<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/NCT02201212</url>
  </required_header>
  <id_info>
    <org_study_id>14-229</org_study_id>
    <secondary_id>CRAD001MUS217T</secondary_id>
    <nct_id>NCT02201212</nct_id>
  </id_info>
  <brief_title>Everolimus for Cancer With TSC1 or TSC2 Mutation</brief_title>
  <official_title>A Phase II Trial of Everolimus for Cancer Patients With Inactivating Mutations in TSC1 or TSC2 or Activating MTOR Mutations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this research study, the investigators are evaluating the clinical benefit of everolimus&#xD;
      in cancer patients with inactivating TSC1 or TSC2 mutations or activating MTOR mutations.&#xD;
&#xD;
      This research study is a Phase II clinical trial, which tests the safety and effectiveness of&#xD;
      an investigational drug called everolimus to learn whether the drug works in treating a&#xD;
      specific cancer. &quot;Investigational&quot; means that the drug is being studied. It also means that&#xD;
      the FDA (the U.S. Food and Drug Administration) has not yet approved everolimus for your type&#xD;
      of cancer.&#xD;
&#xD;
      Everolimus is a drug that may stop cancer cells from growing by blocking an important factor&#xD;
      (mTOR) involved in the growth of cells. This drug has been used in treatment for other&#xD;
      cancers and is approved by the Food and Drug Administration for treatment of several types of&#xD;
      cancer, including renal cell carcinoma. Treatment with this drug has been associated with&#xD;
      responses in some patients whose cancers had mutations in TSC1 or TSC2. The investigators&#xD;
      think that patients whose tumors have mutations in TSC1 or TSC2 may have a good chance of&#xD;
      responding to treatment with drugs like everolimus.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients who fulfill eligibility criteria will be entered into the trial.The participant will&#xD;
      be given a study drug-dosing calendar for each treatment cycle. Each treatment cycle lasts 28&#xD;
      days (4 weeks), during which time the participant will be taking the study drug orally (by&#xD;
      mouth) once daily. The diary will also include special instructions for taking the study&#xD;
      drug. In addition to the administration of the study drugs the participant will be asked to&#xD;
      return to the clinic at various time points so that additional exams can be performed. These&#xD;
      study visits may last as long as 2 hours.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">June 2019</completion_date>
  <primary_completion_date type="Actual">June 2019</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 Response Rate</measure>
    <time_frame>Baseline, Every 8 weeks, 2 Years</time_frame>
    <description>RECIST 1.1 criteria for Objective Response:&#xD;
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>Baseline, Every 8 weeks, 2 Years</time_frame>
    <description>Duration of Response Rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>Baseline, Up to 2 Years</time_frame>
    <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>4 Years</time_frame>
    <description>Overall Survival Rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity Rate</measure>
    <time_frame>2 Years</time_frame>
    <description>CTCAE v4.0 Toxicity Rate Grade 3 or higher</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>TSC1</condition>
  <condition>TSC2</condition>
  <condition>Tuberous Sclerosis Complex</condition>
  <condition>MTOR</condition>
  <arm_group>
    <arm_group_label>Everolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <arm_group_label>Everolimus</arm_group_label>
    <other_name>Afinitor®</other_name>
    <other_name>Zortress</other_name>
    <other_name>Afinitor Disperz®</other_name>
    <other_name>RAD001</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: Participants must meet the following criteria on screening examination&#xD;
        to be eligible to participate in the study:&#xD;
&#xD;
          -  Participants must have histologically confirmed advanced malignancy that is either&#xD;
             metastatic and/or unresectable and/or recurrent, with confirmed inactivating mutations&#xD;
             in TSC1 or TSC2, or activating mutations in MTOR, identified in any CLIA-certified&#xD;
             laboratory. All genetic findings must be reviewed by the study PI, Dr. David&#xD;
             Kwiatkowski, prior to study entry.&#xD;
&#xD;
          -  Biopsy of a primary or metastatic lesion must have been performed within the past two&#xD;
             years. Sufficient pathologic material must be available to enable whole exome&#xD;
             sequencing at the time of study entry.&#xD;
&#xD;
          -  Participants must have measurable disease, defined as at least one lesion that can be&#xD;
             accurately measured in at least one dimension (longest diameter to be recorded) as ≥&#xD;
             20 mm with conventional techniques or as ≥10 mm with spiral CT scan. See section 10&#xD;
             for the evaluation of measureable disease.&#xD;
&#xD;
          -  Participants may have received any number of prior therapies, from 0 to &gt; 10, but&#xD;
             prior treatment with PI3-kinase or mTOR inhibitors is not permitted.&#xD;
&#xD;
          -  Age ≥ 18 years.&#xD;
&#xD;
          -  ECOG performance status &lt;2 (see Appendix A).&#xD;
&#xD;
          -  Participants must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  Leukocytes ≥3,000/mcL&#xD;
&#xD;
               -  Absolute neutrophil count ≥1,500/mcL&#xD;
&#xD;
               -  Platelets ≥100,000/mcL&#xD;
&#xD;
               -  Hemoglobin ≥9.0 gr/dL&#xD;
&#xD;
               -  Total bilirubin ≤1.5 ULN&#xD;
&#xD;
               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal. Patients with&#xD;
                  confirmed liver metastases are permitted to have AST/ALT at levels ≤ 5X the&#xD;
                  institutional upper limit of normal.&#xD;
&#xD;
               -  Creatinine ≤ 1.5 X the institutional upper limit of normal.&#xD;
&#xD;
               -  Total cholesterol &lt; 300 mg/dL&#xD;
&#xD;
               -  Triglycerides &lt; 250 mg/dL&#xD;
&#xD;
          -  The effects of everolimus on the developing human fetus are unknown. For this reason&#xD;
             and because anti-neoplastic agents are known to be teratogenic, women of child-bearing&#xD;
             potential and men must agree to use adequate contraception (hormonal or barrier method&#xD;
             of birth control; abstinence) prior to study entry and for the duration of study&#xD;
             participation. Should a woman become pregnant or suspect she is pregnant while&#xD;
             participating in this study, she should inform her treating physician immediately.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
          -  Participants who achieve either a partial response or stable disease ≥ 4 months must&#xD;
             agree to undergo a tumor biopsy, if safe and feasible, at the time of progressive&#xD;
             disease while on study drug everolimus.&#xD;
&#xD;
        Exclusion Criteria:Participants who exhibit any of the following conditions at screening&#xD;
        will not be eligible for admission into the study.&#xD;
&#xD;
          -  Participants who have had any of the following:&#xD;
&#xD;
          -  chemotherapy in the previous 2 weeks (6 weeks for nitrosoureas or mitomycin C)&#xD;
&#xD;
          -  radiotherapy within 3 weeks&#xD;
&#xD;
          -  investigational agents within 3 weeks prior to entering the study&#xD;
&#xD;
          -  patients who have not recovered from significant (in the opinion of the investigator)&#xD;
             adverse events due to previous agents administered.&#xD;
&#xD;
          -  Child-Pugh B or C hepatic impairment. Patients with a history of hepatitis or&#xD;
             significant exposure risk should be tested for hepatitis B and C with serologic&#xD;
             markers: HBsAg, HBs Ab, HBcoreIgG Ab, HCV Ab. Patients with active hepatitis B or C&#xD;
             are excluded.&#xD;
&#xD;
          -  Any prior exposure to any PI3 kinase or mTOR inhibitor agent.&#xD;
&#xD;
          -  Participants may not be receiving any other research study agents.&#xD;
&#xD;
          -  Uncontrolled brain or leptomeningeal metastases, including patients who continue to&#xD;
             require glucocorticoids for brain or leptomeningeal metastases. Asymptomatic or&#xD;
             treated brain metastases are acceptable.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to everolimus.&#xD;
&#xD;
          -  A list of prohibited medications on study are listed in Section 5.5&#xD;
&#xD;
          -  Chronic treatment with corticosteroids or other immunosuppressive therapy.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because everolimus has the potential for&#xD;
             teratogenic or abortifacient effects. Because there is an unknown but potential risk&#xD;
             of adverse events in nursing infants secondary to treatment of the mother with&#xD;
             everolimus, breastfeeding should be discontinued if the mother is treated with&#xD;
             everolimus. These potential risks may also apply to other agents used in this study.&#xD;
&#xD;
          -  Individuals with a recent history of a different malignancy are ineligible except for&#xD;
             the following circumstances: 1) Individuals with a history of other malignancies are&#xD;
             eligible if they have been disease-free for at least 3 years OR are deemed by the&#xD;
             investigator to be at low risk for recurrence of that malignancy; 2) Individuals with&#xD;
             the following cancers are eligible if diagnosed and treated within the past 3 years:&#xD;
             cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.&#xD;
&#xD;
          -  Individuals with known HIV infection are excluded from this study as combination&#xD;
             antiretroviral therapy could potentially result in significant pharmacokinetic&#xD;
             interactions with everolimus. In addition, these individuals are at increased risk of&#xD;
             lethal infections due to the immunosuppressive effects of mTOR inhibition.&#xD;
&#xD;
          -  Patients who have received live attenuated vaccines within 1 week of start of&#xD;
             Everolimus. Patient should also avoid close contact with others who have received live&#xD;
             attenuated vaccines. Examples of live attenuated vaccines include intranasal&#xD;
             influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a&#xD;
             typhoid vaccines.&#xD;
&#xD;
          -  Uncontrolled diabetes mellitus as defined by HbA1c &gt;8% despite adequate therapy.&#xD;
             Patients with a known history of impaired fasting glucose or diabetes mellitus (DM)&#xD;
             may be included, however blood glucose and antidiabetic treatment must be monitored&#xD;
             closely throughout the trial and adjusted as necessary.&#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>David Kwiatkowski, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</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_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>July 23, 2014</study_first_submitted>
  <study_first_submitted_qc>July 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <results_first_submitted>July 27, 2020</results_first_submitted>
  <results_first_submitted_qc>September 14, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">September 16, 2020</results_first_posted>
  <last_update_submitted>September 14, 2020</last_update_submitted>
  <last_update_submitted_qc>September 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>David Kwiatkowski</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>TSC1</keyword>
  <keyword>TSC2</keyword>
  <keyword>Tuberous Sclerosis Complex</keyword>
  <keyword>MTOR</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberous Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 13, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/12/NCT02201212/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Everolimus</title>
          <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </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>Everolimus</title>
          <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
          </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="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61.5" lower_limit="43" upper_limit="80"/>
                  </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="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </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="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG Performance Status</title>
          <description>This is ECOG Performance Status 0 is the best, meaning in very good condition. 4 is the worse, meaning in very poor condition.</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1" lower_limit="0" upper_limit="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Rate</title>
        <description>RECIST 1.1 criteria for Objective Response:&#xD;
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR</description>
        <time_frame>Baseline, Every 8 weeks, 2 Years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Everolimus</title>
            <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate</title>
          <description>RECIST 1.1 criteria for Objective Response:&#xD;
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR</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="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response</title>
        <description>Duration of Response Rate</description>
        <time_frame>Baseline, Every 8 weeks, 2 Years</time_frame>
        <population>Subjects with Partial Response</population>
        <group_list>
          <group group_id="O1">
            <title>Everolimus</title>
            <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response</title>
          <description>Duration of Response Rate</description>
          <population>Subjects with Partial Response</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <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="12.7" lower_limit="4.8" upper_limit="20.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival</title>
        <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
        <time_frame>Baseline, Up to 2 Years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Everolimus</title>
            <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival</title>
          <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.0" lower_limit="0.4" upper_limit="20.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall Survival Rate</description>
        <time_frame>4 Years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Everolimus</title>
            <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall Survival Rate</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.27" lower_limit="0.43" upper_limit="39.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Toxicity Rate</title>
        <description>CTCAE v4.0 Toxicity Rate Grade 3 or higher</description>
        <time_frame>2 Years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Everolimus</title>
            <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
          </group>
        </group_list>
        <measure>
          <title>Toxicity Rate</title>
          <description>CTCAE v4.0 Toxicity Rate Grade 3 or higher</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="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 months after study discontinuation, up to 5 years</time_frame>
      <desc>National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0)</desc>
      <group_list>
        <group group_id="E1">
          <title>Everolimus</title>
          <description>Everolimus&#xD;
Fixed doses orally once a day per each 28 day cycle&#xD;
Participants will stay on study as long as they do not progress for a maximum of 24 months.&#xD;
Tumor assessments will be performed after every 2 cycles for as long as they are on study.&#xD;
Everolimus</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v4.0</default_vocab>
        <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="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE v4.0</default_vocab>
        <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="20" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>any adverse event per CTCAE v4.0</sub_title>
                <description>any adverse event per CTCAE v4.0</description>
                <counts group_id="E1" events="100" subjects_affected="20" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Dr. David Kwiatkowski</name_or_title>
      <organization>Dana Farber Cancer Institute</organization>
      <phone>8573070781</phone>
      <email>dk@rics.bwh.harvard.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/NCT02201212
org study id: 14-229
secondary id: CRAD001MUS217T
nct id: NCT02201212
lead sponsor: 
collaborator: 
has dmc: Yes
In this research study, the investigators are evaluating the clinical benefit of everolimus
      in cancer patients with inactivating TSC1 or TSC2 mutations or activating MTOR mutations.

      This research study is a Phase II clinical trial, which tests the safety and effectiveness of
      an investigational drug called everolimus to learn whether the drug works in treating a
      specific cancer. "Investigational" means that the drug is being studied. It also means that
      the FDA (the U.S. Food and Drug Administration) has not yet approved everolimus for your type
      of cancer.

      Everolimus is a drug that may stop cancer cells from growing by blocking an important factor
      (mTOR) involved in the growth of cells. This drug has been used in treatment for other
      cancers and is approved by the Food and Drug Administration for treatment of several types of
      cancer, including renal cell carcinoma. Treatment with this drug has been associated with
      responses in some patients whose cancers had mutations in TSC1 or TSC2. The investigators
      think that patients whose tumors have mutations in TSC1 or TSC2 may have a good chance of
      responding to treatment with drugs like everolimus.
Patients who fulfill eligibility criteria will be entered into the trial.The participant will
      be given a study drug-dosing calendar for each treatment cycle. Each treatment cycle lasts 28
      days (4 weeks), during which time the participant will be taking the study drug orally (by
      mouth) once daily. The diary will also include special instructions for taking the study
      drug. In addition to the administration of the study drugs the participant will be asked to
      return to the clinic at various time points so that additional exams can be performed. These
      study visits may last as long as 2 hours.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rate
time frame: Baseline, Every 8 weeks, 2 Years
description: RECIST 1.1 criteria for Objective Response:
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by scan: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
measure: Duration of Response
time frame: Baseline, Every 8 weeks, 2 Years
description: Duration of Response Rate
measure: Progression-free Survival
time frame: Baseline, Up to 2 Years
description: Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
measure: Overall Survival
time frame: 4 Years
description: Overall Survival Rate
measure: Toxicity Rate
time frame: 2 Years
description: CTCAE v4.0 Toxicity Rate Grade 3 or higher
arm group label: Everolimus
arm group type: Experimental
description: Everolimus
Fixed doses orally once a day per each 28 day cycle
Participants will stay on study as long as they do not progress for a maximum of 24 months.
Tumor assessments will be performed after every 2 cycles for as long as they are on study.
intervention type: Drug
intervention name: Everolimus
arm group label: Everolimus
other name: Afinitor®
other name: Zortress
other name: Afinitor Disperz®
other name: RAD001
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: David Kwiatkowski, MD, PhD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: David Kwiatkowski
investigator title: Principal Investigator
mesh term: Tuberous Sclerosis
mesh term: Sclerosis
mesh term: Everolimus
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 