<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/NCT02238496</url>
  </required_header>
  <id_info>
    <org_study_id>AAAM3801</org_study_id>
    <nct_id>NCT02238496</nct_id>
  </id_info>
  <brief_title>Perifosine and Torisel (Temsirolimus) for Recurrent/Progressive Malignant Gliomas</brief_title>
  <official_title>Pilot Trial of Temsirolimus and Perifosine in Recurrent/Progressive Malignant Gliomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Andrew B Lassman, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>AEterna Zentaris</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Columbia University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test the effectiveness of a drug called temsirolimus in&#xD;
      combination with a drug called perifosine in treating brain tumors that have continued to&#xD;
      grow after previous treatment. Temsirolimus is an intravenous drug approved by the FDA for&#xD;
      treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain&#xD;
      tumors. Perifosine is a pill that has not been approved by the FDA which blocks a messenger&#xD;
      that tells cancer cells to grow. Research suggests that combined treatment with both drugs is&#xD;
      better than either alone, and that it is reasonably safe.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Malignant gliomas are the most common primary brain tumors, and glioblastoma (GBM) is the&#xD;
      most common subtype in adults, representing more than 50% of gliomas. Standard initial&#xD;
      treatment for newly diagnosed GBM consists of maximal surgical resection followed by&#xD;
      radiotherapy to the tumor bed and chemotherapy with an oral DNA alkylator, temozolomide.&#xD;
      However, recurrence is nearly universal despite standard therapy. There is no standard&#xD;
      treatment at recurrence. Median survival is about 15 months from diagnosis and 6 months from&#xD;
      recurrence. Once patients develop tumor progression, conventional chemotherapy is generally&#xD;
      ineffective.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 8, 2014</start_date>
  <completion_date type="Actual">February 14, 2021</completion_date>
  <primary_completion_date type="Actual">October 27, 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>No Masking</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical Benefit Rate</measure>
    <time_frame>Up to 6 months from the start of treatment</time_frame>
    <description>Clinical Benefit Rate is defined as the radiographic response rate plus 6-month progression-free survival (PFS) rate.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival Rate</measure>
    <time_frame>Up to 48 months from start of treatment</time_frame>
    <description>Overall survival will be calculated by using the interval between the date in which the first study drug administration took place (Arm A), and first day of study drug administration following surgery (Arm B), until the date of subject expiration.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Brain Tumor, Recurrent</condition>
  <condition>Glioblastoma</condition>
  <condition>Anaplastic Astrocytoma</condition>
  <condition>Anaplastic Oligodendroglioma</condition>
  <condition>Mixed Glioma</condition>
  <arm_group>
    <arm_group_label>Surgical Cohort - cytoreductive surgery</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Cytoreductive surgery planned (surgical cohort). After post-operative standard evaluations, patients will resume therapy. After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose after recovery from surgery. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Medical Cohort - no cytoreductive surgery</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>No-Cytoreductive surgery planned (medical cohort). After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days).</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Cytoreductive surgery</intervention_name>
    <description>Standard of care/routine cytoreductive glioma resection surgery. Arm B only.</description>
    <arm_group_label>Surgical Cohort - cytoreductive surgery</arm_group_label>
    <other_name>Resection</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Perifosine</intervention_name>
    <description>Perifosine is a pill that has not been approved by the FDA which blocks a messenger that tells cancer cells to grow.</description>
    <arm_group_label>Medical Cohort - no cytoreductive surgery</arm_group_label>
    <arm_group_label>Surgical Cohort - cytoreductive surgery</arm_group_label>
    <other_name>AEZS-104/D-21266</other_name>
    <other_name>KRX-0401</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Temsirolimus</intervention_name>
    <description>Temsirolimus is an intravenous drug approved by the FDA for treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain tumors.</description>
    <arm_group_label>Medical Cohort - no cytoreductive surgery</arm_group_label>
    <arm_group_label>Surgical Cohort - cytoreductive surgery</arm_group_label>
    <other_name>Torisel</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed intracranial glioblastoma (GBM), including sub variants&#xD;
&#xD;
          -  At least 15 unstained slides or at least 1 tissue blocks must be collected from at&#xD;
             least one prior surgery.&#xD;
&#xD;
          -  Received prior radiotherapy and prior temozolomide as treatment for the malignant&#xD;
             glioma&#xD;
&#xD;
          -  Recovered from toxic effects of prior therapies and at least 2 weeks must have elapsed&#xD;
             since any prior signaling pathway modulators; in general, at least 4 weeks must have&#xD;
             elapsed from any other anticancer therapy&#xD;
&#xD;
          -  Able to undergo contrast enhanced magnetic resonance imaging (MRI) scans or CT scans&#xD;
&#xD;
          -  Shown unequivocal evidence for contrast enhancing tumor progression by MRI or CT in&#xD;
             comparison to a prior scan&#xD;
&#xD;
          -  Age &gt; or = 18 years&#xD;
&#xD;
          -  Karnofsky Performance Status &gt; or = 70&#xD;
&#xD;
          -  Life expectancy of &gt; 8 weeks&#xD;
&#xD;
          -  Normal organ and marrow function, adequate liver function, and adequate renal function&#xD;
             before starting therapy&#xD;
&#xD;
          -  Platelet count of at least 100,000/mm3 on at least 2 consecutive blood draws at least&#xD;
             1 week apart with results stable or trending upward&#xD;
&#xD;
          -  Normal coagulation&#xD;
&#xD;
          -  Cholesterol level &lt; or = 350 mg/dl and triglycerides level &lt; or = 400 mg/dl&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             prior to study entry and for the duration of study participation&#xD;
&#xD;
          -  Women of childbearing potential must have a negative beta-human chorionic gonadotropin&#xD;
             (B-hCG) pregnancy test documented within 7 days prior to treatment&#xD;
&#xD;
          -  Women must agree not to breast feed&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
          -  Ability to swallow tablets&#xD;
&#xD;
        Group A (medical) specific inclusion criteria:&#xD;
&#xD;
          -  Fulfill all of the general inclusion criteria&#xD;
&#xD;
          -  At least 3 months between any prior brain radiotherapy and initiation of study therapy&#xD;
&#xD;
          -  MRI/CT must demonstrate measurable enhancing tumor of at least 1cm squared in&#xD;
             cross-sectional area to allow assessment of radiographic response&#xD;
&#xD;
          -  On stable or decreasing dose of corticosteroids for a minimum of 5 days before the&#xD;
             baseline MRI/CT&#xD;
&#xD;
          -  The baseline brain MRI/CT must be performed less than 15 days prior to initiation of&#xD;
             study treatment. Otherwise it must be repeated&#xD;
&#xD;
        Group B (surgical) specific inclusion criteria:&#xD;
&#xD;
          -  Fulfill all of the general inclusion criteria&#xD;
&#xD;
          -  Have cytoreductive surgery as part of their routine care for recurrent tumor&#xD;
&#xD;
          -  Have cytoreductive surgery as part of their routine care for recurrent tumor&#xD;
&#xD;
          -  A brain MRI/CT must be performed less than 15 days prior to initiation of study&#xD;
             treatment. Otherwise it must be repeated&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  There is no limit on the number or type of prior chemotherapies except:&#xD;
&#xD;
               1. convection enhanced delivery, catheter based intra-tumoral treatment, or&#xD;
                  carmustine (BCNU)/Gliadel® wafers&#xD;
&#xD;
               2. stereotactic radiosurgery, or re-irradiation of any type&#xD;
&#xD;
               3. agent designed to inhibit mTOR or PI3K/AKT&#xD;
&#xD;
               4. direct Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth&#xD;
                  Factor Receptors (VEGFR) inhibitors&#xD;
&#xD;
          -  Smoking or plan to smoke tobacco or marijuana during study therapy&#xD;
&#xD;
          -  Plan to eat grapefruit or drink grapefruit juice during study therapy&#xD;
&#xD;
          -  Receiving any other investigational agents concurrently with study treatment&#xD;
&#xD;
          -  Taking hepatic Enzyme Inducing Anti-Epileptic Drug (EIAED)&#xD;
&#xD;
          -  Taking medications that are inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) for&#xD;
             at least two weeks prior to study treatment&#xD;
&#xD;
          -  Uncontrolled intercurrent illness&#xD;
&#xD;
          -  HIV-positive patients on combination antiretroviral therapy&#xD;
&#xD;
          -  Other active concurrent malignancy&#xD;
&#xD;
          -  History of gout which can be exacerbated by perifosine&#xD;
&#xD;
          -  Known history of allergic reactions attributed to compounds of similar chemical or&#xD;
             biologic composition to temsirolimus or perifosine&#xD;
&#xD;
          -  Therapeutic anticoagulation&#xD;
&#xD;
          -  History of hemorrhagic or ischemic stroke&#xD;
&#xD;
          -  Prior intratumoral bleeding must be evaluated with a non-contrast head CT to exclude&#xD;
             acute blood prior to start of treatment&#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>Andrew B. Lassman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Columbia University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Columbia University Irving Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan-Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://hiccc.columbia.edu/clinicaltrials</url>
    <description>Herbert Irving Comprehensive Cancer Center (HICCC) Clinical Trials Page</description>
  </link>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>August 29, 2014</study_first_submitted>
  <study_first_submitted_qc>September 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2014</study_first_posted>
  <last_update_submitted>May 23, 2023</last_update_submitted>
  <last_update_submitted_qc>May 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Columbia University</investigator_affiliation>
    <investigator_full_name>Andrew B Lassman, MD</investigator_full_name>
    <investigator_title>John Harris Associate Professor of Neurology</investigator_title>
  </responsible_party>
  <keyword>Glioblastoma</keyword>
  <keyword>Anaplastic Astrocytoma</keyword>
  <keyword>Anaplastic Oligodendroglioma</keyword>
  <keyword>Mixed Glioma</keyword>
  <keyword>akt-Oncogene Protein</keyword>
  <keyword>mTOR Protein</keyword>
  <keyword>Glioma</keyword>
  <keyword>Brain Neoplasms</keyword>
  <keyword>Brain Tumor, Recurrent</keyword>
  <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>Brain Neoplasms</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Oligodendroglioma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Temsirolimus</mesh_term>
    <mesh_term>MTOR Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02238496
org study id: AAAM3801
nct id: NCT02238496
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to test the effectiveness of a drug called temsirolimus in
      combination with a drug called perifosine in treating brain tumors that have continued to
      grow after previous treatment. Temsirolimus is an intravenous drug approved by the FDA for
      treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain
      tumors. Perifosine is a pill that has not been approved by the FDA which blocks a messenger
      that tells cancer cells to grow. Research suggests that combined treatment with both drugs is
      better than either alone, and that it is reasonably safe.
Malignant gliomas are the most common primary brain tumors, and glioblastoma (GBM) is the
      most common subtype in adults, representing more than 50% of gliomas. Standard initial
      treatment for newly diagnosed GBM consists of maximal surgical resection followed by
      radiotherapy to the tumor bed and chemotherapy with an oral DNA alkylator, temozolomide.
      However, recurrence is nearly universal despite standard therapy. There is no standard
      treatment at recurrence. Median survival is about 15 months from diagnosis and 6 months from
      recurrence. Once patients develop tumor progression, conventional chemotherapy is generally
      ineffective.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: No Masking
measure: Clinical Benefit Rate
time frame: Up to 6 months from the start of treatment
description: Clinical Benefit Rate is defined as the radiographic response rate plus 6-month progression-free survival (PFS) rate.
measure: Median Overall Survival Rate
time frame: Up to 48 months from start of treatment
description: Overall survival will be calculated by using the interval between the date in which the first study drug administration took place (Arm A), and first day of study drug administration following surgery (Arm B), until the date of subject expiration.
arm group label: Surgical Cohort - cytoreductive surgery
arm group type: Other
description: Cytoreductive surgery planned (surgical cohort). After post-operative standard evaluations, patients will resume therapy. After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose after recovery from surgery. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days).
arm group label: Medical Cohort - no cytoreductive surgery
arm group type: Other
description: No-Cytoreductive surgery planned (medical cohort). After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days).
intervention type: Procedure
intervention name: Cytoreductive surgery
description: Standard of care/routine cytoreductive glioma resection surgery. Arm B only.
arm group label: Surgical Cohort - cytoreductive surgery
other name: Resection
intervention type: Drug
intervention name: Perifosine
description: Perifosine is a pill that has not been approved by the FDA which blocks a messenger that tells cancer cells to grow.
arm group label: Medical Cohort - no cytoreductive surgery
arm group label: Surgical Cohort - cytoreductive surgery
other name: AEZS-104/D-21266
other name: KRX-0401
intervention type: Drug
intervention name: Temsirolimus
description: Temsirolimus is an intravenous drug approved by the FDA for treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain tumors.
arm group label: Medical Cohort - no cytoreductive surgery
arm group label: Surgical Cohort - cytoreductive surgery
other name: Torisel
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrew B. Lassman, MD
role: Principal Investigator
affiliation: Columbia University
facility: 
facility: 
country: United States
url: http://hiccc.columbia.edu/clinicaltrials
description: Herbert Irving Comprehensive Cancer Center (HICCC) Clinical Trials Page
responsible party type: Sponsor-Investigator
investigator affiliation: Columbia University
investigator full name: Andrew B Lassman, MD
investigator title: John Harris Associate Professor of Neurology
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Brain Neoplasms
mesh term: Astrocytoma
mesh term: Oligodendroglioma
mesh term: Recurrence
mesh term: Sirolimus
mesh term: Temsirolimus
mesh term: MTOR Inhibitors
sharing ipd: No