<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/NCT01701037</url>
  </required_header>
  <id_info>
    <org_study_id>VICC MEL 1263</org_study_id>
    <secondary_id>NCI-2012-01699</secondary_id>
    <nct_id>NCT01701037</nct_id>
  </id_info>
  <brief_title>Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery</brief_title>
  <official_title>Biomarkers of Response and Resistance to Sequential B-RAF and MEK Targeted Therapy in a Pre-Surgical Model of Advanced, Operable Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt-Ingram Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Comprehensive Cancer Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt-Ingram Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well giving dabrafenib alone and in combination with&#xD;
      trametinib before surgery works in treating patients with advanced melanoma that can be&#xD;
      removed by surgery. Studying samples of tumor tissue in the laboratory from patients&#xD;
      receiving dabrafenib and trametinib may help doctors learn more about the effects of these&#xD;
      drugs on cells and help identify biomarkers that determine which patients will respond to&#xD;
      these drugs best.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To identify markers of intrinsic resistance to v-Raf murine sarcoma viral oncogene homolog&#xD;
      B1 (B-RAF) targeted therapy in B-RAF mutation-positive melanoma.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine if intrinsic resistance can be reversed by mitogen activated protein kinase&#xD;
      (MEK) targeted therapy and to identify biomarkers that correlate with this response.&#xD;
&#xD;
      II. To evaluate the feasibility of pre-surgical targeted therapy and serial tumor biopsies in&#xD;
      patients with advanced, operable melanoma to determine if this model can be used to evaluate&#xD;
      novel combinations of molecular targeted therapy in the future.&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. To determine if pre-surgical B-RAF and MEK targeted therapy is active and well tolerated&#xD;
      in patients with advanced, operable melanoma. These findings may be used to support clinical&#xD;
      trials in un-resectable, B-RAF mutation-positive melanoma.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 adding trametinib on&#xD;
      days 15-28 followed by surgery on days 28-30. Treatment continues until the day prior to&#xD;
      surgery in the absence of unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 3 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    PI leaving VICC, low future accrual predicted, continued funding improbable,&#xD;
  </why_stopped>
  <start_date>January 2013</start_date>
  <completion_date type="Actual">April 2015</completion_date>
  <primary_completion_date type="Actual">February 2015</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical Tumor Response Rate (Response is Based on Greater Than 30% Reduction From Baseline in Tumor Volume by RECIST Criteria) at Day 14.</measure>
    <time_frame>day 14</time_frame>
    <description>Tumor response is defined as greater than 30% reduction from baseline in tumor volume by RECIST criteria. To determine whether a patient is responded at day 14, the patient must have the tumor volume evaluated at both baseline and day 14. The tumor response rate is calculated as the proportion of patients responded among all evaluated patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Tumor Volume Reduction in Participants With Intrinsic Resistance to B-RAF Targeted Therapy From Day 14 to Day 28.</measure>
    <time_frame>Day 14 and day 28</time_frame>
    <description>Tumor volume reduction is calculated as the tumor volume change relative to the baseline measurement (percent). Change in tumor volume reduction from day 14 to day 28 is calculated as the difference of tumor volume reduction at day 28 and day 14. The median and Inter-Quartile Range are reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Worst Grade Toxicities by Grade According to National Cancer Institute (NCI) CTCAE Version 4.0</measure>
    <time_frame>Up to 3 months</time_frame>
    <description>The intensity of the adverse event will be graded according to Version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (June 14, 2010):&#xD;
Grade 1 - Mild Grade 2 - Moderate Grade 3 - Severe or medically significant Grade 4 - Life-threatening Grade 5 - Death related to adverse event</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Investigational Agent Taken</measure>
    <time_frame>Up to 3 months</time_frame>
    <description>Median number of pills taken</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of Patients Completing Second and Third (Surgical) Biopsies</measure>
    <time_frame>Up to 3 months</time_frame>
    <description>Biopsies will be assessed whether or not tissue is acquired at specified time points. Tissue is obtained through core, punch, incisional or excisional biopsy or surgical resection, based upon the clinical situation. Standard operating procedures for biopsies, sample preparation and analysis have been defined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Biopsies With Adequate Tissue for Biomarker Analysis</measure>
    <time_frame>Up to 3 months</time_frame>
    <description>Measured by the percent of tumor necrosis on hematoxylin and eosin stains; RNA gel electrophoresis, percent of adequate tissue for immunohistochemical stains in tissue microarray and cyTOF analysis.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Recurrent Melanoma</condition>
  <condition>Stage IIB Melanoma (Locally Advanced)</condition>
  <condition>Stage IIC Melanoma (Locally Advanced)</condition>
  <condition>Stage IIIA Melanoma</condition>
  <condition>Stage IIIB Melanoma</condition>
  <condition>Stage IIIC Melanoma</condition>
  <condition>Stage IV Melanoma (Limited, Resectable)</condition>
  <arm_group>
    <arm_group_label>Dabrafenib and Trametinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>dabrafenib</intervention_name>
    <description>150 mg given PO</description>
    <arm_group_label>Dabrafenib and Trametinib</arm_group_label>
    <other_name>BRAF inhibitor GSK2118436</other_name>
    <other_name>GSK2118436</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>trametinib</intervention_name>
    <description>2 mg given PO</description>
    <arm_group_label>Dabrafenib and Trametinib</arm_group_label>
    <other_name>GSK1120212</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Dabrafenib and Trametinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
          -  Patients with locally-or regionally advanced melanoma being considered for resection&#xD;
             of the lesion(s) for local-regional control and potential cure&#xD;
&#xD;
               -  Patients with limited, resectable metastatic disease (three or fewer lesions) are&#xD;
                  eligible if surgical resection is considered to be the best therapeutic option&#xD;
&#xD;
               -  Patients with AJCC clinical stage IIb-IV disease at initial diagnosis, or&#xD;
                  patients with melanoma of any stage with advanced local or regional recurrence,&#xD;
                  with or without limited resectable metastatic disease, would be eligible&#xD;
&#xD;
          -  B-RAF V-600 mutation positive by snapshot molecular analysis&#xD;
&#xD;
               -  Individuals with B-RAF V-600 mutations other than V600E are eligible&#xD;
&#xD;
          -  Measurable disease, i.e. presenting with at least one measurable lesion per Response&#xD;
             Evaluation Criteria in Solid tumors (RECIST) 1.1&#xD;
&#xD;
          -  All prior treatment related toxicities must be Common Terminology Criteria for Adverse&#xD;
             Events (CTCAE) (Version 4.0) =&lt; Grade 1 at the time of enrollment&#xD;
&#xD;
          -  Adequate baseline organ function defined by the criteria below:&#xD;
&#xD;
               -  Absolute Neutrophil Count (ANC) &gt;= 1.5 X 10^9/L&#xD;
&#xD;
               -  Platelet Count &gt;= 60 X 10^9/L&#xD;
&#xD;
               -  Hemoglobin &gt;= 9 g/dl&#xD;
&#xD;
               -  Creatinine =&lt; 2 mg/dl&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) =&lt; 100 U/L&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) =&lt; 100 U/L&#xD;
&#xD;
               -  Alkaline Phosphatase =&lt; 380 U/L&#xD;
&#xD;
               -  Total Bilirubin =&lt; 2.0 mg/dl&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test within 14&#xD;
             days of first dose of study treatment and agree to use effective contraception during&#xD;
             the study and for 7 days following the last dose of study treatment&#xD;
&#xD;
          -  Men with a female partner of childbearing potential must have either had a prior&#xD;
             vasectomy or agree to use effective contraception from 1 day prior to administration&#xD;
             of the first dose of study treatment until 7 days after the last dose of study&#xD;
             treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  ECOG Performance Status &gt; 2&#xD;
&#xD;
          -  Lactating female&#xD;
&#xD;
          -  Any serious and/or unstable pre-existing medical, psychiatric disorder, or other&#xD;
             conditions that could interfere with subject's safety, obtaining informed consent or&#xD;
             compliance to the study procedures&#xD;
&#xD;
          -  Any serious medical condition that would render the patient unable to undergo surgical&#xD;
             resection or would limit life expectancy to less than 1 year&#xD;
&#xD;
          -  Any prohibited medication&#xD;
&#xD;
          -  Administration of an investigational drug within 30 days or 5 half-lives, whichever is&#xD;
             longer, preceding the first dose of study treatment&#xD;
&#xD;
          -  A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
             chemically related to GSK-2118436 (dabrafenib) or GSK-1120212 (trametinib) or&#xD;
             excipient that contraindicates their participation&#xD;
&#xD;
          -  Patients with a history of severe cardiovascular disease as defined:&#xD;
&#xD;
               -  Symptomatic or uncontrolled cardiac arrhythmias&#xD;
&#xD;
               -  Treatment refractory hypertension, defined as a systolic blood pressure &gt; 160mm&#xD;
                  Hg and/or diastolic &gt; 100 mmHg which cannot be controlled by antihypertensive&#xD;
                  therapy.&#xD;
&#xD;
               -  Current ≥ NYHA Class II congestive heart failure&#xD;
&#xD;
               -  History of myocardial infarction or unstable angina within 6 months prior to&#xD;
                  study entry.&#xD;
&#xD;
               -  History of stroke or TIA within 6 months prior to study entry&#xD;
&#xD;
               -  QTc ≥ 480 msec&#xD;
&#xD;
               -  Cardiac valvular disease ≥ grade 2.&#xD;
&#xD;
          -  Patients with a history of interstitial lung disease or interstitial pneumonitis&#xD;
&#xD;
          -  A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or&#xD;
             Hepatitis C Virus (HCV) infection.&#xD;
&#xD;
          -  History of another active malignancy within the past 5 years, or any malignancy with a&#xD;
             confirmed activating RAS mutation. Please note that prospective RAS mutation testing&#xD;
             is not required, however, if results of previous RAS testing are known, they must be&#xD;
             used in assessing eligibility. Subjects with a history of completely resected&#xD;
             non-melanoma skin cancer are eligible.&#xD;
&#xD;
          -  A history or current evidence/risk of retinal vein occlusion (RVO) or CSR including:&#xD;
&#xD;
          -  a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or&#xD;
             ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a&#xD;
             history of hyperviscosity or hypercoagulability syndromes); or&#xD;
&#xD;
          -  b. Visible retinal pathology as assessed by ophthalmic examination that is considered&#xD;
             a risk factor for RVO or CSR such as:&#xD;
&#xD;
               -  i. Evidence of new optic disc cupping;&#xD;
&#xD;
               -  ii. Evidence of new visual field defects on automated perimetry;&#xD;
&#xD;
               -  iii. Intraocular pressure &gt;21 mmHg as measured by tonography.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark Kelley</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt-Ingram Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt-Ingram Cancer Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232-6838</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.vicc.org/ct/</url>
    <description>Vanderbilt-Ingram Cancer Center, Find a Clinical Trial</description>
  </link>
  <results_reference>
    <citation>Johnson AS, Crandall H, Dahlman K, Kelley MC. Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma. J Am Coll Surg. 2015 Apr;220(4):581-93.e1. doi: 10.1016/j.jamcollsurg.2014.12.057. Epub 2015 Jan 30.</citation>
    <PMID>25797743</PMID>
  </results_reference>
  <verification_date>June 2017</verification_date>
  <study_first_submitted>September 21, 2012</study_first_submitted>
  <study_first_submitted_qc>October 2, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <results_first_submitted>March 10, 2017</results_first_submitted>
  <results_first_submitted_qc>June 20, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">June 23, 2017</results_first_posted>
  <last_update_submitted>June 20, 2017</last_update_submitted>
  <last_update_submitted_qc>June 20, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 23, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt-Ingram Cancer Center</investigator_affiliation>
    <investigator_full_name>Mark Kelley, MD</investigator_full_name>
    <investigator_title>Chief, Division of Surgical Oncology and Endocrine Surgery; Associate Professor of Surgery; Surgical Oncologist</investigator_title>
  </responsible_party>
  <keyword>Melanoma, B-RAF, biomarkers, targeted therapy, resistance</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>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study opened to accrual at Vanderbilt-Ingram Cancer Center (VICC) in January 2013 and ran through March 2015 when it closed prematurely due to PI's departure.</recruitment_details>
      <pre_assignment_details>Thirteen patients participated in this study, all completed the study as defined by protocol.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Basic Science (Dabrafenib, Trametinib)</title>
          <description>Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.&#xD;
dabrafenib: 150 mg given PO&#xD;
trametinib: 2 mg given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
              </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>Basic Science (Dabrafenib, Trametinib)</title>
          <description>Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.&#xD;
dabrafenib: 150 mg given PO&#xD;
trametinib: 2 mg given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="13"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>20-29</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30-39</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>40-49</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>50-59</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>60-69</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>70-79</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </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="6"/>
                  </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="13"/>
                  </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="13"/>
                  </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>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Clinical Tumor Response Rate (Response is Based on Greater Than 30% Reduction From Baseline in Tumor Volume by RECIST Criteria) at Day 14.</title>
        <description>Tumor response is defined as greater than 30% reduction from baseline in tumor volume by RECIST criteria. To determine whether a patient is responded at day 14, the patient must have the tumor volume evaluated at both baseline and day 14. The tumor response rate is calculated as the proportion of patients responded among all evaluated patients.</description>
        <time_frame>day 14</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib</title>
            <description>Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.&#xD;
dabrafenib: 150 mg given PO&#xD;
trametinib: 2 mg given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Tumor Response Rate (Response is Based on Greater Than 30% Reduction From Baseline in Tumor Volume by RECIST Criteria) at Day 14.</title>
          <description>Tumor response is defined as greater than 30% reduction from baseline in tumor volume by RECIST criteria. To determine whether a patient is responded at day 14, the patient must have the tumor volume evaluated at both baseline and day 14. The tumor response rate is calculated as the proportion of patients responded among all evaluated patients.</description>
          <units>proportion of responders</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="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.833" lower_limit="0.552" upper_limit="0.953"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Tumor Volume Reduction in Participants With Intrinsic Resistance to B-RAF Targeted Therapy From Day 14 to Day 28.</title>
        <description>Tumor volume reduction is calculated as the tumor volume change relative to the baseline measurement (percent). Change in tumor volume reduction from day 14 to day 28 is calculated as the difference of tumor volume reduction at day 28 and day 14. The median and Inter-Quartile Range are reported.</description>
        <time_frame>Day 14 and day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib</title>
            <description>Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.&#xD;
dabrafenib: 150 mg given PO&#xD;
trametinib: 2 mg given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Tumor Volume Reduction in Participants With Intrinsic Resistance to B-RAF Targeted Therapy From Day 14 to Day 28.</title>
          <description>Tumor volume reduction is calculated as the tumor volume change relative to the baseline measurement (percent). Change in tumor volume reduction from day 14 to day 28 is calculated as the difference of tumor volume reduction at day 28 and day 14. The median and Inter-Quartile Range are reported.</description>
          <units>percentage of reduction</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.0" lower_limit="16.5" upper_limit="23.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Worst Grade Toxicities by Grade According to National Cancer Institute (NCI) CTCAE Version 4.0</title>
        <description>The intensity of the adverse event will be graded according to Version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (June 14, 2010):&#xD;
Grade 1 - Mild Grade 2 - Moderate Grade 3 - Severe or medically significant Grade 4 - Life-threatening Grade 5 - Death related to adverse event</description>
        <time_frame>Up to 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib</title>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Worst Grade Toxicities by Grade According to National Cancer Institute (NCI) CTCAE Version 4.0</title>
          <description>The intensity of the adverse event will be graded according to Version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (June 14, 2010):&#xD;
Grade 1 - Mild Grade 2 - Moderate Grade 3 - Severe or medically significant Grade 4 - Life-threatening Grade 5 - Death related to adverse event</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Number of patients with worst-grade toxicity 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with worst-grade toxicity 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with worst-grade toxicity 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with worst-grade toxicity 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of patients with worst-grade toxicity 5</title>
              <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>Investigational Agent Taken</title>
        <description>Median number of pills taken</description>
        <time_frame>Up to 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib</title>
            <description>Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.&#xD;
dabrafenib: 150 mg given PO&#xD;
trametinib: 2 mg given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Investigational Agent Taken</title>
          <description>Median number of pills taken</description>
          <units>Number of pills taken</units>
          <param>Median</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Median number of GSK1120212 taken</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13" spread="1.90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Median number of GSK2118436 taken</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54" spread="6.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent of Patients Completing Second and Third (Surgical) Biopsies</title>
        <description>Biopsies will be assessed whether or not tissue is acquired at specified time points. Tissue is obtained through core, punch, incisional or excisional biopsy or surgical resection, based upon the clinical situation. Standard operating procedures for biopsies, sample preparation and analysis have been defined.</description>
        <time_frame>Up to 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib</title>
          </group>
        </group_list>
        <measure>
          <title>Percent of Patients Completing Second and Third (Surgical) Biopsies</title>
          <description>Biopsies will be assessed whether or not tissue is acquired at specified time points. Tissue is obtained through core, punch, incisional or excisional biopsy or surgical resection, based upon the clinical situation. Standard operating procedures for biopsies, sample preparation and analysis have been defined.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Biopsies With Adequate Tissue for Biomarker Analysis</title>
        <description>Measured by the percent of tumor necrosis on hematoxylin and eosin stains; RNA gel electrophoresis, percent of adequate tissue for immunohistochemical stains in tissue microarray and cyTOF analysis.</description>
        <time_frame>Up to 3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib and Trametinib</title>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Biopsies With Adequate Tissue for Biomarker Analysis</title>
          <description>Measured by the percent of tumor necrosis on hematoxylin and eosin stains; RNA gel electrophoresis, percent of adequate tissue for immunohistochemical stains in tissue microarray and cyTOF analysis.</description>
          <units>percentage of biopsies w/adequate tissue</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Serious adverse events and Adverse events were collected over 25 months period.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Basic Science (Dabrafenib, Trametinib)</title>
          <description>Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.&#xD;
dabrafenib: 150 mg given PO&#xD;
trametinib: 2 mg given PO&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Stroke</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Kidney Injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Constipationi</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Edema, limbs</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Facial pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Seroma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cholesterol high</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Other</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </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" events="7" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Generalized skin senstivity</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Erythroderma</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </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>Mark C. Kelley</name_or_title>
      <organization>Vanderbilt-Ingram Cancer Center</organization>
      <phone>615-936-7423</phone>
      <email>mark.kelley@vanderbilt.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/NCT01701037
org study id: VICC MEL 1263
secondary id: NCI-2012-01699
nct id: NCT01701037
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This phase II trial studies how well giving dabrafenib alone and in combination with
      trametinib before surgery works in treating patients with advanced melanoma that can be
      removed by surgery. Studying samples of tumor tissue in the laboratory from patients
      receiving dabrafenib and trametinib may help doctors learn more about the effects of these
      drugs on cells and help identify biomarkers that determine which patients will respond to
      these drugs best.
PRIMARY OBJECTIVES:

      I. To identify markers of intrinsic resistance to v-Raf murine sarcoma viral oncogene homolog
      B1 (B-RAF) targeted therapy in B-RAF mutation-positive melanoma.

      SECONDARY OBJECTIVES:

      I. To determine if intrinsic resistance can be reversed by mitogen activated protein kinase
      (MEK) targeted therapy and to identify biomarkers that correlate with this response.

      II. To evaluate the feasibility of pre-surgical targeted therapy and serial tumor biopsies in
      patients with advanced, operable melanoma to determine if this model can be used to evaluate
      novel combinations of molecular targeted therapy in the future.

      TERTIARY OBJECTIVES:

      I. To determine if pre-surgical B-RAF and MEK targeted therapy is active and well tolerated
      in patients with advanced, operable melanoma. These findings may be used to support clinical
      trials in un-resectable, B-RAF mutation-positive melanoma.

      OUTLINE:

      Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 adding trametinib on
      days 15-28 followed by surgery on days 28-30. Treatment continues until the day prior to
      surgery in the absence of unacceptable toxicity.

      After completion of study treatment, patients are followed up for 3 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Clinical Tumor Response Rate (Response is Based on Greater Than 30% Reduction From Baseline in Tumor Volume by RECIST Criteria) at Day 14.
time frame: day 14
description: Tumor response is defined as greater than 30% reduction from baseline in tumor volume by RECIST criteria. To determine whether a patient is responded at day 14, the patient must have the tumor volume evaluated at both baseline and day 14. The tumor response rate is calculated as the proportion of patients responded among all evaluated patients.
measure: Change in Tumor Volume Reduction in Participants With Intrinsic Resistance to B-RAF Targeted Therapy From Day 14 to Day 28.
time frame: Day 14 and day 28
description: Tumor volume reduction is calculated as the tumor volume change relative to the baseline measurement (percent). Change in tumor volume reduction from day 14 to day 28 is calculated as the difference of tumor volume reduction at day 28 and day 14. The median and Inter-Quartile Range are reported.
measure: Number of Patients With Worst Grade Toxicities by Grade According to National Cancer Institute (NCI) CTCAE Version 4.0
time frame: Up to 3 months
description: The intensity of the adverse event will be graded according to Version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (June 14, 2010):
Grade 1 - Mild Grade 2 - Moderate Grade 3 - Severe or medically significant Grade 4 - Life-threatening Grade 5 - Death related to adverse event
measure: Investigational Agent Taken
time frame: Up to 3 months
description: Median number of pills taken
measure: Percent of Patients Completing Second and Third (Surgical) Biopsies
time frame: Up to 3 months
description: Biopsies will be assessed whether or not tissue is acquired at specified time points. Tissue is obtained through core, punch, incisional or excisional biopsy or surgical resection, based upon the clinical situation. Standard operating procedures for biopsies, sample preparation and analysis have been defined.
measure: Percentage of Biopsies With Adequate Tissue for Biomarker Analysis
time frame: Up to 3 months
description: Measured by the percent of tumor necrosis on hematoxylin and eosin stains; RNA gel electrophoresis, percent of adequate tissue for immunohistochemical stains in tissue microarray and cyTOF analysis.
arm group label: Dabrafenib and Trametinib
arm group type: Experimental
description: Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.
intervention type: Drug
intervention name: dabrafenib
description: 150 mg given PO
arm group label: Dabrafenib and Trametinib
other name: BRAF inhibitor GSK2118436
other name: GSK2118436
intervention type: Drug
intervention name: trametinib
description: 2 mg given PO
arm group label: Dabrafenib and Trametinib
other name: GSK1120212
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Dabrafenib and Trametinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Mark Kelley
role: Principal Investigator
affiliation: Vanderbilt-Ingram Cancer Center
facility: 
country: United States
url: http://www.vicc.org/ct/
description: Vanderbilt-Ingram Cancer Center, Find a Clinical Trial
citation: Johnson AS, Crandall H, Dahlman K, Kelley MC. Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma. J Am Coll Surg. 2015 Apr;220(4):581-93.e1. doi: 10.1016/j.jamcollsurg.2014.12.057. Epub 2015 Jan 30.
PMID: 25797743
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt-Ingram Cancer Center
investigator full name: Mark Kelley, MD
investigator title: Chief, Division of Surgical Oncology and Endocrine Surgery; Associate Professor of Surgery; Surgical Oncologist
mesh term: Melanoma
mesh term: Trametinib
mesh term: Dabrafenib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 