<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/NCT01721603</url>
  </required_header>
  <id_info>
    <org_study_id>12857</org_study_id>
    <nct_id>NCT01721603</nct_id>
  </id_info>
  <brief_title>Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets</brief_title>
  <official_title>A Phase 2 Prospective Trial of Dabrafenib and Trametinib With Stereotactic Radiosurgery in BRAF Mutant Melanoma Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test the safety and find out what effects, good and/or bad,&#xD;
      dabrafenib (a BRAF inhibitor) alone or dabrafenib when given in combination with gamma knife&#xD;
      radiosurgery has on participants with a certain type of skin cancer (BRAFV600E melanoma) and&#xD;
      brain metastases (tumors that have spread to the brain).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single arm Phase II clinical trial. All patients will receive continuous dosing of&#xD;
      dabrafenib at 150 mg PO bid and trametinib beginning at Cycle 3 Day 1, at a starting dose of&#xD;
      2 mg PO once daily until progression of disease, withdrawal of consent, or the development of&#xD;
      intolerable treatment associated toxicity. An MRI will be performed after 28 days of&#xD;
      treatment with dabrafenib. Patients who have unequivocal disease progression in the brain at&#xD;
      that time will be deemed to have disease progression at 4 weeks. Patients with a complete&#xD;
      response of all lesions in the brain will continue to receive dabrafenib and trametinib on&#xD;
      study but they will not undergo SRS. For patients with stable disease or partial tumor&#xD;
      responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day&#xD;
      1 (+/- 3 days, 28 day cycle) using a stereotactic head frame and MRI imaging in accordance&#xD;
      with FDA-approved procedures.&#xD;
&#xD;
      Melanoma brain metastases&#xD;
&#xD;
      Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is&#xD;
      currently expected that approximately 132,000 people will be diagnosed with melanoma each&#xD;
      year and some 37,000 people are expected to die of the disease annually. Brain metastases are&#xD;
      a major source of morbidity and mortality in patients with metastatic melanoma and&#xD;
      approximately 3 out of 4 develop brain metastases at some point in their disease course. The&#xD;
      prognosis of metastatic melanoma with CNS involvement is dismal1, and, until recently, no&#xD;
      medical therapy demonstrated clear evidence of activity against melanoma in the brain. For&#xD;
      patients with fewer than 4 brain lesions and no brain lesion greater than 3 cm in diameter,&#xD;
      stereotactic radiosurgery (SRS) is the standard-of-care. By delivering highly focal&#xD;
      irradiation to melanoma brain metastases, SRS confers local control rates exceeding 80% for&#xD;
      lesions under 2 cm in diameter. However, SRS does not treat micrometastatic disease in the&#xD;
      brain, and new brain metastases develop in approximately half of patients treated.&#xD;
&#xD;
      Furthermore, local control rates are lower for lesions larger than 2 cm in diameter. As a&#xD;
      result, the median overall survival for melanoma patient treated with SRS is only 7 months.&#xD;
&#xD;
      BRAF mutant melanoma&#xD;
&#xD;
      The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human cancers. This&#xD;
      pathway can be constitutively activated by alterations in specific proteins, including BRAF,&#xD;
      which phosphorylates MEK1 and MEK2 on two regulatory serine residues. Approximately 90% of&#xD;
      all identified BRAF mutations that occur in human result in a V600 E/D/Kamino acid&#xD;
      substitution. This mutation appears to mimic regulatory phophorylation and increases BRAF&#xD;
      activity approximately 10-fold compared to wild type. BRAF mutations have been identified at&#xD;
      a high frequency in specific cancers, including approximately 40-60% of melanoma. The&#xD;
      frequency of this activating mutation and the pathway addiction to which it leads makes&#xD;
      mutated BRAF an extremely attractive target.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Low accrual&#xD;
  </why_stopped>
  <start_date>April 2013</start_date>
  <completion_date type="Actual">January 2016</completion_date>
  <primary_completion_date type="Actual">January 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>Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS)</measure>
    <time_frame>Up to 6 months after surgery</time_frame>
    <description>Determine whether dabrafenib combined with stereotactic radiosurgery (SRS) and trametinib improves the 6 month DBMFS rate of BRAFV600E melanoma patients for whom the standard of care is stereotactic radiosurgery (≤4 brain lesions and no lesion &gt; 3 cm) in comparison with similar historical controls treated with radiosurgery alone.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patients Displaying 6-month Local Control Rate</measure>
    <time_frame>From surgery up to 6 months</time_frame>
    <description>Determine whether dabrafenib combined with SRS and trametinib improves the 6-month local control rate of BRAFV600E melanoma brain metastases compared with historical controls treated with SRS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best Overall Response Rate (by RECIST v1.1 )</measure>
    <time_frame>From surgery up to 12 months</time_frame>
    <description>Determine the best overall response rate (by RECIST v1.1 ).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Duration of Freedom From New Brain Metastases( by RECIST v1.1 )</measure>
    <time_frame>From surgery up to 12 months</time_frame>
    <description>Determine median duration of freedom from new brain metastases of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Time to Progression</measure>
    <time_frame>From surgery up to 12 months</time_frame>
    <description>Determine the median time to progression in the brain of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic Overall Response Rate</measure>
    <time_frame>From surgery up to 12 months</time_frame>
    <description>Determine the systemic best overall response rate of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.&#xD;
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).&#xD;
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Progression-free Survival</measure>
    <time_frame>From surgery up to 12 months</time_frame>
    <description>Determine the median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival</measure>
    <time_frame>From surgery up to 12 months</time_frame>
    <description>Determine the median overall survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>BRAFV600E Melanoma Patients</condition>
  <arm_group>
    <arm_group_label>Dabrafenib + Trametinib + gamma knife radiosurgery</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabrafenib</intervention_name>
    <description>150 mg capsule by mouth twice daily</description>
    <arm_group_label>Dabrafenib + Trametinib + gamma knife radiosurgery</arm_group_label>
    <other_name>GSK2118436</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Gamma Knife Radiosurgery</intervention_name>
    <description>This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.</description>
    <arm_group_label>Dabrafenib + Trametinib + gamma knife radiosurgery</arm_group_label>
    <other_name>SRS</other_name>
    <other_name>Stereotactic Radiosurgery</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trametinib</intervention_name>
    <description>2 mg by mouth once daily from beginning at Cycle 3 Day 1, until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.</description>
    <arm_group_label>Dabrafenib + Trametinib + gamma knife radiosurgery</arm_group_label>
    <other_name>GSK1120212</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically-confirmed BRAFV600E melanoma&#xD;
&#xD;
          2. Up to 4 untreated brain metastases (at least 1 &gt; 0.5 cm) with no metastasis larger&#xD;
             than 3 cm as assessed by a gadolinium-enhanced MRI of the brain. Detection of&#xD;
             additional lesions at time of Gamma Knife radiosurgery MRI scan will not be considered&#xD;
             exclusionary if the detection of these lesions are thought to be due solely to&#xD;
             difference in imaging techniques (i. e. higher sensitivity, double gadolinium contrast&#xD;
             MRI utilized at the time of Gamma Knife radiosurgery compared with conventional MRI&#xD;
             imaging).&#xD;
&#xD;
          3. ECOG PS 0-2&#xD;
&#xD;
          4. 14 days elapsed from last treatment with surgery.&#xD;
&#xD;
          5. At least 28 days or five half-lives (whichever is longer) have elapsed from last dose&#xD;
             of any approved or investigational therapy for metastatic melanoma.&#xD;
&#xD;
          6. Appropriate birth control for men and women with childbearing potential&#xD;
&#xD;
          7. Corticosteroid dose stable for at least 14 days&#xD;
&#xD;
          8. Adequate end-organ function:&#xD;
&#xD;
               -  ANC ≥ 1.5x109/L&#xD;
&#xD;
               -  Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
               -  Platelets ≥100 x109/L&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5x ULN&#xD;
&#xD;
               -  AST and ALT ≤ 2.5x ULN&#xD;
&#xD;
               -  Creatinine ≤ 1.5 mg/dL&#xD;
&#xD;
               -  PT/PTT ≤ 1.5x ULN&#xD;
&#xD;
               -  LVEF ≥ 50%&#xD;
&#xD;
          9. Age ≥ 18 years&#xD;
&#xD;
         10. Recipients of prior radiation therapy to the brain including stereotactic radiosurgery&#xD;
             or whole brain irradiation may be included if there are 1-4 untreated or progressing&#xD;
             brain lesions. At his discretion, the Study Chair may review any enrollment decision&#xD;
             regarding which subjects will be enrolled prior to the initiation of treatment on&#xD;
             trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Neurological symptoms from melanoma brain metastases&#xD;
&#xD;
          2. Patients may not have received prior therapy with dabrafenib, vemurafenib, or other&#xD;
             potent, highly effective BRAF inhibitors. Prior therapy with sorafenib is permitted.&#xD;
&#xD;
          3. Any indication for urgent or emergent neurosurgery. Patient may enroll after&#xD;
             neurosurgery at least 14 days after neurosurgery as long as they meet all other study&#xD;
             qualifications.&#xD;
&#xD;
          4. Pregnant or lactating women. The effects of dabrafenib on the developing human fetus&#xD;
             are unknown. For this reason, women of child-bearing potential and men must agree to&#xD;
             use a highly effective method of contraception including: hormonal contraceptives&#xD;
             (oral contraceptives, Nuvaring, Depo Provera) an intrauterine device, true abstinence&#xD;
             or two barrier methods of birth control including condoms with cervical cap or&#xD;
             diaphragm. Baseline pregnancy testing is required for all women of child-bearing&#xD;
             potential. Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
             partner is participating in this study, she should inform her treating physician&#xD;
             immediately. Men treated or enrolled on this protocol who are sexually active with&#xD;
             women of child bearing potential must also agree to use adequate contraception prior&#xD;
             to and during the study as outlined above, and for, and four months after completion&#xD;
             of study drug administration.&#xD;
&#xD;
          5. History of known cardiac arrhythmias or acute coronary syndromes within the past 24&#xD;
             weeks.&#xD;
&#xD;
          6. History of a second malignancy with evidence of active disease within the past 3 years&#xD;
             except non-melanoma skin cancer, indolent prostate cancer, and stable CLL without&#xD;
             lymphadenopathy&#xD;
&#xD;
          7. Complete resection of a single brain metastasis or of all known brain metastases.&#xD;
             Patients who have undergone subtotal resection are eligible providing residual disease&#xD;
             is &lt; 2.0 cm in maximum diameter.&#xD;
&#xD;
          8. Patients with metastases within 2 mm of the optic nerve or optic chiasm so that some&#xD;
             portion of the optic nerve or chiasm would receive &gt; 9 Gy from radiosurgery.&#xD;
&#xD;
          9. Patients with metastases in the brainstem.&#xD;
&#xD;
         10. Contraindication to MRI (such as cardiac pacemaker).&#xD;
&#xD;
         11. The following medications or non-drug therapies are prohibited:&#xD;
&#xD;
               -  Other anti-cancer therapy while on treatment in this study.&#xD;
&#xD;
               -  Use of other investigational drugs within 28 days preceding the first dose of&#xD;
                  dabrafenib.&#xD;
&#xD;
               -  Antiretroviral drugs. Subjects with known HIV are ineligible for study&#xD;
                  participation.&#xD;
&#xD;
               -  Herbal remedies (i.e., St. John's wort).&#xD;
&#xD;
               -  Drugs that are strong inhibitors or inducers of CYP3A or CYP2C8, p-glycoprotein&#xD;
                  (Pgp) or Bcrp transporter because they may alter dabrafenib concentrations. The&#xD;
                  list may be modified based on emerging data. These include but are not limited to&#xD;
                  those listed in Appendix 2; consider therapeutic substitutions for these&#xD;
                  medications.&#xD;
&#xD;
         12. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for&#xD;
             Adverse Events, version 4.0. Grade 2 or higher from previous anti-cancer therapy,&#xD;
             except alopecia.&#xD;
&#xD;
         13. Presence of active gastrointestinal disease or other condition that will interfere&#xD;
             significantly with the absorption of drugs. If clarification is needed as to whether a&#xD;
             condition will significantly affect absorption of drugs, contact the Study Chair for&#xD;
             permission to enroll the subject. Study Chair has final decision regarding which&#xD;
             subjects will be enrolled.&#xD;
&#xD;
         14. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or&#xD;
             Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of HBV clearance&#xD;
             may be enrolled with permission of the GSK medical monitor.&#xD;
&#xD;
         15. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.&#xD;
&#xD;
         16. Corrected QT (QTc) interval ≥480 msecs; history of acute coronary syndromes (including&#xD;
             unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class&#xD;
             II, III, or IV heart failure as defined by the New York Heart Association (NYHA)&#xD;
             functional classification system; abnormal cardiac valve morphology documented by&#xD;
             echocardiogram (subjects with minimal abnormalities including mild&#xD;
             regurgitation/stenosis can be entered on study with approval from the GSK medical&#xD;
             monitor); or history of known cardiac arrhythmias.&#xD;
&#xD;
         17. Treatment refractory hypertension defined as a blood pressure of systolic&gt; 140 mmHg&#xD;
             and/or diastolic &gt; 90 mm Hg which cannot be controlled by anti-hypertensive therapy.&#xD;
&#xD;
         18. History of RVO or CSR, or predisposing factors to RVO or CSR(e.g. uncontrolled&#xD;
             glaucoma or ocular hypertension, uncontrolled systemic disease such as diabetes&#xD;
             mellitus, hypertension, or history of hyperviscosity or hypercoagulability syndromes)&#xD;
&#xD;
         19. Visible retinal pathology as assessed by ophthalmic exam that is considered a risk&#xD;
             factor for RVO or CSR such as:&#xD;
&#xD;
               -  Evidence of new optic disc cupping&#xD;
&#xD;
               -  Evidence of new visual field defects&#xD;
&#xD;
               -  Intraocular pressure &gt; 21 mm Hg as measured by tonography&#xD;
&#xD;
         20. Psychological, familial, sociological, or geographical conditions that do not permit&#xD;
             compliance with the protocol; or unwillingness or inability to follow the procedures&#xD;
             required in the protocol.&#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>Alain Algazi, MD</last_name>
    <role>Study Chair</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of San Francisco, California</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2017</verification_date>
  <study_first_submitted>November 1, 2012</study_first_submitted>
  <study_first_submitted_qc>November 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 6, 2012</study_first_posted>
  <results_first_submitted>December 19, 2017</results_first_submitted>
  <results_first_submitted_qc>December 19, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">January 23, 2018</results_first_posted>
  <last_update_submitted>December 19, 2017</last_update_submitted>
  <last_update_submitted_qc>December 19, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">January 23, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Alain Algazi</investigator_full_name>
    <investigator_title>Assistant Clinical Professor</investigator_title>
  </responsible_party>
  <keyword>BRAFV600E melanoma patients</keyword>
  <keyword>melanoma</keyword>
  <keyword>stereotactic radiosurgery</keyword>
  <keyword>BRAFV600E melanoma brain metastases</keyword>
  <keyword>dabrafenib</keyword>
  <keyword>SRS</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>
      <group_list>
        <group group_id="P1">
          <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
          <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </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>Dabrafenib Given in Combination With Gamma Knife Radiosurgery</title>
          <description>All patients will receive continuous, oral dosing of dabrafenib at a starting dose of 150 mg twice daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity&#xD;
Dabrafenib: 150mg capsule by mouth twice daily&#xD;
Gamma Knife Radiosurgery: This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS)</title>
        <description>Determine whether dabrafenib combined with stereotactic radiosurgery (SRS) and trametinib improves the 6 month DBMFS rate of BRAFV600E melanoma patients for whom the standard of care is stereotactic radiosurgery (≤4 brain lesions and no lesion &gt; 3 cm) in comparison with similar historical controls treated with radiosurgery alone.</description>
        <time_frame>Up to 6 months after surgery</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS)</title>
          <description>Determine whether dabrafenib combined with stereotactic radiosurgery (SRS) and trametinib improves the 6 month DBMFS rate of BRAFV600E melanoma patients for whom the standard of care is stereotactic radiosurgery (≤4 brain lesions and no lesion &gt; 3 cm) in comparison with similar historical controls treated with radiosurgery alone.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patients Displaying 6-month Local Control Rate</title>
        <description>Determine whether dabrafenib combined with SRS and trametinib improves the 6-month local control rate of BRAFV600E melanoma brain metastases compared with historical controls treated with SRS.</description>
        <time_frame>From surgery up to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Patients Displaying 6-month Local Control Rate</title>
          <description>Determine whether dabrafenib combined with SRS and trametinib improves the 6-month local control rate of BRAFV600E melanoma brain metastases compared with historical controls treated with SRS.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Best Overall Response Rate (by RECIST v1.1 )</title>
        <description>Determine the best overall response rate (by RECIST v1.1 ).</description>
        <time_frame>From surgery up to 12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Best Overall Response Rate (by RECIST v1.1 )</title>
          <description>Determine the best overall response rate (by RECIST v1.1 ).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Duration of Freedom From New Brain Metastases( by RECIST v1.1 )</title>
        <description>Determine median duration of freedom from new brain metastases of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression.</description>
        <time_frame>From surgery up to 12 months</time_frame>
        <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Duration of Freedom From New Brain Metastases( by RECIST v1.1 )</title>
          <description>Determine median duration of freedom from new brain metastases of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression.</description>
          <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</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>Median Time to Progression</title>
        <description>Determine the median time to progression in the brain of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.</description>
        <time_frame>From surgery up to 12 months</time_frame>
        <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Time to Progression</title>
          <description>Determine the median time to progression in the brain of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.</description>
          <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</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>Systemic Overall Response Rate</title>
        <description>Determine the systemic best overall response rate of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.&#xD;
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).&#xD;
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.</description>
        <time_frame>From surgery up to 12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Systemic Overall Response Rate</title>
          <description>Determine the systemic best overall response rate of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.&#xD;
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).&#xD;
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Progression-free Survival</title>
        <description>Determine the median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.</description>
        <time_frame>From surgery up to 12 months</time_frame>
        <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Progression-free Survival</title>
          <description>Determine the median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.</description>
          <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</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>Median Overall Survival</title>
        <description>Determine the median overall survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.</description>
        <time_frame>From surgery up to 12 months</time_frame>
        <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</population>
        <group_list>
          <group group_id="O1">
            <title>Dabrafenib + Trametinib + Gamma Knife Radiosurgery</title>
            <description>1 cycle = 28 days&#xD;
Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous&#xD;
Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.&#xD;
For patients with stable disease or partial tumor responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day 1 (+/- 3 days) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Overall Survival</title>
          <description>Determine the median overall survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.</description>
          <population>Study was terminated due to low accrual. Secondary outcome measure was not accessed.</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_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Dabrafenib With Gamma Knife Radiosurgery</title>
          <description>Dabrafenib: 150mg capsule by mouth twice daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity&#xD;
Gamma Knife Radiosurgery: This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>External ear canal hyperkeratosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </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="2"/>
              </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="2"/>
              </event>
              <event>
                <sub_title>Foot pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </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="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Nipple hyperkeratosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Rhinorrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hand foot reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </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="2"/>
              </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>Alain Algazi, MD</name_or_title>
      <organization>University of California, San Francisco</organization>
      <phone>(415) 353-7552</phone>
      <email>Alain.Algazi@ucsf.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/NCT01721603
org study id: 12857
nct id: NCT01721603
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to test the safety and find out what effects, good and/or bad,
      dabrafenib (a BRAF inhibitor) alone or dabrafenib when given in combination with gamma knife
      radiosurgery has on participants with a certain type of skin cancer (BRAFV600E melanoma) and
      brain metastases (tumors that have spread to the brain).
This is a single arm Phase II clinical trial. All patients will receive continuous dosing of
      dabrafenib at 150 mg PO bid and trametinib beginning at Cycle 3 Day 1, at a starting dose of
      2 mg PO once daily until progression of disease, withdrawal of consent, or the development of
      intolerable treatment associated toxicity. An MRI will be performed after 28 days of
      treatment with dabrafenib. Patients who have unequivocal disease progression in the brain at
      that time will be deemed to have disease progression at 4 weeks. Patients with a complete
      response of all lesions in the brain will continue to receive dabrafenib and trametinib on
      study but they will not undergo SRS. For patients with stable disease or partial tumor
      responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day
      1 (+/- 3 days, 28 day cycle) using a stereotactic head frame and MRI imaging in accordance
      with FDA-approved procedures.

      Melanoma brain metastases

      Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is
      currently expected that approximately 132,000 people will be diagnosed with melanoma each
      year and some 37,000 people are expected to die of the disease annually. Brain metastases are
      a major source of morbidity and mortality in patients with metastatic melanoma and
      approximately 3 out of 4 develop brain metastases at some point in their disease course. The
      prognosis of metastatic melanoma with CNS involvement is dismal1, and, until recently, no
      medical therapy demonstrated clear evidence of activity against melanoma in the brain. For
      patients with fewer than 4 brain lesions and no brain lesion greater than 3 cm in diameter,
      stereotactic radiosurgery (SRS) is the standard-of-care. By delivering highly focal
      irradiation to melanoma brain metastases, SRS confers local control rates exceeding 80% for
      lesions under 2 cm in diameter. However, SRS does not treat micrometastatic disease in the
      brain, and new brain metastases develop in approximately half of patients treated.

      Furthermore, local control rates are lower for lesions larger than 2 cm in diameter. As a
      result, the median overall survival for melanoma patient treated with SRS is only 7 months.

      BRAF mutant melanoma

      The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human cancers. This
      pathway can be constitutively activated by alterations in specific proteins, including BRAF,
      which phosphorylates MEK1 and MEK2 on two regulatory serine residues. Approximately 90% of
      all identified BRAF mutations that occur in human result in a V600 E/D/Kamino acid
      substitution. This mutation appears to mimic regulatory phophorylation and increases BRAF
      activity approximately 10-fold compared to wild type. BRAF mutations have been identified at
      a high frequency in specific cancers, including approximately 40-60% of melanoma. The
      frequency of this activating mutation and the pathway addiction to which it leads makes
      mutated BRAF an extremely attractive target.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS)
time frame: Up to 6 months after surgery
description: Determine whether dabrafenib combined with stereotactic radiosurgery (SRS) and trametinib improves the 6 month DBMFS rate of BRAFV600E melanoma patients for whom the standard of care is stereotactic radiosurgery (≤4 brain lesions and no lesion > 3 cm) in comparison with similar historical controls treated with radiosurgery alone.
measure: Patients Displaying 6-month Local Control Rate
time frame: From surgery up to 6 months
description: Determine whether dabrafenib combined with SRS and trametinib improves the 6-month local control rate of BRAFV600E melanoma brain metastases compared with historical controls treated with SRS.
measure: Best Overall Response Rate (by RECIST v1.1 )
time frame: From surgery up to 12 months
description: Determine the best overall response rate (by RECIST v1.1 ).
measure: Median Duration of Freedom From New Brain Metastases( by RECIST v1.1 )
time frame: From surgery up to 12 months
description: Determine median duration of freedom from new brain metastases of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression.
measure: Median Time to Progression
time frame: From surgery up to 12 months
description: Determine the median time to progression in the brain of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.
measure: Systemic Overall Response Rate
time frame: From surgery up to 12 months
description: Determine the systemic best overall response rate of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
measure: Median Progression-free Survival
time frame: From surgery up to 12 months
description: Determine the median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.
measure: Median Overall Survival
time frame: From surgery up to 12 months
description: Determine the median overall survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.
arm group label: Dabrafenib + Trametinib + gamma knife radiosurgery
arm group type: Experimental
intervention type: Drug
intervention name: Dabrafenib
description: 150 mg capsule by mouth twice daily
arm group label: Dabrafenib + Trametinib + gamma knife radiosurgery
other name: GSK2118436
intervention type: Procedure
intervention name: Gamma Knife Radiosurgery
description: This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.
arm group label: Dabrafenib + Trametinib + gamma knife radiosurgery
other name: SRS
other name: Stereotactic Radiosurgery
intervention type: Drug
intervention name: Trametinib
description: 2 mg by mouth once daily from beginning at Cycle 3 Day 1, until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.
arm group label: Dabrafenib + Trametinib + gamma knife radiosurgery
other name: GSK1120212
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alain Algazi, MD
role: Study Chair
affiliation: University of California, San Francisco
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Alain Algazi
investigator title: Assistant Clinical Professor
mesh term: Melanoma
mesh term: Trametinib
mesh term: Dabrafenib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 