappearance of all target lesions; Partial Response as a >=30% decrease in the sum of the longest diameter of target lesions, and Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.
measure: Progression Free Survival (PFS)
time frame: One year post treatment
description: PFS is defined as the time from Day 1 of protocol treatment to the date of progression as measured radiographically using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or to the date of death. Per RECIST, Progressive Disease as a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesions.
measure: Rate of Overall Survival (OS) at 12 Months
time frame: One year post treatment
description: The rate of overall survival is defined as the percentage of patients still alive at one year from Day 1 of protocol treatment
arm group label: BRAF (dabrafenib) and MEK (trametinib) inhibitors
arm group type: Experimental
description: Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.
intervention type: Drug
intervention name: BRAF inhibitor dabrafenib and MEK inhibitor trametinib
description: Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.
arm group label: BRAF (dabrafenib) and MEK (trametinib) inhibitors
other name: BRAF Inhibitor Dabrafenib GSK2118436
other name: MEK Inhibitor Trametinib GSK1120212
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Carrie Lee, MD
role: Principal Investigator
affiliation: UNC Lineberger Comprehensive Cancer Center
facility: 
country: United States
url: http://www.unclineberger.org
description: Lineberger Comprehensive Cancer Center, UNC Chapel Hill, NC
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Trametinib
mesh term: Dabrafenib
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 