<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/NCT02186509</url>
  </required_header>
  <id_info>
    <org_study_id>13P.528</org_study_id>
    <secondary_id>2013-12</secondary_id>
    <nct_id>NCT02186509</nct_id>
  </id_info>
  <brief_title>Alisertib and Fractionated Stereotactic Radiosurgery in Treating Patients With Recurrent High Grade Gliomas</brief_title>
  <official_title>Phase I Study of Alisertib With Concurrent Fractionated Stereotactic Radiation Treatment for Recurrent High Grade Gliomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Cancer Center at Thomas Jefferson University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Millennium Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Thomas Jefferson University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of alisertib when combined with&#xD;
      fractionated stereotactic radiosurgery in treating patients with high-grade gliomas that have&#xD;
      returned after previous treatment with radiation therapy (recurrent). Alisertib may stop the&#xD;
      growth of tumor cells by blocking an enzyme needed for the cells to divide. Radiation therapy&#xD;
      uses high energy x rays to kill tumor cells. Stereotactic radiosurgery uses special&#xD;
      positioning equipment to send a single high dose of radiation directly to the tumor and cause&#xD;
      less damage to normal tissue. Delivering stereotactic radiosurgery over multiple doses&#xD;
      (fractionation) may cause more damage to tumor tissue than normal tissue while maintaining&#xD;
      the advantage of its accuracy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Evaluate the safety and tolerability of the study treatment. II. To determine the maximum&#xD;
      tolerated dose (MTD) of daily oral alisertib when combined with fractionated stereotactic&#xD;
      radiation treatment for recurrent high grade glioma.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To estimate 6 month progression free survival rate. II. To estimate the median time to&#xD;
      progression. III. To estimate overall survival. IV. To estimate the impact on quality of life&#xD;
      (QoL).&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of alisertib.&#xD;
&#xD;
      CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery once daily (QD)&#xD;
      every weekday for 10 days and receive alisertib orally (PO) twice daily (BID) concurrently&#xD;
      with radiation therapy for 10 days.&#xD;
&#xD;
      MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21&#xD;
      days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months for 1 year and&#xD;
      then every 4-6 months thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 30, 2015</start_date>
  <completion_date type="Actual">December 31, 2018</completion_date>
  <primary_completion_date type="Actual">March 31, 2017</primary_completion_date>
  <phase>Phase 1</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>Maximum Tolerated Dose (MTD) of Alisertib</measure>
    <time_frame>Up to 30 days after completion of radiation therapy</time_frame>
    <description>Defined as the dose at which &gt;= 2 patients experience dose-limiting toxicity, graded in severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Complete or Partial Response</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>95% confidence intervals will be computed. Response was defined by the Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Work Group (RANO)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Progression Free Survival at 6 Months</measure>
    <time_frame>At 6 months</time_frame>
    <description>Estimated through the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Overall Survival at 6 Months</measure>
    <time_frame>At 6 months</time_frame>
    <description>Estimated through the Kaplan-Meier method.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Adult Anaplastic Astrocytoma</condition>
  <condition>Adult Anaplastic Ependymoma</condition>
  <condition>Adult Anaplastic Oligodendroglioma</condition>
  <condition>Adult Brain Stem Glioma</condition>
  <condition>Adult Diffuse Astrocytoma</condition>
  <condition>Adult Giant Cell Glioblastoma</condition>
  <condition>Adult Glioblastoma</condition>
  <condition>Adult Gliosarcoma</condition>
  <condition>Adult Mixed Glioma</condition>
  <condition>Adult Oligodendroglioma</condition>
  <condition>Adult Pilocytic Astrocytoma</condition>
  <condition>Adult Pineal Gland Astrocytoma</condition>
  <condition>Adult Subependymal Giant Cell Astrocytoma</condition>
  <condition>Recurrent Adult Brain Tumor</condition>
  <arm_group>
    <arm_group_label>Alisertib, fractionated stereotactic radiosurgery</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Hyperfractionated radiation therapy</intervention_name>
    <description>Undergo hyperfractionated radiation therapy</description>
    <arm_group_label>Alisertib, fractionated stereotactic radiosurgery</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic radiosurgery</intervention_name>
    <description>Undergo stereotactic radiosurgery</description>
    <arm_group_label>Alisertib, fractionated stereotactic radiosurgery</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alisertib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Alisertib, fractionated stereotactic radiosurgery</arm_group_label>
    <other_name>MLN8237</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Quality-of-life assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Alisertib, fractionated stereotactic radiosurgery</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients must have a previously histologically or cytologically confirmed high grade&#xD;
             glioma (astrocytic or oligodendroglial supratentorial tumors grade 3 or 4) that has&#xD;
             been previously treated with fractionated radiation therapy and now shows evidence of&#xD;
             recurrence.&#xD;
&#xD;
          2. Patients must have recovered from the toxic effects of prior therapy.&#xD;
&#xD;
          3. Patients must have recovered from the effects of surgery. There must be a minimum of&#xD;
             21 days from the day of surgery to the day of protocol treatment. For core or needle&#xD;
             biopsy, a minimum of 7 days must have elapsed prior to the day of protocol treatment.&#xD;
&#xD;
          4. Prior treatment with cytotoxic and biological agents is permissible. There should be&#xD;
             at least a 2-week break between prior treatment and the protocol treatment.&#xD;
&#xD;
          5. Prior treatment with fractionated radiation therapy (up to 60Gy) is an eligibility&#xD;
             criterion, however there should not have been a second course of fractionated&#xD;
             radiotherapy to the supratentorial area.&#xD;
&#xD;
          6. One prior single fraction radiosurgical procedure within the treatment field is&#xD;
             acceptable if V12&lt;5 cc (V12 is the volume of normal brain (outside GTV) receiving 12&#xD;
             or more Gy). Additional radiosurgical procedures outside of the treatment area are&#xD;
             acceptable.&#xD;
&#xD;
          7. Subject must be able to take oral medication and to maintain a fast, is required for 2&#xD;
             hours before and 1 hour after MLN8237 administration.&#xD;
&#xD;
          8. ANC &gt; 1500/mm³, platelets &gt; 100,000/mm³, Hgb &gt; 9 g/dL. Values must be obtained without&#xD;
             need for myeloid growth factor or platelet transfusion support within 14 days of&#xD;
             registration. However, erythrocyte growth factor is allowed as per published ASCO&#xD;
             guidelines.&#xD;
&#xD;
          9. Total bilirubin ≤ ULN, SGOT (AST) and SGPT (ALT)&lt; 1.5 x ULN, within 14 days of&#xD;
             registration.&#xD;
&#xD;
         10. Adequate renal function as defined by: calculated creatinine clearance must be ≥40&#xD;
             mL/minute (Cockcroft-Gault), within 14 days of registration.&#xD;
&#xD;
         11. Age &gt;18 years.&#xD;
&#xD;
         12. ECOG performance status &lt;2 (see Appendix I).&#xD;
&#xD;
         13. Life expectancy of greater than 2 months.&#xD;
&#xD;
         14. Women of childbearing potential must have a negative β-HCG pregnancy test documented&#xD;
             within 7 days prior to registration.&#xD;
&#xD;
         15. Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for&#xD;
             4 months after last dose.&#xD;
&#xD;
         16. Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known history of uncontrolled sleep apnea syndrome and other conditions that could&#xD;
             result in excessive daytime sleepiness such as severe chronic obstructive pulmonary&#xD;
             disease requiring supplemental oxygen.&#xD;
&#xD;
          2. Systemic infection requiring IV antibiotic therapy within 14 days preceding the first&#xD;
             dose of study drug, or other severe infection.&#xD;
&#xD;
          3. Myocardial infarction within 6 months prior to enrollment, New York Heart Association&#xD;
             (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled&#xD;
             ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active&#xD;
             conduction system abnormalities. Prior to study entry, any ECG abnormality at&#xD;
             Screening has to be documented by the investigator as not medically relevant.&#xD;
&#xD;
          4. Female subject is pregnant or breast-feeding. Confirmation that the subject is not&#xD;
             pregnant must be established by a negative serum β-human chorionic gonadotropin&#xD;
             (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not&#xD;
             required for post-menopausal or surgically sterilized women.&#xD;
&#xD;
          5. Patient has received other investigational drugs within 14 days before enrollment&#xD;
&#xD;
          6. Serious medical or psychiatric illness likely to interfere with participation in this&#xD;
             clinical study.&#xD;
&#xD;
          7. Other severe acute or chronic medical or psychiatric condition, including uncontrolled&#xD;
             diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement&#xD;
             for pancreatic enzymes, any condition that would modify small bowel absorption of oral&#xD;
             medications, or laboratory abnormality that may increase the risk associated with&#xD;
             study participation or investigational product administration or may interfere with&#xD;
             the interpretation of study results and, in the judgment of the investigator, would&#xD;
             make the patient inappropriate for enrollment in this study.&#xD;
&#xD;
          8. Treatment with clinically significant enzyme inducers, such as the enzyme-inducing&#xD;
             antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin,&#xD;
             rifapentine or St. John's wort within 14 days prior to the first dose of MLN8237 and&#xD;
             during the study.&#xD;
&#xD;
          9. Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or&#xD;
             hepatitis C. Testing is not required in the absence of clinical findings or suspicion.&#xD;
&#xD;
         10. Patients have a history of any other malignancy from which the patient has been&#xD;
             disease-free for less than 2 years, with the exception of adequately treated basal or&#xD;
             squamous cell carcinoma of skin, superficial bladder cancer or carcinoma in situ of&#xD;
             cervix, AJCC (version 7.0) stage 0 or I breast cancer, AJCC (version 7.0) stage I, or&#xD;
             II prostate cancer.&#xD;
&#xD;
         11. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is&#xD;
             considered to be over 25%.&#xD;
&#xD;
         12. Patients who cannot swallow whole tablets (i.e. medication tablets)&#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>Wenyin Shi, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Thomas Jefferson University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sidney Kimmel Cancer Center at Thomas Jefferson University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.jeffersonhealth.org/clinical-specialties/cancer</url>
    <description>Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center</description>
  </link>
  <link>
    <url>http://www.JeffersonHospital.org</url>
    <description>Thomas Jefferson University Hospitals</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 10, 2014</study_first_posted>
  <results_first_submitted>May 16, 2019</results_first_submitted>
  <results_first_submitted_qc>August 8, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">September 9, 2019</results_first_posted>
  <last_update_submitted>September 5, 2023</last_update_submitted>
  <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2023</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>Glioblastoma</mesh_term>
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Ependymoma</mesh_term>
    <mesh_term>Gliosarcoma</mesh_term>
    <mesh_term>Oligodendroglioma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_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>September 13, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/09/NCT02186509/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Alisertib, Fractionated Stereotactic Radiosurgery</title>
          <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Hyperfractionated radiation therapy: Undergo hyperfractionated radiation therapy&#xD;
Stereotactic radiosurgery: Undergo stereotactic radiosurgery&#xD;
Alisertib: Given PO&#xD;
Quality-of-life assessment: Ancillary studies</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
              </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>Alisertib, Fractionated Stereotactic Radiosurgery</title>
          <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Hyperfractionated radiation therapy: Undergo hyperfractionated radiation therapy&#xD;
Stereotactic radiosurgery: Undergo stereotactic radiosurgery&#xD;
Alisertib: Given PO&#xD;
Quality-of-life assessment: Ancillary studies</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="17"/>
          </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="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </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="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Alisertib</title>
        <description>Defined as the dose at which &gt;= 2 patients experience dose-limiting toxicity, graded in severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0</description>
        <time_frame>Up to 30 days after completion of radiation therapy</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Alisertib, Fractionated Stereotactic Radiosurgery</title>
            <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Hyperfractionated radiation therapy: Undergo hyperfractionated radiation therapy&#xD;
Stereotactic radiosurgery: Undergo stereotactic radiosurgery&#xD;
Alisertib: Given PO&#xD;
Quality-of-life assessment: Ancillary studies</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Alisertib</title>
          <description>Defined as the dose at which &gt;= 2 patients experience dose-limiting toxicity, graded in severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0</description>
          <units>mg dose of Alisertib</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Complete or Partial Response</title>
        <description>95% confidence intervals will be computed. Response was defined by the Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Work Group (RANO)</description>
        <time_frame>Up to 5 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Alisertib, Fractionated Stereotactic Radiosurgery</title>
            <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Hyperfractionated radiation therapy: Undergo hyperfractionated radiation therapy&#xD;
Stereotactic radiosurgery: Undergo stereotactic radiosurgery&#xD;
Alisertib: Given PO&#xD;
Quality-of-life assessment: Ancillary studies</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Complete or Partial Response</title>
          <description>95% confidence intervals will be computed. Response was defined by the Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Work Group (RANO)</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="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Progression Free Survival at 6 Months</title>
        <description>Estimated through the Kaplan-Meier method.</description>
        <time_frame>At 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Alisertib, Fractionated Stereotactic Radiosurgery</title>
            <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Hyperfractionated radiation therapy: Undergo hyperfractionated radiation therapy&#xD;
Stereotactic radiosurgery: Undergo stereotactic radiosurgery&#xD;
Alisertib: Given PO&#xD;
Quality-of-life assessment: Ancillary studies</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Progression Free Survival at 6 Months</title>
          <description>Estimated through the Kaplan-Meier method.</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="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Overall Survival at 6 Months</title>
        <description>Estimated through the Kaplan-Meier method.</description>
        <time_frame>At 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Alisertib, Fractionated Stereotactic Radiosurgery</title>
            <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Hyperfractionated radiation therapy: Undergo hyperfractionated radiation therapy&#xD;
Stereotactic radiosurgery: Undergo stereotactic radiosurgery&#xD;
Alisertib: Given PO&#xD;
Quality-of-life assessment: Ancillary studies</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Overall Survival at 6 Months</title>
          <description>Estimated through the Kaplan-Meier method.</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="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>18 months from baseline</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Alisertib, Fractionated Stereotactic Radiosurgery</title>
          <description>CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.&#xD;
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Hyperfractionated radiation therapy: Undergo hyperfractionated radiation therapy&#xD;
Stereotactic radiosurgery: Undergo stereotactic radiosurgery&#xD;
Alisertib: Given PO&#xD;
Quality-of-life assessment: Ancillary studies</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="15" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </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="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>1</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="17" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyperlipidemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral Edema</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Transaminitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyperbilirubinemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hpocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle Weakness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Focal seizure</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Gait Disturbance</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
              </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>Dr. Wenyin Shi</name_or_title>
      <organization>Sidney Kimmel Cancer Center at Thomas Jefferson University</organization>
      <phone>215-955-6702</phone>
      <email>Wenyin.Shi@jefferson.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/NCT02186509
org study id: 13P.528
secondary id: 2013-12
nct id: NCT02186509
lead sponsor: 
collaborator: 
has dmc: Yes
This phase I trial studies the side effects and best dose of alisertib when combined with
      fractionated stereotactic radiosurgery in treating patients with high-grade gliomas that have
      returned after previous treatment with radiation therapy (recurrent). Alisertib may stop the
      growth of tumor cells by blocking an enzyme needed for the cells to divide. Radiation therapy
      uses high energy x rays to kill tumor cells. Stereotactic radiosurgery uses special
      positioning equipment to send a single high dose of radiation directly to the tumor and cause
      less damage to normal tissue. Delivering stereotactic radiosurgery over multiple doses
      (fractionation) may cause more damage to tumor tissue than normal tissue while maintaining
      the advantage of its accuracy.
PRIMARY OBJECTIVES:

      I. Evaluate the safety and tolerability of the study treatment. II. To determine the maximum
      tolerated dose (MTD) of daily oral alisertib when combined with fractionated stereotactic
      radiation treatment for recurrent high grade glioma.

      SECONDARY OBJECTIVES:

      I. To estimate 6 month progression free survival rate. II. To estimate the median time to
      progression. III. To estimate overall survival. IV. To estimate the impact on quality of life
      (QoL).

      OUTLINE: This is a dose-escalation study of alisertib.

      CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery once daily (QD)
      every weekday for 10 days and receive alisertib orally (PO) twice daily (BID) concurrently
      with radiation therapy for 10 days.

      MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21
      days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year and
      then every 4-6 months thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of Alisertib
time frame: Up to 30 days after completion of radiation therapy
description: Defined as the dose at which >= 2 patients experience dose-limiting toxicity, graded in severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
measure: Number of Participants With Complete or Partial Response
time frame: Up to 5 years
description: 95% confidence intervals will be computed. Response was defined by the Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Work Group (RANO)
measure: Number of Participants With Progression Free Survival at 6 Months
time frame: At 6 months
description: Estimated through the Kaplan-Meier method.
measure: Number of Participants With Overall Survival at 6 Months
time frame: At 6 months
description: Estimated through the Kaplan-Meier method.
arm group label: Alisertib, fractionated stereotactic radiosurgery
arm group type: Experimental
description: CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.
MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
intervention type: Radiation
intervention name: Hyperfractionated radiation therapy
description: Undergo hyperfractionated radiation therapy
arm group label: Alisertib, fractionated stereotactic radiosurgery
intervention type: Radiation
intervention name: Stereotactic radiosurgery
description: Undergo stereotactic radiosurgery
arm group label: Alisertib, fractionated stereotactic radiosurgery
intervention type: Drug
intervention name: Alisertib
description: Given PO
arm group label: Alisertib, fractionated stereotactic radiosurgery
other name: MLN8237
intervention type: Procedure
intervention name: Quality-of-life assessment
description: Ancillary studies
arm group label: Alisertib, fractionated stereotactic radiosurgery
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wenyin Shi, MD, PhD
role: Principal Investigator
affiliation: Thomas Jefferson University
facility: 
country: United States
url: https://www.jeffersonhealth.org/clinical-specialties/cancer
description: Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center
url: http://www.JeffersonHospital.org
description: Thomas Jefferson University Hospitals
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Astrocytoma
mesh term: Ependymoma
mesh term: Gliosarcoma
mesh term: Oligodendroglioma
mesh term: Recurrence
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 