<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/NCT02230306</url>
  </required_header>
  <id_info>
    <org_study_id>13-123</org_study_id>
    <secondary_id>ML29155</secondary_id>
    <nct_id>NCT02230306</nct_id>
  </id_info>
  <brief_title>Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases</brief_title>
  <acronym>CoBRIM-B</acronym>
  <official_title>Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Melissa Burgess, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib&#xD;
      with cobimetinib in patients with active melanoma brain metastases.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    closed due to slow accrual&#xD;
  </why_stopped>
  <start_date>February 2015</start_date>
  <completion_date type="Actual">March 2016</completion_date>
  <primary_completion_date type="Actual">March 2016</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>Objective Intracranial Response (OIRR)</measure>
    <time_frame>Until disease progression, less than or equal to 5 years.</time_frame>
    <description>Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response</measure>
    <time_frame>Until disease progression, less than or equal to 5 years.</time_frame>
    <description>Response to study treatment achieved by individual patients as indicated by an overall change in size of the sum of diameters from baseline of up to 5 intracranial target lesions and up to 5 extracranial target lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Time (number of months) from first documented evidence of overall Complete Response (CR) or Partial Response (PR) until time of first documented disease progression or death due to any cause (for individual patients). Progression as defined by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) is a ≥ 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Number of months of survival for individual patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>Until disease progression, less than or equal to 5 years.</time_frame>
    <description>Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patient</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune Modulation in Peripheral Blood</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early Markers of Progression in Peripheral Blood</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure general quality of life (QOL) that reflects symptoms or problems associated with brain malignancies across 5 scales. The brain subscale is usually used along with the core (general) questionnaire that includes 27 items. The measure yields information about total QOL, as well as information about the dimensions of physical well-being, social/family well-being, emotional well being, functional well-being, and disease-specific concerns. Patients rate all 5 items using a five-point Likert scale ranging from 0 &quot;not at all&quot; to 4 &quot;very much.&quot; Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Scoring range is 0-200.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Active Melanoma Brain Metastases</condition>
  <arm_group>
    <arm_group_label>Cobimetinib in Combination with Vemurafenib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Vemurafenib (960 mg twice a day) will be taken on Days 1 - 28 of each 28-day treatment cycle. The first dose of vemurafenib should be taken in the morning, and the second dose should be taken in the evening. Vemurafenib can be taken with or without a meal and should be taken with a glass of water.&#xD;
Cobimetinib (60 mg once a day) will be taken on Days 1 - 21 of each 28-day treatment cycle. The cobimetinib tablet should be taken at approximately the same time each day in the morning with the vemurafenib dose, but no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal and should never be chewed, cut, or crushed and should be taken with a glass of water.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cobimetinib</intervention_name>
    <description>60mg once a day; will be taken on days 1-21 of each 28 day treatment cycle; will be taken in combination with Vemurafenib;</description>
    <arm_group_label>Cobimetinib in Combination with Vemurafenib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vemurafenib</intervention_name>
    <description>960mg twice a day; 28 day treatment cycle; will be taken in combination with Cobimetinib;</description>
    <arm_group_label>Cobimetinib in Combination with Vemurafenib</arm_group_label>
    <other_name>Zelboraf</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600-mutation&#xD;
&#xD;
          -  Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved&#xD;
             laboratory&#xD;
&#xD;
          -  At least one measurable intracranial target lesion for which all of the following&#xD;
             criteria are met:&#xD;
&#xD;
               1. previously untreated or progressive according to RECIST 1.1 (equal to or greater&#xD;
                  than 20% increase in longest diameter on baseline scan) after previous local&#xD;
                  therapy (SRS and/or craniotomy)&#xD;
&#xD;
               2. immediate local therapy clinically not indicated or patient is not a suitable&#xD;
                  candidate to receive immediate local therapy (SRS and/or craniotomy)&#xD;
&#xD;
               3. largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced MRI&#xD;
&#xD;
          -  Prior therapies for extracranial metastatic melanoma including chemo-, cytokine-,&#xD;
             immuno-, biological- and vaccine-therapy will be allowed but prior BRAF or MEK not&#xD;
             allowed&#xD;
&#xD;
          -  ECOG PS 0-2&#xD;
&#xD;
          -  Life expectancy &gt;12 weeks&#xD;
&#xD;
          -  Age 18 years or older&#xD;
&#xD;
          -  Adequate bone marrow function as indicated by the following:&#xD;
&#xD;
               1. ANC &gt; 1500/µL&#xD;
&#xD;
               2. Platelets ≥ 100,000/µL&#xD;
&#xD;
               3. Hemoglobin &gt; 9 g/dL&#xD;
&#xD;
          -  Adequate renal function, as indicated by creatinine =/&lt; 1.5 x the upper limit of&#xD;
             normal (ULN)&#xD;
&#xD;
          -  Adequate liver function, as indicated by bilirubin =/&lt; 1.5 x ULN&#xD;
&#xD;
          -  AST or ALT &lt; 3 x ULN (patients with documented liver metastases: AST and/or ALT =/&lt; 5&#xD;
             x ULN)&#xD;
&#xD;
          -  Able to swallow pills&#xD;
&#xD;
          -  Negative serum pregnancy test within 7 days prior to commencement of dosing in&#xD;
             premenopausal women. Women of non-childbearing potential may be included without serum&#xD;
             pregnancy test if they are either surgically sterile or have been postmenopausal for ≥&#xD;
             1 year&#xD;
&#xD;
          -  Fertile men and women must use an effective method of contraception during treatment&#xD;
             and for at least 6 months after completion of treatment as directed by their&#xD;
             physician. Effective methods of contraception are defined as those which result in a&#xD;
             low failure rate (i.e., less than 1% per year) when used consistently and correctly&#xD;
             (for example implants, injectables, combined oral contraception or intra-uterine&#xD;
             devices). At the discretion of the Investigator, acceptable methods of contraception&#xD;
             may include total abstinence in cases where the lifestyle of the patient ensures&#xD;
             compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal,&#xD;
             post-ovulation methods] and withdrawal are not acceptable methods of contraception.)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Active infection&#xD;
&#xD;
          -  Prior therapy with BRAFi and/or MEKi&#xD;
&#xD;
          -  Leptomeningeal disease&#xD;
&#xD;
          -  Symptomatic brain metastases requiring immediate local interventions such as&#xD;
             craniotomy or SRS&#xD;
&#xD;
          -  Increasing corticosteroid dose in 7 days prior to administration of first dose of&#xD;
             study drug. Symptomatic patients that have stable or decreasing corticosteroid use in&#xD;
             the past 7 days will be allowed&#xD;
&#xD;
          -  Current use of therapeutic warfarin&#xD;
&#xD;
          -  Unresolved toxicity of National Cancer Institute Common Terminology Criteria for&#xD;
             Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous&#xD;
             anti-cancer therapy, except alopecia&#xD;
&#xD;
          -  Conditions that will interfere significantly with the absorption of drugs&#xD;
&#xD;
          -  Inability to undergo MRI secondary to metal, claustrophobia, Gadolinium Contrast&#xD;
             allergy&#xD;
&#xD;
          -  Pregnant, lactating, or breast feeding women&#xD;
&#xD;
          -  Prior radiation therapy within the last 14 days&#xD;
&#xD;
          -  Concomitant malignancies or previous malignancies within the last 5 years, with the&#xD;
             exception of adequately treated basal or squamous cell carcinoma of the skin or&#xD;
             carcinoma in situ of the cervix&#xD;
&#xD;
          -  Unwillingness or inability to comply with study and follow-up procedures&#xD;
&#xD;
          -  The following foods/supplements are prohibited at least 7 days prior to initiation of&#xD;
             and during study treatment:&#xD;
&#xD;
               1. St. John's wort or hyperforin&#xD;
&#xD;
               2. Grapefruit juice&#xD;
&#xD;
          -  History of or evidence of retinal pathology on ophthalmologic examination that is&#xD;
             considered a risk factor for neurosensory retinal detachment, Retinal Vein Occlusion&#xD;
             (RVO), or neovascular macular degeneration&#xD;
&#xD;
          -  Uncontrolled glaucoma with intra-ocular pressures &gt; 21mmHg&#xD;
&#xD;
          -  Serum cholesterol ≥ Grade 2&#xD;
&#xD;
          -  Hypertriglyceridemia ≥ Grade 2&#xD;
&#xD;
          -  Hyperglycemia (fasting) ≥ Grade 2&#xD;
&#xD;
          -  History of clinically significant cardiac dysfunction, including the following:&#xD;
&#xD;
               1. Current unstable angina&#xD;
&#xD;
               2. Current symptomatic congestive heart failure of NYHA class 2 or higher&#xD;
&#xD;
               3. History of congenital long QT syndrome or mean QTcF &gt; 450 msec at baseline or&#xD;
                  uncorrectable electrolyte abnormalities&#xD;
&#xD;
               4. Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension&#xD;
                  controlled with anti-hypertensives to ≤ Grade 1 are eligible)&#xD;
&#xD;
               5. Left ventricular ejection fraction (LVEF) below 50%&#xD;
&#xD;
               6. Uncontrolled Arrhythmias&#xD;
&#xD;
               7. Myocardial infarction, severe/unstable angina, symptomatic congestive heart&#xD;
                  failure, cerebrovascular accident or transient ischemic attack within the&#xD;
                  previous 6 months&#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>Melissa Burgess, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Richard Carvajal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Anna Pavlick, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NYU Clinical Cancer Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mohammed Milhem, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Univ of Iowa</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ravi Amaravadi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Univ of Pennsylvania</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Harriet Kluger, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale New Haven Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Harriet Kluger</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mohammed Milhem, MD</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Anna Pavlick, MD</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ravi Amaravadi, MD</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>August 27, 2014</study_first_submitted>
  <study_first_submitted_qc>August 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2014</study_first_posted>
  <results_first_submitted>July 14, 2017</results_first_submitted>
  <results_first_submitted_qc>September 11, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">October 12, 2017</results_first_posted>
  <last_update_submitted>September 11, 2017</last_update_submitted>
  <last_update_submitted_qc>September 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 12, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Melissa Burgess, MD</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vemurafenib</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Cobimetinib in Combination With Vemurafenib</title>
          <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Did not receive study treatment</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Cobimetinib in Combination With Vemurafenib</title>
          <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="5"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>years</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Patient 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="63"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Objective Intracranial Response (OIRR)</title>
        <description>Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients.</description>
        <time_frame>Until disease progression, less than or equal to 5 years.</time_frame>
        <population>Patients who received study treatment and were assessed by MRI every 8 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Intracranial Response (OIRR)</title>
          <description>Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients.</description>
          <population>Patients who received study treatment and were assessed by MRI every 8 weeks.</population>
          <units>centimeters</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patient #1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response</title>
        <description>Response to study treatment achieved by individual patients as indicated by an overall change in size of the sum of diameters from baseline of up to 5 intracranial target lesions and up to 5 extracranial target lesions.</description>
        <time_frame>Until disease progression, less than or equal to 5 years.</time_frame>
        <population>Patients who received study treatment and were assessed by MRI every 8 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response</title>
          <description>Response to study treatment achieved by individual patients as indicated by an overall change in size of the sum of diameters from baseline of up to 5 intracranial target lesions and up to 5 extracranial target lesions.</description>
          <population>Patients who received study treatment and were assessed by MRI every 8 weeks.</population>
          <units>centimeters</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patient #1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS)</title>
        <description>Time (number of months) from first documented evidence of overall Complete Response (CR) or Partial Response (PR) until time of first documented disease progression or death due to any cause (for individual patients). Progression as defined by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) is a ≥ 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.</description>
        <time_frame>Up to 5 years</time_frame>
        <population>Patients who received study treatment and were assessed by MRI every 8 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS)</title>
          <description>Time (number of months) from first documented evidence of overall Complete Response (CR) or Partial Response (PR) until time of first documented disease progression or death due to any cause (for individual patients). Progression as defined by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) is a ≥ 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.</description>
          <population>Patients who received study treatment and were assessed by MRI every 8 weeks.</population>
          <units>months</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patient #1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>Number of months of survival for individual patients.</description>
        <time_frame>Up to 5 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>Number of months of survival for individual patients.</description>
          <units>months</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patient #1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response</title>
        <description>Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patient</description>
        <time_frame>Until disease progression, less than or equal to 5 years.</time_frame>
        <population>Patients for whom response duration data was obtainable in those that received MRI tumor assessments every 8 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response</title>
          <description>Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patient</description>
          <population>Patients for whom response duration data was obtainable in those that received MRI tumor assessments every 8 weeks.</population>
          <units>months</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patient #1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Immune Modulation in Peripheral Blood</title>
        <time_frame>Up to 5 years</time_frame>
        <population>Data were not able to be collected and thus zero participants were analyzed for this outcome.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Immune Modulation in Peripheral Blood</title>
          <population>Data were not able to be collected and thus zero participants were analyzed for this outcome.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Early Markers of Progression in Peripheral Blood</title>
        <time_frame>Up to 5 years</time_frame>
        <population>Zero participants were analyzed for this outcome.</population>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Early Markers of Progression in Peripheral Blood</title>
          <population>Zero participants were analyzed for this outcome.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)</title>
        <description>The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure general quality of life (QOL) that reflects symptoms or problems associated with brain malignancies across 5 scales. The brain subscale is usually used along with the core (general) questionnaire that includes 27 items. The measure yields information about total QOL, as well as information about the dimensions of physical well-being, social/family well-being, emotional well being, functional well-being, and disease-specific concerns. Patients rate all 5 items using a five-point Likert scale ranging from 0 &quot;not at all&quot; to 4 &quot;very much.&quot; Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Scoring range is 0-200.</description>
        <time_frame>Up to 5 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cobimetinib in Combination With Vemurafenib</title>
            <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)</title>
          <description>The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure general quality of life (QOL) that reflects symptoms or problems associated with brain malignancies across 5 scales. The brain subscale is usually used along with the core (general) questionnaire that includes 27 items. The measure yields information about total QOL, as well as information about the dimensions of physical well-being, social/family well-being, emotional well being, functional well-being, and disease-specific concerns. Patients rate all 5 items using a five-point Likert scale ranging from 0 &quot;not at all&quot; to 4 &quot;very much.&quot; Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Scoring range is 0-200.</description>
          <units>scores on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patient #1 - Cycle 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="107"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #1 - Cycle 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #1 - Cycle 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="110"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #1 - Cycle 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2 - Cycle 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2 - Cycle 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2 - Cycle 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="104"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #2 - Cycle 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4 - Cycle 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4 - Cycle 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4 - Cycle 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4 - Cycle 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="101"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4 - Cycle 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="119"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #4 - Cycle 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #5 - Cycle 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #5 - Cycle 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="103"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patient #5 - Cycle 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="104"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Cobimetinib in Combination With Vemurafenib</title>
          <description>Vemurafenib (960 mg twice a day) taken on Days 1 - 28 of each 28-day treatment cycle. Cobimetinib (60 mg once a day) taken on Days 1 - 21 of each 28-day treatment cycle.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>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="4" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </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="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Hydrocephalus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Photosensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>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="4" subjects_at_risk="4"/>
              </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="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear and labyrinth disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hearing impaired</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Photophobia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Retinal detachment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Retinopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Injury, poisoning and procedural complications - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Cholesterol high</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Lymphocyte count increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </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="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </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="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Muscle weakness upper limb</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Sinus pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </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="4"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Photosensitivity</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
              </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>Melissa Burgess, MD</name_or_title>
      <organization>University of Pittsburgh Cancer Institute</organization>
      <phone>412-623-7277</phone>
      <email>burgessma@upmc.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/NCT02230306
org study id: 13-123
secondary id: ML29155
nct id: NCT02230306
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib
      with cobimetinib in patients with active melanoma brain metastases.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Intracranial Response (OIRR)
time frame: Until disease progression, less than or equal to 5 years.
description: Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients.
measure: Overall Response
time frame: Until disease progression, less than or equal to 5 years.
description: Response to study treatment achieved by individual patients as indicated by an overall change in size of the sum of diameters from baseline of up to 5 intracranial target lesions and up to 5 extracranial target lesions.
measure: Progression-free Survival (PFS)
time frame: Up to 5 years
description: Time (number of months) from first documented evidence of overall Complete Response (CR) or Partial Response (PR) until time of first documented disease progression or death due to any cause (for individual patients). Progression as defined by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) is a ≥ 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.
measure: Overall Survival (OS)
time frame: Up to 5 years
description: Number of months of survival for individual patients.
measure: Duration of Response
time frame: Until disease progression, less than or equal to 5 years.
description: Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patient
measure: Immune Modulation in Peripheral Blood
time frame: Up to 5 years
measure: Early Markers of Progression in Peripheral Blood
time frame: Up to 5 years
measure: Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)
time frame: Up to 5 years
description: The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure general quality of life (QOL) that reflects symptoms or problems associated with brain malignancies across 5 scales. The brain subscale is usually used along with the core (general) questionnaire that includes 27 items. The measure yields information about total QOL, as well as information about the dimensions of physical well-being, social/family well-being, emotional well being, functional well-being, and disease-specific concerns. Patients rate all 5 items using a five-point Likert scale ranging from 0 "not at all" to 4 "very much." Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Scoring range is 0-200.
arm group label: Cobimetinib in Combination with Vemurafenib
arm group type: Experimental
description: Vemurafenib (960 mg twice a day) will be taken on Days 1 - 28 of each 28-day treatment cycle. The first dose of vemurafenib should be taken in the morning, and the second dose should be taken in the evening. Vemurafenib can be taken with or without a meal and should be taken with a glass of water.
Cobimetinib (60 mg once a day) will be taken on Days 1 - 21 of each 28-day treatment cycle. The cobimetinib tablet should be taken at approximately the same time each day in the morning with the vemurafenib dose, but no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal and should never be chewed, cut, or crushed and should be taken with a glass of water.
intervention type: Drug
intervention name: Cobimetinib
description: 60mg once a day; will be taken on days 1-21 of each 28 day treatment cycle; will be taken in combination with Vemurafenib;
arm group label: Cobimetinib in Combination with Vemurafenib
intervention type: Drug
intervention name: Vemurafenib
description: 960mg twice a day; 28 day treatment cycle; will be taken in combination with Cobimetinib;
arm group label: Cobimetinib in Combination with Vemurafenib
other name: Zelboraf
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Melissa Burgess, MD
role: Principal Investigator
affiliation: University of Pittsburgh
last name: Richard Carvajal, MD
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
last name: Anna Pavlick, MD
role: Principal Investigator
affiliation: NYU Clinical Cancer Center
last name: Mohammed Milhem, MD
role: Principal Investigator
affiliation: Univ of Iowa
last name: Ravi Amaravadi, MD
role: Principal Investigator
affiliation: Univ of Pennsylvania
last name: Harriet Kluger, MD
role: Principal Investigator
affiliation: Yale New Haven Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Melissa Burgess, MD
investigator title: Assistant Professor
mesh term: Melanoma
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
mesh term: Vemurafenib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 