<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/NCT02202993</url>
  </required_header>
  <id_info>
    <org_study_id>1406014067</org_study_id>
    <nct_id>NCT02202993</nct_id>
  </id_info>
  <brief_title>TAU-2014-1: Mibefradil and Hypofractionated Re-Irradiation Therapy in Recurrent GBM</brief_title>
  <official_title>TAU-2014-1: Phase I Trial of Mibefradil Dihydrochloride With Hypofractionated Re-Irradiation Therapy in Treating Patients With Recurrent Glioblastoma Multiforme (GBM)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jazz Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Jazz Pharmaceuticals</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a dose-escalation study that will assess the safety and determine the maximum&#xD;
      tolerated dose (MTD) of mibefradil dihydrochloride, a partially selective T-type calcium&#xD;
      channel blocker, combined with hypofractionated radiation therapy (RT) in subjects with&#xD;
      recurrent glioblastoma multiforme (GBM).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day&#xD;
      until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is&#xD;
      reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4&#xD;
      divided doses per day for 17 consecutive days to the MTD. The MTD will be determined&#xD;
      according to dose-limiting toxicities (DLTs) graded using the Common Terminology Criteria for&#xD;
      Adverse Events version 4.0. Radiation therapy (RT) consists of 5 fractions of 600 centigray&#xD;
      (cGy) each, delivered over 2 consecutive weeks for a total dose of 3,000 cGy, using&#xD;
      stereotactic, intensity-modulated radiation therapy (IMRT).&#xD;
&#xD;
      The primary endpoint of the study is to determine the MTD of mibefradil dihydrochloride when&#xD;
      given with concurrent hypofractionated RT. Secondary and tertiary endpoints include&#xD;
      evaluating the efficacy of mibefradil dihydrochloride and RT in terms of progression-free&#xD;
      survival (PFS) and overall survival (OS), and to perform translational research on resected&#xD;
      tumor tissue.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">September 29, 2017</completion_date>
  <primary_completion_date type="Actual">September 29, 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>Dose limiting toxicities</measure>
    <time_frame>Monitored continuously, 27 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum tolerated dose</measure>
    <time_frame>Monitored continuously, 27 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>27 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mibefradil dihydrochloride steady state plasma concentrations</measure>
    <time_frame>27 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival of treated patients</measure>
    <time_frame>27 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival of treated patients</measure>
    <time_frame>27 months</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Intra-tumoral concentration of mibefradil dihydrochloride</measure>
    <time_frame>27 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Western blot characterization of resected tumor tissue following 5 days of mibefradil dihydrochloride</measure>
    <time_frame>27 months</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Glioblastoma Multiforme (GBM)</condition>
  <arm_group>
    <arm_group_label>Mibefradil with Radiation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4 divided doses per day for 17 consecutive days to the MTD.&#xD;
This will be given concurrently with hypofractionated radiation therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mibefradil with Radiation</intervention_name>
    <description>Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4 divided doses per day for 17 consecutive days to the MTD.&#xD;
This will be given concurrently with hypofractionated radiation therapy.</description>
    <arm_group_label>Mibefradil with Radiation</arm_group_label>
    <other_name>mibefradil</other_name>
    <other_name>mibefradil dihydrochloride</other_name>
    <other_name>Posicor</other_name>
    <other_name>hypo fractionated radiation</other_name>
    <other_name>intensity modulated radiation</other_name>
    <other_name>IMRT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Sign written informed consent.&#xD;
&#xD;
          -  Histologically proven glioblastoma multiforme (GBM) that is progressive or recurrent&#xD;
             following standard radiation therapy (RT) and temozolomide (i.e., at least&#xD;
             &quot;biopsy-proven&quot; recurrent disease). Previous salvage therapies after first recurrence&#xD;
             are permitted.&#xD;
&#xD;
          -  Measurable contrast-enhancing progressive or recurrent GBM (single or multiple&#xD;
             lesions) by MRI imaging with an interval of greater than or equal to 6 months between&#xD;
             recurrence and completion of prior radiotherapy.&#xD;
&#xD;
          -  Patients who have not passed an interval of at least 6 months may still be eligible if&#xD;
             they meet the following criteria: convincing histologic evidence of disease recurrence&#xD;
             which is not thought to predominantly represent radionecrosis, standard focal external&#xD;
             beam radiation therapy (EBRT) treatment with acceptable doses to tumor and normal&#xD;
             tissue which suggest re-irradiation is feasible.&#xD;
&#xD;
          -  Prior history of standard dose focal RT to 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy&#xD;
             fractions, or equivalent or lower doses. Patients who have received prior treatment&#xD;
             with non-standard RT dose and fractionation schemes are still eligible, provided they&#xD;
             have only received a single course of RT. However, subjects treated with interstitial&#xD;
             brachytherapy or single-fraction stereotactic radiosurgery are not eligible for this&#xD;
             trial.&#xD;
&#xD;
          -  Karnofsky performance status ≥60%&#xD;
&#xD;
          -  Clinical laboratory:&#xD;
&#xD;
          -  absolute neutrophil count &gt;1,500/microliter (mcL)&#xD;
&#xD;
          -  platelets &gt;100,000/mcL&#xD;
&#xD;
          -  hemoglobin &gt; 9 g/ dL serum bilirubin &lt; 1.5 times the upper limit of normal (ULN);&#xD;
             unless due to Gilbert's syndrome (in which &lt;2 times ULN acceptable)&#xD;
&#xD;
          -  serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) &lt; 2.5 times ULN&#xD;
&#xD;
          -  serum Creatinine &lt; 1.5 times ULN&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception.&#xD;
&#xD;
          -  Women of childbearing potential must have a negative pregnancy test prior to&#xD;
             treatment.&#xD;
&#xD;
          -  Recovered to Common Toxicity Criteria for Adverse Effects (CTCAE) grade ≤ 2 from prior&#xD;
             therapy toxicities&#xD;
&#xD;
          -  30 days since previous treatment of brain tumor with any other agents.&#xD;
&#xD;
          -  Stable or decreasing corticosteroid regimen (no increase for 7 days) prior to the&#xD;
             start of treatment.&#xD;
&#xD;
          -  &gt;18 years of age&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Concurrent malignancy except curatively treated non-melanoma skin cancer or carcinoma&#xD;
             in situ of the cervix, breast, or bladder. Subjects with prior malignancies must be&#xD;
             disease-free for ≥ five years.&#xD;
&#xD;
          -  Biopsy-confirmed exclusive radionecrosis after initial GBM therapy.&#xD;
&#xD;
          -  Receipt of other investigational agents or anti-cancer agents within 30 days&#xD;
&#xD;
          -  Serious concurrent infection or medical illness, which would jeopardize the ability of&#xD;
             the subject to receive treatment safely.&#xD;
&#xD;
          -  Systolic blood pressure &lt;100 mm Hg, diastolic &lt;60 mm Hg.&#xD;
&#xD;
          -  Requirement for calcium channel blocker for blood pressure control that cannot be&#xD;
             switched to an antihypertensive with an alternative mechanism of action. Permitted&#xD;
             anti-hypertensive medications include: chlorothiazide, hydrochlorothiazide, atenolol,&#xD;
             nadolol, enalapril, lisinopril, eprosartan, and irbesartan.&#xD;
&#xD;
          -  Known, active hepatitis.&#xD;
&#xD;
          -  corrected QT (QTc) interval ≥ 450 milliseconds (mSec) for males or ≥470 mSec for&#xD;
             females. PR interval &gt; 250 mSec for males and females&#xD;
&#xD;
          -  High-grade (second degree or above) atria-ventricular (AV) block or persistent sinus&#xD;
             bradycardia of less than 50 beats per minute (BPM).&#xD;
&#xD;
          -  Known HIV-positivity&#xD;
&#xD;
          -  Pregnant and/or lactating women&#xD;
&#xD;
          -  Anti-arrhythmia medication other than beta-blockers or digoxin.&#xD;
&#xD;
          -  Treatment with concurrent enzyme-inducing anti-epileptic drugs (EIAEDs).&#xD;
&#xD;
          -  Treatment with unfractionated heparin. Patients taking an anticoagulant must use&#xD;
             warfarin or a low molecular weight heparin.&#xD;
&#xD;
          -  Treatment with specified drugs that are substrates of cytochrome 3A4 (CYP3A4),&#xD;
             cytochrome 2D6 (CYP2D6), cytochrome 1A2 (CYP1A2)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ranjit S Bindra, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>July 15, 2014</study_first_submitted>
  <study_first_submitted_qc>July 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 29, 2014</study_first_posted>
  <last_update_submitted>July 22, 2019</last_update_submitted>
  <last_update_submitted_qc>July 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 24, 2019</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mibefradil</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/NCT02202993
org study id: 1406014067
nct id: NCT02202993
lead sponsor: 
collaborator: 
has dmc: Yes
This is a dose-escalation study that will assess the safety and determine the maximum
      tolerated dose (MTD) of mibefradil dihydrochloride, a partially selective T-type calcium
      channel blocker, combined with hypofractionated radiation therapy (RT) in subjects with
      recurrent glioblastoma multiforme (GBM).
Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day
      until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is
      reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4
      divided doses per day for 17 consecutive days to the MTD. The MTD will be determined
      according to dose-limiting toxicities (DLTs) graded using the Common Terminology Criteria for
      Adverse Events version 4.0. Radiation therapy (RT) consists of 5 fractions of 600 centigray
      (cGy) each, delivered over 2 consecutive weeks for a total dose of 3,000 cGy, using
      stereotactic, intensity-modulated radiation therapy (IMRT).

      The primary endpoint of the study is to determine the MTD of mibefradil dihydrochloride when
      given with concurrent hypofractionated RT. Secondary and tertiary endpoints include
      evaluating the efficacy of mibefradil dihydrochloride and RT in terms of progression-free
      survival (PFS) and overall survival (OS), and to perform translational research on resected
      tumor tissue.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose limiting toxicities
time frame: Monitored continuously, 27 months
measure: Maximum tolerated dose
time frame: Monitored continuously, 27 months
measure: Adverse events
time frame: 27 months
measure: Mibefradil dihydrochloride steady state plasma concentrations
time frame: 27 months
measure: Progression-free survival of treated patients
time frame: 27 months
measure: Overall survival of treated patients
time frame: 27 months
measure: Intra-tumoral concentration of mibefradil dihydrochloride
time frame: 27 months
measure: Western blot characterization of resected tumor tissue following 5 days of mibefradil dihydrochloride
time frame: 27 months
arm group label: Mibefradil with Radiation
arm group type: Experimental
description: Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4 divided doses per day for 17 consecutive days to the MTD.
This will be given concurrently with hypofractionated radiation therapy.
intervention type: Drug
intervention name: Mibefradil with Radiation
description: Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4 divided doses per day for 17 consecutive days to the MTD.
This will be given concurrently with hypofractionated radiation therapy.
arm group label: Mibefradil with Radiation
other name: mibefradil
other name: mibefradil dihydrochloride
other name: Posicor
other name: hypo fractionated radiation
other name: intensity modulated radiation
other name: IMRT
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Ranjit S Bindra, MD PhD
role: Principal Investigator
affiliation: Yale University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Mibefradil