<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/NCT02254954</url>
  </required_header>
  <id_info>
    <org_study_id>AC-055-118</org_study_id>
    <nct_id>NCT02254954</nct_id>
  </id_info>
  <brief_title>Clinical Study on Macitentan, RT and TMZ Concurrent Therapy Followed by Maintenance Macitentan and TMZ in Newly Diagnosed Glioblastoma</brief_title>
  <official_title>A Single-center, Open-label, Phase 1 Study of Macitentan, Radiotherapy and Temozolomide Concurrent Therapy Followed by Maintenance Therapy With Macitentan and Temozolomide in Subjects With Newly Diagnosed Glioblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Actelion</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Actelion</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective, single-center, open-label, 3+3 dose escalation Phase 1 safety study.&#xD;
      Adults with newly diagnosed GBM or gliosarcoma will receive macitentan in addition to the&#xD;
      standard of care treatment for GBM. The study consists of a screening period, a treatment&#xD;
      period, and a 30-day safety follow up period. The treatment period includes 6 weeks of&#xD;
      concurrent therapy (macitentan+RT+TMZ), 4 weeks of monotherapy (macitentan) and 12 cycles of&#xD;
      maintenance therapy (macitentan+TMZ). The study will end when the last treated subject has&#xD;
      completed study treatment and the 30-day safety follow-up period.&#xD;
&#xD;
      The planned duration of the study is approximately 34-38 months depending on the number of&#xD;
      dose levels and cohorts of subjects enrolled. Subject participation in the study will be for&#xD;
      approximately 16 months.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Sponsor decision due to low recruitment&#xD;
  </why_stopped>
  <start_date type="Actual">January 8, 2015</start_date>
  <completion_date type="Actual">September 29, 2016</completion_date>
  <primary_completion_date type="Actual">September 29, 2016</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>Number of subjects with dose-limiting toxicities observed during the first 10 weeks of study treatment (i.e., 6 weeks of concurrent therapy with macitentan, RT and TMZ and 4 weeks of monotherapy with macitentan).</measure>
    <time_frame>Start of treatment to week 10</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma concentrations of endothelin-1</measure>
    <time_frame>Baseline, Weeks 2, 6, and 10</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentrations of macitentan and its metabolite</measure>
    <time_frame>Baseline, Weeks 2 and 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve (AUCτ) for macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak plasma concentration (Cmax) of macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach peak plasma concentration (Tmax) of macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of adverse events (per Common Terminology Criteria for Adverse Events [CTCAE] criteria, version 4.03]) leading to premature discontinuation of study treatment</measure>
    <time_frame>Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with marked laboratory abnormalities or abnormal electrocardiogram (ECG) findings</measure>
    <time_frame>Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in pulse rate, systolic &amp; diastolic blood pressure</measure>
    <time_frame>Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory efficacy endpoint of proportion of subjects with progression free survival (PFS) at 6 and 12 months</measure>
    <time_frame>6 and 12 months after the start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of adverse events (per CTCAE] criteria, version 4.03]) as a measure of safety and tolerability.</measure>
    <time_frame>Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Glioblastoma</condition>
  <arm_group>
    <arm_group_label>Macitentan in combination with RT &amp; TMZ</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Escalating doses of macitentan in combination with RT and TMZ, and maintenance TMZ.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Macitentan in combination with RT and TMZ</intervention_name>
    <description>Escalating doses of macitentan in combination with RT and TMZ, and maintenance TMZ.</description>
    <arm_group_label>Macitentan in combination with RT &amp; TMZ</arm_group_label>
    <other_name>Temodar (temozolomide [TMZ])</other_name>
    <other_name>macitentan</other_name>
    <other_name>Radiotherapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects at least 18 years of age&#xD;
&#xD;
          -  Histologically proven supratentorial GBM or gliosarcoma&#xD;
&#xD;
          -  Use of effective contraception by women of childbearing potental.&#xD;
&#xD;
          -  Use of effective contraception by fertile males with a female partner of childbearing&#xD;
             potential.&#xD;
&#xD;
          -  Interval of at least 3 weeks after biopsy or open surgery and able to begin study&#xD;
             treatment.&#xD;
&#xD;
          -  Result from a post-operative contrast-enhanced brain MRI within 72 hours after surgery&#xD;
             or biopsy.&#xD;
&#xD;
          -  Adequate bone marrow function&#xD;
&#xD;
          -  Karnofsky Performance Score of at least 70.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior treatment for glioblastoma or gliosarcoma.&#xD;
&#xD;
          -  Evidence of leptomeningeal spread of glibolastoma or gliosarcoma.&#xD;
&#xD;
          -  Tumor foci below the tentorium or beyond the cranial vault.&#xD;
&#xD;
          -  Evidence of recent hemorrhage on post-operative contrast enhanced brain MRI (except&#xD;
             hemosiderin, resolving hemorrhage changes related to surgery, presence of punctuate&#xD;
             hemorrhage in tumor).&#xD;
&#xD;
          -  Aspartate aminotransferase or alanine aminotransferase &gt; 3 times the upper limit of&#xD;
             normal.&#xD;
&#xD;
          -  Supine systolic blood pressure &lt; 100 mmHg or diastolic blood pressure &lt; 50 mmHg.&#xD;
&#xD;
          -  Medical history of orthostatic hypotension.&#xD;
&#xD;
          -  International normalized ratio &gt; 1.5 on anticoagulant therapy, active bleeding on low&#xD;
             molecular weight heparin, or chronic condition with a high risk of bleeding.&#xD;
&#xD;
          -  Severe renal impairment.&#xD;
&#xD;
          -  Severe hepatic impairment.&#xD;
&#xD;
          -  Severe, active co-morbidity: (e.g. cardiac disease; respiratory disease; chronic&#xD;
             hepatitis; hemtological and bone marrow diseases; severe malabsoprtion; human&#xD;
             immunodeficiency virus).&#xD;
&#xD;
          -  No concurrent strong CYP3A4 inducers or inhibitors.&#xD;
&#xD;
          -  No investigational drug within 4 weeks of starting study treatment.&#xD;
&#xD;
          -  Any life-threatening condition that could affect protocol compliance.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>Investigational Site Web Address</description>
  </link>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>September 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2014</study_first_posted>
  <last_update_submitted>February 26, 2018</last_update_submitted>
  <last_update_submitted_qc>February 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>glioblastoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Temozolomide</mesh_term>
    <mesh_term>Macitentan</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02254954
org study id: AC-055-118
nct id: NCT02254954
lead sponsor: 
has dmc: No
This is a prospective, single-center, open-label, 3+3 dose escalation Phase 1 safety study.
      Adults with newly diagnosed GBM or gliosarcoma will receive macitentan in addition to the
      standard of care treatment for GBM. The study consists of a screening period, a treatment
      period, and a 30-day safety follow up period. The treatment period includes 6 weeks of
      concurrent therapy (macitentan+RT+TMZ), 4 weeks of monotherapy (macitentan) and 12 cycles of
      maintenance therapy (macitentan+TMZ). The study will end when the last treated subject has
      completed study treatment and the 30-day safety follow-up period.

      The planned duration of the study is approximately 34-38 months depending on the number of
      dose levels and cohorts of subjects enrolled. Subject participation in the study will be for
      approximately 16 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of subjects with dose-limiting toxicities observed during the first 10 weeks of study treatment (i.e., 6 weeks of concurrent therapy with macitentan, RT and TMZ and 4 weeks of monotherapy with macitentan).
time frame: Start of treatment to week 10
measure: Plasma concentrations of endothelin-1
time frame: Baseline, Weeks 2, 6, and 10
measure: Plasma concentrations of macitentan and its metabolite
time frame: Baseline, Weeks 2 and 6
measure: Area under the plasma concentration-time curve (AUCτ) for macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher
time frame: Week 4
measure: Peak plasma concentration (Cmax) of macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher
time frame: Week 4
measure: Time to reach peak plasma concentration (Tmax) of macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher
time frame: Week 4
measure: Number of adverse events (per Common Terminology Criteria for Adverse Events [CTCAE] criteria, version 4.03]) leading to premature discontinuation of study treatment
time frame: Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up
measure: Number of subjects with marked laboratory abnormalities or abnormal electrocardiogram (ECG) findings
time frame: Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up
measure: Change from baseline in pulse rate, systolic & diastolic blood pressure
time frame: Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days follow-up
measure: Exploratory efficacy endpoint of proportion of subjects with progression free survival (PFS) at 6 and 12 months
time frame: 6 and 12 months after the start of treatment
measure: Number of adverse events (per CTCAE] criteria, version 4.03]) as a measure of safety and tolerability.
time frame: Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up
arm group label: Macitentan in combination with RT & TMZ
arm group type: Experimental
description: Escalating doses of macitentan in combination with RT and TMZ, and maintenance TMZ.
intervention type: Drug
intervention name: Macitentan in combination with RT and TMZ
description: Escalating doses of macitentan in combination with RT and TMZ, and maintenance TMZ.
arm group label: Macitentan in combination with RT & TMZ
other name: Temodar (temozolomide [TMZ])
other name: macitentan
other name: Radiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
url: http://www.mdanderson.org
description: Investigational Site Web Address
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Temozolomide
mesh term: Macitentan