<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/NCT01665768</url>
  </required_header>
  <id_info>
    <org_study_id>J1228</org_study_id>
    <secondary_id>NA_00067315</secondary_id>
    <nct_id>NCT01665768</nct_id>
  </id_info>
  <brief_title>Maintenance Rituximab With mTor Inhibition After High-dose Consolidative Therapy in Lymphoma</brief_title>
  <official_title>A Trial of Maintenance Rituximab With mTor Inhibition After High-dose Consolidative Therapy in CD20+, B-cell Lymphomas, Gray Zone Lymphoma, and Hodgkin's Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research is being done to determine if combining an investigational drug called&#xD;
      Everolimus with Rituximab can reduce the risk of your cancer from returning after high dose&#xD;
      chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Everolimus is a pill that interferes with lymphoma cell growth by blocking a cellular pathway&#xD;
      important in causing cancer cells to grow, called mTor. Rituximab is an intravenous&#xD;
      medication that specifically attacks a protein commonly found on lymphoma cells called CD20.&#xD;
&#xD;
      Rituximab is already widely used to treat multiple forms of lymphoma. Moreover, continuing&#xD;
      rituximab after the completion of chemotherapy is already commonly used to help patients stay&#xD;
      in remission longer. Everolimus has been shown in many types of relapsed lymphoma to decrease&#xD;
      the size of lymph nodes by itself. Everolimus is approved by the Food and Drug Administration&#xD;
      (FDA) for the treatment of advanced kidney cancer and subependymal giant cell astocytoma. It&#xD;
      is not approved for use in lymphoma. The use of everolimus in this research study is&#xD;
      investigational. The word &quot;investigational&quot; means that everolimus is not approved for&#xD;
      marketing by the Food and Drug Administration (FDA). The FDA is allowing the use of&#xD;
      everolimus in this study.&#xD;
&#xD;
      The combination of everolimus and rituximab for 1 year after high dose therapy is also new.&#xD;
      We believe the combination of these medications right after your chemotherapy will be more&#xD;
      effective in attacking your remaining cancer before they have time to re-grow.&#xD;
&#xD;
      The usual treatment of lymphoma after high-dose chemotherapy is observation. After your body&#xD;
      has fully recovered from the effects of the chemotherapy, you will receive everolimus daily&#xD;
      for one year and IV rituximab four times during that year.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2012</start_date>
  <completion_date type="Actual">August 2020</completion_date>
  <primary_completion_date type="Actual">October 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety as Assessed by Avoidance of Grade 3-4 Adverse Events</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Number of participants who did not experience at least one grade 3-4 adverse event by CTCAE 4.0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Event Free Survival (EFS)</measure>
    <time_frame>2.5 years</time_frame>
    <description>Percentage of participants alive without disease progression. As defined by Cheson criteria, disease progression is a new lesion or &gt;= 50% increase in the size of previously identified sites of disease. EFS was estimated using Kaplan-Meier survival analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage Change in the Frequency of Circulating Cancer Cells</measure>
    <time_frame>Baseline, 1 year, 2 years and 3 years</time_frame>
    <description>Percentage change in circulating cancer cells between baseline and each timepoint noted below.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied</measure>
    <time_frame>1 year, 2 years, and 3 years</time_frame>
    <description>Percentage change in cancer cells when mTOR inhibition is applied in the laboratory. Samples from participants will be evaluated at each timepoint noted below.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">56</enrollment>
  <condition>CD20+, B-cell Lymphomas</condition>
  <condition>Mantle Cell Lymphoma</condition>
  <condition>Non-Mantle Cell Low Grade B Cell Lymphomas (SLL/CLL)</condition>
  <condition>Transformed Lymphoma/DLBCL/PMBCL</condition>
  <condition>Hodgkin's Disease</condition>
  <condition>Gray Zone Lymphoma</condition>
  <arm_group>
    <arm_group_label>Everolimus and Rituximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Everolimus daily for one year and IV rituximab four times during that year.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL.</description>
    <arm_group_label>Everolimus and Rituximab</arm_group_label>
    <other_name>RAD001</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
    <arm_group_label>Everolimus and Rituximab</arm_group_label>
    <other_name>Rituxan</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;18 years of age&#xD;
&#xD;
          -  ECOG performance status ≤ 2&#xD;
&#xD;
          -  INR ≤ 2&#xD;
&#xD;
          -  Adequate renal and hepatic function defined as a serum creatinine &lt;2.0mg/dL, total&#xD;
             bilirubin &lt;5mg/dL, and AST and ALT ˂ 2.5 ULN.&#xD;
&#xD;
          -  Platelet count &gt;75 x 109/L&#xD;
&#xD;
          -  Hemoglobin &gt;10mg/dL&#xD;
&#xD;
          -  ANC &gt;3.0x109/L&#xD;
&#xD;
          -  Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L and fasting triglycerides ≤ 2.5 x&#xD;
             ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only&#xD;
             be included after initiation of appropriate lipid lowering medication.&#xD;
&#xD;
          -  A willingness to use an accepted and effective method of birth control for sexually&#xD;
             active women of childbearing potential during the study and for 8 weeks after the end&#xD;
             of study drug treatment.&#xD;
&#xD;
          -  Ability to sign informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patient who have previously received an mTor inhibitor&#xD;
&#xD;
          -  Patients who are pre-terminal or moribund&#xD;
&#xD;
          -  Patients currently receiving anticancer therapies or who have received anticancer&#xD;
             therapies within 4 weeks of the start of Everolimus (including chemotherapy, radiation&#xD;
             therapy, antibody based therapy, etc.)&#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;
&#xD;
          -  Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or&#xD;
             inhaled cortosteroids are allowed&#xD;
&#xD;
          -  Patients who have received live attenuated vaccines within 1 week of start of&#xD;
             Everolimus and during the study. Patient should also avoid close contact with others&#xD;
             who have received live attenuated vaccines. Examples of live attenuated vaccines&#xD;
             include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,&#xD;
             varicella and TY21a typhoid vaccines;&#xD;
&#xD;
          -  Patients who have a history of another primary solild malignancy, with the exceptions&#xD;
             of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast&#xD;
             from which the patient has been disease free for ≥3 years;&#xD;
&#xD;
          -  Patients with a history of non-compliance to medical regimens or who are considered&#xD;
             potentially unreliable or will not be able to complete the entire study;&#xD;
&#xD;
          -  Patients with active bacterial or fungal infections requiring oral or intravenous&#xD;
             antimicrobials are not eligible until resolution of the infection&#xD;
&#xD;
          -  Female patients who are pregnant or breast feeding, or of reproductive potential whoe&#xD;
             are not using effective birth control methods. Adequate contraception must be used&#xD;
             throughout the trial and for 8 weeks after the last dose of study drug.&#xD;
&#xD;
          -  Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate&#xD;
             contraception, during the study and for 8 weeks after the end of treatment&#xD;
&#xD;
          -  Patients with known intolerance to rituximab&#xD;
&#xD;
          -  Known history of HIV or Hepatitis C&#xD;
&#xD;
          -  Active Hepatitis B as defined by seropositivity for hepatitis B surface antigen.&#xD;
             Subjects with positive hepatitis B core antibody titers and normal liver transaminases&#xD;
             are allowed provided that prophylaxis is administered per institutional guidelines.&#xD;
             Please see Addendum 8 for the action to be taken for patients with positive baseline&#xD;
             hepatitis B results.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Douglas Gladstone, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Schoch LK, Asiama A, Zahurak M, Shanbhag S, Hurtt J, Sawyer K, Swinnen LJ, Wagner-Johnston N, Jones RJ, Ambinder RF, Gladstone DE. Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients. Cancer Chemother Pharmacol. 2018 Feb;81(2):347-354. doi: 10.1007/s00280-017-3499-y. Epub 2017 Dec 13.</citation>
    <PMID>29234922</PMID>
  </results_reference>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>July 27, 2012</study_first_submitted>
  <study_first_submitted_qc>August 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 15, 2012</study_first_posted>
  <results_first_submitted>November 9, 2018</results_first_submitted>
  <results_first_submitted_qc>December 21, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">December 26, 2018</results_first_posted>
  <last_update_submitted>October 4, 2021</last_update_submitted>
  <last_update_submitted_qc>October 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 26, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    <mesh_term>Hodgkin Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Everolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <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>May 7, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/68/NCT01665768/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>7 participants were screen failures.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Everolimus and Rituximab</title>
          <description>Everolimus daily for one year and IV rituximab four times during that year.&#xD;
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.&#xD;
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Everolimus and Rituximab</title>
          <description>Everolimus daily for one year and IV rituximab four times during that year.&#xD;
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.&#xD;
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="49"/>
          </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="37"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </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="59" lower_limit="36" upper_limit="72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                  </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>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="43"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Prior Therapies</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Two Prior Therapies</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Three Prior Therapies</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Four Prior Therapies</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Safety as Assessed by Avoidance of Grade 3-4 Adverse Events</title>
        <description>Number of participants who did not experience at least one grade 3-4 adverse event by CTCAE 4.0.</description>
        <time_frame>Up to 3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Everolimus and Rituximab</title>
            <description>Everolimus daily for one year and IV rituximab four times during that year.&#xD;
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.&#xD;
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
          </group>
        </group_list>
        <measure>
          <title>Safety as Assessed by Avoidance of Grade 3-4 Adverse Events</title>
          <description>Number of participants who did not experience at least one grade 3-4 adverse event by CTCAE 4.0.</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="49"/>
              </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>Event Free Survival (EFS)</title>
        <description>Percentage of participants alive without disease progression. As defined by Cheson criteria, disease progression is a new lesion or &gt;= 50% increase in the size of previously identified sites of disease. EFS was estimated using Kaplan-Meier survival analysis.</description>
        <time_frame>2.5 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Everolimus and Rituximab</title>
            <description>Everolimus daily for one year and IV rituximab four times during that year.&#xD;
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.&#xD;
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
          </group>
        </group_list>
        <measure>
          <title>Event Free Survival (EFS)</title>
          <description>Percentage of participants alive without disease progression. As defined by Cheson criteria, disease progression is a new lesion or &gt;= 50% increase in the size of previously identified sites of disease. EFS was estimated using Kaplan-Meier survival analysis.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58" lower_limit="45" upper_limit="76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage Change in the Frequency of Circulating Cancer Cells</title>
        <description>Percentage change in circulating cancer cells between baseline and each timepoint noted below.</description>
        <time_frame>Baseline, 1 year, 2 years and 3 years</time_frame>
        <population>Data was not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Everolimus and Rituximab</title>
            <description>Everolimus daily for one year and IV rituximab four times during that year.&#xD;
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.&#xD;
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage Change in the Frequency of Circulating Cancer Cells</title>
          <description>Percentage change in circulating cancer cells between baseline and each timepoint noted below.</description>
          <population>Data was not collected.</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>Percentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied</title>
        <description>Percentage change in cancer cells when mTOR inhibition is applied in the laboratory. Samples from participants will be evaluated at each timepoint noted below.</description>
        <time_frame>1 year, 2 years, and 3 years</time_frame>
        <population>Data was not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Everolimus and Rituximab</title>
            <description>Everolimus daily for one year and IV rituximab four times during that year.&#xD;
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.&#xD;
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied</title>
          <description>Percentage change in cancer cells when mTOR inhibition is applied in the laboratory. Samples from participants will be evaluated at each timepoint noted below.</description>
          <population>Data was not collected.</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>
      <time_frame>Up to 3 years</time_frame>
      <desc>Adverse events were assessed every 2 weeks for the first 2 months, monthly for the remainder of the first year, every 90 days for the second year, and every 6 months for the third year. Per protocol, all adverse events were collected for the first 13 participants. Only grade 3-4 and all serious adverse events were collected for the remaining participants.</desc>
      <group_list>
        <group group_id="E1">
          <title>Everolimus and Rituximab</title>
          <description>Everolimus daily for one year and IV rituximab four times during that year.&#xD;
Everolimus: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. Previously the study allowed for starting doses of 5mg and 10mg; the starting dose was reduced in subsequent amendments due to a high incidence of dose reductions. 2.5mg was the most frequent daily dose for all patients, and the entire population was analyzed as one arm.&#xD;
Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</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="0" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Retinal tear</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>MRSA</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Zoster</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin lesions</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</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="47" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pain - throat</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ALT increased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="5" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="25" subjects_affected="10" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" events="17" subjects_affected="10" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="73" subjects_affected="31" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" events="15" subjects_affected="6" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="75" subjects_affected="29" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="18" subjects_affected="8" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Neuropathy</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Mucositis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="49"/>
              </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>Douglas Gladstone, MD</name_or_title>
      <organization>Johns Hopkins University</organization>
      <phone>4109558781</phone>
      <email>dgladst1@jhmi.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/NCT01665768
org study id: J1228
secondary id: NA_00067315
nct id: NCT01665768
lead sponsor: 
collaborator: 
has dmc: Yes
This research is being done to determine if combining an investigational drug called
      Everolimus with Rituximab can reduce the risk of your cancer from returning after high dose
      chemotherapy.
Everolimus is a pill that interferes with lymphoma cell growth by blocking a cellular pathway
      important in causing cancer cells to grow, called mTor. Rituximab is an intravenous
      medication that specifically attacks a protein commonly found on lymphoma cells called CD20.

      Rituximab is already widely used to treat multiple forms of lymphoma. Moreover, continuing
      rituximab after the completion of chemotherapy is already commonly used to help patients stay
      in remission longer. Everolimus has been shown in many types of relapsed lymphoma to decrease
      the size of lymph nodes by itself. Everolimus is approved by the Food and Drug Administration
      (FDA) for the treatment of advanced kidney cancer and subependymal giant cell astocytoma. It
      is not approved for use in lymphoma. The use of everolimus in this research study is
      investigational. The word "investigational" means that everolimus is not approved for
      marketing by the Food and Drug Administration (FDA). The FDA is allowing the use of
      everolimus in this study.

      The combination of everolimus and rituximab for 1 year after high dose therapy is also new.
      We believe the combination of these medications right after your chemotherapy will be more
      effective in attacking your remaining cancer before they have time to re-grow.

      The usual treatment of lymphoma after high-dose chemotherapy is observation. After your body
      has fully recovered from the effects of the chemotherapy, you will receive everolimus daily
      for one year and IV rituximab four times during that year.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety as Assessed by Avoidance of Grade 3-4 Adverse Events
time frame: Up to 3 years
description: Number of participants who did not experience at least one grade 3-4 adverse event by CTCAE 4.0.
measure: Event Free Survival (EFS)
time frame: 2.5 years
description: Percentage of participants alive without disease progression. As defined by Cheson criteria, disease progression is a new lesion or >= 50% increase in the size of previously identified sites of disease. EFS was estimated using Kaplan-Meier survival analysis.
measure: Percentage Change in the Frequency of Circulating Cancer Cells
time frame: Baseline, 1 year, 2 years and 3 years
description: Percentage change in circulating cancer cells between baseline and each timepoint noted below.
measure: Percentage Change in Cancer Cells When mTOR Kinase Inhibition is Applied
time frame: 1 year, 2 years, and 3 years
description: Percentage change in cancer cells when mTOR inhibition is applied in the laboratory. Samples from participants will be evaluated at each timepoint noted below.
arm group label: Everolimus and Rituximab
arm group type: Experimental
description: Everolimus daily for one year and IV rituximab four times during that year.
intervention type: Drug
intervention name: Everolimus
description: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL.
arm group label: Everolimus and Rituximab
other name: RAD001
intervention type: Biological
intervention name: Rituximab
description: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)
arm group label: Everolimus and Rituximab
other name: Rituxan
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: Douglas Gladstone, MD
role: Principal Investigator
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
facility: 
country: United States
citation: Schoch LK, Asiama A, Zahurak M, Shanbhag S, Hurtt J, Sawyer K, Swinnen LJ, Wagner-Johnston N, Jones RJ, Ambinder RF, Gladstone DE. Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients. Cancer Chemother Pharmacol. 2018 Feb;81(2):347-354. doi: 10.1007/s00280-017-3499-y. Epub 2017 Dec 13.
PMID: 29234922
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Mantle-Cell
mesh term: Hodgkin Disease
mesh term: Rituximab
mesh term: Everolimus
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 