<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/NCT01663012</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-24833</org_study_id>
    <secondary_id>SU-06212012-10228</secondary_id>
    <secondary_id>NCI-2012-01288</secondary_id>
    <secondary_id>BRN0021</secondary_id>
    <nct_id>NCT01663012</nct_id>
  </id_info>
  <brief_title>Phase II NKTR-102 In Bevacizumab-Resistant High Grade Glioma</brief_title>
  <official_title>A Phase II, Single Arm, Open Label Study Of NKTR-102 In Bevacizumab-Resistant High Grade Glioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawrence Recht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Nektar Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      High Grade Gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas and&#xD;
      glioblastomas (GBM), are the most common and most aggressive primary brain tumors. Prognosis&#xD;
      for patients with high-grade gliomas remains poor. The estimated median survival for patients&#xD;
      with GBM is between 12 to 18 months. Recurrence after initial therapy with temozolomide and&#xD;
      radiation is nearly universal. Since May 2009, the majority of patients in the US with an&#xD;
      initial recurrence of high-grade glioma receive bevacizumab, a monoclonal antibody against&#xD;
      vascular endothelial growth factor (VEGF), which is thought to prevent angiogenesis in these&#xD;
      highly vascular tumors. BEV has response rates from 32-62% and has improved overall median&#xD;
      survival in patients with recurrent high-grade gliomas1. However, the response is short&#xD;
      lived, and nearly 100% of patients eventually progress despite bevacizumab. No&#xD;
      chemotherapeutic agent administered following progression through bevacizumab has made a&#xD;
      significant impact on survival. Patients progress to death within 1-5 months after resistance&#xD;
      develops. Therefore, patients with high-grade gliomas who have progressed through bevacizumab&#xD;
      represent a population in dire need of a feasible and tolerable treatment.&#xD;
&#xD;
      NKTR-102 is a topoisomerase I inhibitor polymer conjugate that was engineered by attaching&#xD;
      irinotecan molecules to a polyethylene glycol (PEG) polymer using a biodegradable linker.&#xD;
      Irinotecan released from NKTR-102 following administration is further metabolized to the&#xD;
      active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), that causes DNA damage through&#xD;
      inhibition of topoisomerase. The goal in designing NKTR-102 was to attenuate or eliminate&#xD;
      some of the limiting side effects of irinotecan while improving efficacy by modifying the&#xD;
      distribution of the agent within the body. The size and structure of NKTR-102 results in&#xD;
      marked alteration in pharmacokinetic (PK) profile for the SN38 derived from NKTR-102 compared&#xD;
      to that following irinotecan: the maximal plasma concentration (Cmax) is reduced 5- to&#xD;
      10-fold and the half-life (t1/2 ) of SN38 is increased from 2 days to approximately 50 days.&#xD;
      This altered profile leads to constant exposure of the tumor to the active drug. In addition,&#xD;
      the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account&#xD;
      for relatively higher concentrations of the compound and the active metabolites in tumor&#xD;
      tissues in in vivo models, where the local vasculature may be relatively more permeable. A&#xD;
      145 mg/m2 dose of NKTR-102, the dose intended for use in this phase II clinical trial (and&#xD;
      being used in the phase III clinical program), results in approximately the same plasma&#xD;
      exposure to SN38 as a 350 mg/m2 dose of irinotecan, but exposure is protracted, resulting in&#xD;
      continuous exposure between dosing cycles and lower Cmax. NKTR-102 was therefore developed as&#xD;
      a new chemotherapeutic agent that may improve the clinical outcomes of patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>July 2012</start_date>
  <completion_date type="Actual">February 2015</completion_date>
  <primary_completion_date type="Actual">February 2015</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>Progression Free Survival, Assessed by Revised Assessment in Neuro-oncology (RANO) Criteria</measure>
    <time_frame>6 weeks from first administration of NKTR-102</time_frame>
    <description>Will be described using Kaplan-Meier estimates. The PFS probability at 6 weeks (PFS-6week) will be estimated with an 80% power and 95% confidence intervals (80% in accord with the planned alpha level, 95% for comparability with other studies, confidence intervals based on the Greenwood formula for the variance of a survival probability).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Survival From the Time of First NKTR-102 Dose for Patients With BEV-resistant Glioma Receiving NKTR-102 to Date of Death</measure>
    <time_frame>From date of first dose of NKTR-102 to date of death, assessed up to 2 years</time_frame>
    <description>Will be described using Kaplan-Meier estimates.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival From Time of Diagnosis</measure>
    <time_frame>From date of pathologic diagnosis/confirmation of high grade glioma to date of death, assessed up to 2 years.</time_frame>
    <description>Will be described using Kaplan-Meier estimates.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Anaplastic Astrocytomas</condition>
  <condition>Anaplastic Oligodendrogliomas</condition>
  <condition>Glioblastomas (GBM)</condition>
  <arm_group>
    <arm_group_label>Drug: Etirinotecan pegol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>145 mg/m2 dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etirinotecan pegol</intervention_name>
    <arm_group_label>Drug: Etirinotecan pegol</arm_group_label>
    <other_name>NKTR-102</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pathologically proven high-grade glioma (WHO III or IV) with astrocytic component and&#xD;
             must be in recurrence after treatment with bevacizumab&#xD;
&#xD;
          -  Patients must have received conventional radiation therapy of total radiation dosage&#xD;
             (ranging from 5400 to 6000 cGy administered in daily fractions of 150 to 200 cGy over&#xD;
             6 weeks) with concurrent temozolomide.&#xD;
&#xD;
        Patients must have received bevacizumab and be in recurrence after bevacizumab treatment.&#xD;
&#xD;
          -  Patients must be at least 28 days from last administration of cytotoxic chemotherapy&#xD;
             and at least 14 days from the last administration of bevacizumab.&#xD;
&#xD;
               -  Patients must be &gt;18 years of age.&#xD;
&#xD;
               -  Patients must have a life expectancy &gt; 6 weeks&#xD;
&#xD;
               -  Patients must have a Karnofsky Performance Score (KPS) &gt;=50&#xD;
&#xD;
               -  If female, patients of childbearing potential must have a negative serum beta-hCG&#xD;
                  pregnancy test and must agree to use hormonal or barrier birth control with&#xD;
                  spermicidal gel to avoid pregnancy during the study&#xD;
&#xD;
               -  Adequate organ function (obtained within 14 days prior to randomization and&#xD;
                  analyzed by the central laboratory) as evidenced by:&#xD;
&#xD;
                    1. Absolute neutrophil count (ANC) &gt;=1.5 X 10^9/L without myeloid growth factor&#xD;
                       support for 7 days preceding the lab assessment;&#xD;
&#xD;
                    2. Hemoglobin (Hgb) &gt;= 9 g/dL (90 g/L); &lt; 9 g/dL (&lt; 90 g/L) is acceptable if&#xD;
                       hemoglobin is corrected to &gt;= 9 g/dL (90 g/L) as by growth factor or&#xD;
                       transfusion prior to randomization;&#xD;
&#xD;
                    3. Platelet count &gt;=100 X 10^9/L without blood transfusions for 7 days&#xD;
                       preceding the lab assessment;&#xD;
&#xD;
                    4. Bilirubin &lt;= 1.5 X upper limit of normal (ULN), except for patients with&#xD;
                       documented history of Gilbert's disease;&#xD;
&#xD;
                    5. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) &lt;= 2.5&#xD;
                       X ULN&#xD;
&#xD;
                    6. Alkaline phosphatase (AP) &lt;= 3 X ULN&#xD;
&#xD;
                    7. Serum creatinine &lt;= 1.5 mg/dL (133 µmol/L) or calculated creatinine&#xD;
                       clearance &gt;= 50 mL/min (using Cockcroft-Gault formula);&#xD;
&#xD;
                    8. Women of childbearing potential (WCBP): negative serum pregnancy test (this&#xD;
                       test is required of all women unless post-menopausal, defined as 12&#xD;
                       consecutive months since last regular menses, or surgically sterile).&#xD;
&#xD;
               -  Patients must be willing and able to comply with the protocol and provide written&#xD;
                  informed consent prior to study-specific screening procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients who meet any of the following criteria must not be permitted entry to the study.&#xD;
&#xD;
          -  Patients who have had chemotherapy within 28 days, radiotherapy within 28 days,&#xD;
             biological therapy within 14 days, and investigational therapy within 21 days prior to&#xD;
             first dose of experimental drug.&#xD;
&#xD;
          -  Patients who have received prior treatment for cancer with a camptothecin derivative&#xD;
             (eg, irinotecan, topotecan, and investigational agents including but not limited to&#xD;
             exatecan, rubitecan, gimatecan, karenitecan, SN38 investigational agents, EZN-2208,&#xD;
             SN-2310, and AR-67).&#xD;
&#xD;
          -  Patients with the following co-morbid disease or incurrent illness:&#xD;
&#xD;
               1. Patients with chronic or acute GI disorders resulting in diarrhea of any severity&#xD;
                  grade; patients who are using chronic anti-diarrheal supportive care (more than 3&#xD;
                  days/week) to control diarrhea in the 28 days prior to first dose of&#xD;
                  investigational drug.&#xD;
&#xD;
               2. Patients with known cirrhosis diagnosed with Child-Pugh Class A or higher liver&#xD;
                  disease.&#xD;
&#xD;
               3. Prior malignancy except for non-melanoma skin cancer and carcinoma in situ (of&#xD;
                  the cervix or bladder), unless diagnosed and definitively treated more than 3&#xD;
                  years prior to first dose of investigational drug.&#xD;
&#xD;
               4. Severe/uncontrolled inter-current illness within the previous 28 days prior to&#xD;
                  first dose of investigational drug.&#xD;
&#xD;
               5. Significant known cardiovascular impairment (NYHA CHF &gt; grade 2, unstable angina,&#xD;
                  myocardial infarction within the previous 6 months prior to first dose of&#xD;
                  investigational drug, or existing serious cardiac arrhythmia).&#xD;
&#xD;
               6. Patients who require daily use of oxygen supplementation in the 28 days prior to&#xD;
                  first dose of investigational drug.&#xD;
&#xD;
               7. Any other significant co-morbid conditions that in the opinion of the&#xD;
                  Investigator would impair study participation or cooperation.&#xD;
&#xD;
          -  Patients with a known allergy or hypersensitivity to any of the components of the&#xD;
             investigational therapy, including PEG or topoisomerase inhibitors.&#xD;
&#xD;
          -  Patients receiving the following medications at the time of first dose of&#xD;
             investigational drug:&#xD;
&#xD;
               -  Pharmacotherapy for hepatitis B or C, tuberculosis, or HIV.&#xD;
&#xD;
               -  enzyme inducing anti-epileptic medications (EIAEDs)&#xD;
&#xD;
               -  other chemotherapy, other investigational agents , or biologic agents for&#xD;
&#xD;
               -  the treatment of cancer including antibodies(eg, bevacizumab,&#xD;
&#xD;
               -  trastuzumab, or pertuzumab) or any investigational agent(s).&#xD;
&#xD;
          -  Pregnant or nursing patients will be excluded from the study.&#xD;
&#xD;
          -  Patients receiving active treatment for HIV will be excluded from this study because&#xD;
             non-nucleoside reverse transcriptase inhibitors, protease inhibitors and maraviroc (a&#xD;
             CCR5-antagonist) are extensively metabolized by the cytochrome P450 system.&#xD;
             Interactions with these drugs may induce or inhibit irinotecan or SN38 metabolism,&#xD;
             leading to over or under-dosing.&#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>Lawrence Recht, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University School of Medicine</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2016</verification_date>
  <study_first_submitted>August 2, 2012</study_first_submitted>
  <study_first_submitted_qc>August 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2012</study_first_posted>
  <results_first_submitted>May 28, 2015</results_first_submitted>
  <results_first_submitted_qc>May 28, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">June 11, 2015</results_first_posted>
  <last_update_submitted>January 25, 2016</last_update_submitted>
  <last_update_submitted_qc>January 25, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 24, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Lawrence Recht</investigator_full_name>
    <investigator_title>Professor of Neurology and Neurological Sciences</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Oligodendroglioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Etirinotecan pegol</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Drug: Etirinotecan Pegol</title>
          <description>145 mg/m2 dose&#xD;
Etirinotecan pegol</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </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>Drug: Etirinotecan Pegol</title>
          <description>145 mg/m2 dose&#xD;
Etirinotecan pegol</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
          </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="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </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="49.5" lower_limit="20" upper_limit="73"/>
                  </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="8"/>
                  </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="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                  </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="3"/>
                  </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="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="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="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival, Assessed by Revised Assessment in Neuro-oncology (RANO) Criteria</title>
        <description>Will be described using Kaplan-Meier estimates. The PFS probability at 6 weeks (PFS-6week) will be estimated with an 80% power and 95% confidence intervals (80% in accord with the planned alpha level, 95% for comparability with other studies, confidence intervals based on the Greenwood formula for the variance of a survival probability).</description>
        <time_frame>6 weeks from first administration of NKTR-102</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Drug: Etirinotecan Pegol</title>
            <description>145 mg/m2 dose&#xD;
Etirinotecan pegol</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival, Assessed by Revised Assessment in Neuro-oncology (RANO) Criteria</title>
          <description>Will be described using Kaplan-Meier estimates. The PFS probability at 6 weeks (PFS-6week) will be estimated with an 80% power and 95% confidence intervals (80% in accord with the planned alpha level, 95% for comparability with other studies, confidence intervals based on the Greenwood formula for the variance of a survival probability).</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Survival From the Time of First NKTR-102 Dose for Patients With BEV-resistant Glioma Receiving NKTR-102 to Date of Death</title>
        <description>Will be described using Kaplan-Meier estimates.</description>
        <time_frame>From date of first dose of NKTR-102 to date of death, assessed up to 2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Drug: Etirinotecan Pegol</title>
            <description>145 mg/m2 dose&#xD;
Etirinotecan pegol</description>
          </group>
        </group_list>
        <measure>
          <title>Survival From the Time of First NKTR-102 Dose for Patients With BEV-resistant Glioma Receiving NKTR-102 to Date of Death</title>
          <description>Will be described using Kaplan-Meier estimates.</description>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.5" lower_limit="2.4" upper_limit="5.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival From Time of Diagnosis</title>
        <description>Will be described using Kaplan-Meier estimates.</description>
        <time_frame>From date of pathologic diagnosis/confirmation of high grade glioma to date of death, assessed up to 2 years.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Drug: Etirinotecan Pegol</title>
            <description>145 mg/m2 dose&#xD;
Etirinotecan pegol</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival From Time of Diagnosis</title>
          <description>Will be described using Kaplan-Meier estimates.</description>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.1" lower_limit="10.0" upper_limit="36.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Open-ended until 30 days after last dose of Etirinotecan Pegol</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Drug: Etirinotecan Pegol</title>
          <description>145 mg/m2 dose&#xD;
Etirinotecan pegol</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, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Pancytopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </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="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehyrdation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hyponatermia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Malignant Neoplasms, Brain Primary</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </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="1" subjects_affected="1" subjects_at_risk="20"/>
              </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="20"/>
              </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="20" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutrophil Count Decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred Vision</sub_title>
                <counts group_id="E1" events="13" subjects_affected="9" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dry Eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Eye Twitching</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pressure Behind Eyes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="41" subjects_affected="14" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Fecal Incontinence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Gastroesophageal Reflux Disease</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Tongue Swelling</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="21" subjects_affected="14" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema Limbs</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="18" subjects_affected="12" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Non Cardiac Chest Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bladder Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Upper Respiratory Infection</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine Aminotransferase Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Musculoskeletal Pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Generalized Muscle Weakness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Left Sided Muscle Weakness</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Muscle Weakness Lower Limb</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cognative Disturbance</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="11" subjects_affected="7" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Peripheral Motor Neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="11" subjects_affected="8" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Bladder Spasm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Urinary Incontinence</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Urinary Tract Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </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>Lawrence Recht, MD, Professor of Neurology</name_or_title>
      <organization>Stanford University School of Medicine650-</organization>
      <phone>650-725-8630</phone>
      <email>lrecht@stanford.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/NCT01663012
org study id: IRB-24833
secondary id: SU-06212012-10228
secondary id: NCI-2012-01288
secondary id: BRN0021
nct id: NCT01663012
lead sponsor: 
collaborator: 
has dmc: Yes
High Grade Gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas and
      glioblastomas (GBM), are the most common and most aggressive primary brain tumors. Prognosis
      for patients with high-grade gliomas remains poor. The estimated median survival for patients
      with GBM is between 12 to 18 months. Recurrence after initial therapy with temozolomide and
      radiation is nearly universal. Since May 2009, the majority of patients in the US with an
      initial recurrence of high-grade glioma receive bevacizumab, a monoclonal antibody against
      vascular endothelial growth factor (VEGF), which is thought to prevent angiogenesis in these
      highly vascular tumors. BEV has response rates from 32-62% and has improved overall median
      survival in patients with recurrent high-grade gliomas1. However, the response is short
      lived, and nearly 100% of patients eventually progress despite bevacizumab. No
      chemotherapeutic agent administered following progression through bevacizumab has made a
      significant impact on survival. Patients progress to death within 1-5 months after resistance
      develops. Therefore, patients with high-grade gliomas who have progressed through bevacizumab
      represent a population in dire need of a feasible and tolerable treatment.

      NKTR-102 is a topoisomerase I inhibitor polymer conjugate that was engineered by attaching
      irinotecan molecules to a polyethylene glycol (PEG) polymer using a biodegradable linker.
      Irinotecan released from NKTR-102 following administration is further metabolized to the
      active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), that causes DNA damage through
      inhibition of topoisomerase. The goal in designing NKTR-102 was to attenuate or eliminate
      some of the limiting side effects of irinotecan while improving efficacy by modifying the
      distribution of the agent within the body. The size and structure of NKTR-102 results in
      marked alteration in pharmacokinetic (PK) profile for the SN38 derived from NKTR-102 compared
      to that following irinotecan: the maximal plasma concentration (Cmax) is reduced 5- to
      10-fold and the half-life (t1/2 ) of SN38 is increased from 2 days to approximately 50 days.
      This altered profile leads to constant exposure of the tumor to the active drug. In addition,
      the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account
      for relatively higher concentrations of the compound and the active metabolites in tumor
      tissues in in vivo models, where the local vasculature may be relatively more permeable. A
      145 mg/m2 dose of NKTR-102, the dose intended for use in this phase II clinical trial (and
      being used in the phase III clinical program), results in approximately the same plasma
      exposure to SN38 as a 350 mg/m2 dose of irinotecan, but exposure is protracted, resulting in
      continuous exposure between dosing cycles and lower Cmax. NKTR-102 was therefore developed as
      a new chemotherapeutic agent that may improve the clinical outcomes of patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival, Assessed by Revised Assessment in Neuro-oncology (RANO) Criteria
time frame: 6 weeks from first administration of NKTR-102
description: Will be described using Kaplan-Meier estimates. The PFS probability at 6 weeks (PFS-6week) will be estimated with an 80% power and 95% confidence intervals (80% in accord with the planned alpha level, 95% for comparability with other studies, confidence intervals based on the Greenwood formula for the variance of a survival probability).
measure: Survival From the Time of First NKTR-102 Dose for Patients With BEV-resistant Glioma Receiving NKTR-102 to Date of Death
time frame: From date of first dose of NKTR-102 to date of death, assessed up to 2 years
description: Will be described using Kaplan-Meier estimates.
measure: Overall Survival From Time of Diagnosis
time frame: From date of pathologic diagnosis/confirmation of high grade glioma to date of death, assessed up to 2 years.
description: Will be described using Kaplan-Meier estimates.
arm group label: Drug: Etirinotecan pegol
arm group type: Experimental
description: 145 mg/m2 dose
intervention type: Drug
intervention name: Etirinotecan pegol
arm group label: Drug: Etirinotecan pegol
other name: NKTR-102
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lawrence Recht, MD
role: Principal Investigator
affiliation: Stanford University
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Stanford University
investigator full name: Lawrence Recht
investigator title: Professor of Neurology and Neurological Sciences
mesh term: Glioblastoma
mesh term: Astrocytoma
mesh term: Oligodendroglioma
mesh term: Etirinotecan pegol
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 