<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/NCT01700569</url>
  </required_header>
  <id_info>
    <org_study_id>ICO 2012-02</org_study_id>
    <secondary_id>2012-000774-31</secondary_id>
    <nct_id>NCT01700569</nct_id>
  </id_info>
  <brief_title>Phase-1 Study of Folinic Acid to Modulate MGMT Gene in Glioblastoma</brief_title>
  <acronym>FOLAGLI</acronym>
  <official_title>Phase I Study of Escalated Pharmacologic Dose, of Oral Folinic Acid in Combination With Temozolomide, According to Stupp R. Regimen, in Patients With Operated Grade-IV Astocytoma and a Non-methylated Gene Status of MGMT.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Cancerologie de l'Ouest</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centre Antoine Lacassagne</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospices Civils de Lyon</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut Cancerologie de l'Ouest</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      O6-méthylguanine méthyltransférase (MGMT) is the main repair gene after DNA lesion induced by&#xD;
      Temozolomide in combination with radiation therapy of Glioblastoma (GBM) in Stupp.R et al&#xD;
      published regimen. In preclinical models, it has been demonstrated that MGMT methylation&#xD;
      (which is silencing the DNA repair process) is achievable by folic acid. About half of the&#xD;
      patients with operated GBM have an un-methylated MGMT gene status and therefore a poorer&#xD;
      prognosis. A phase-1 dose escalation study is proposed with pharmacologic doses of folinic&#xD;
      acid in combination with temozolomide and radiotherapy of operated GBM.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Glioblastoma treated by Stupp regimen (Temozolomide + radiation therapy) have a different&#xD;
      outcome depending on the methylation status of MGMT gene: when the gene is unmethylated, the&#xD;
      repair process is active and the prognostic poor. In pre-clinical models, it has been&#xD;
      demonstrated that Folic acid could re-methylate the MGMT gene and therefore the repair&#xD;
      process to radiation and temozolomide could be limited, allowing a better prognosis. The&#xD;
      proposed phase-1 study will explore the safety and efficacy of escalated doses of oral&#xD;
      Folinic acid concomitantly with Stupp regimen. To determine the MTD is the main objective of&#xD;
      the study, then the toxicty profile, the RDP2 and the methylation process efficacy at the&#xD;
      MGMT gene level.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    changing the standard of care&#xD;
  </why_stopped>
  <start_date type="Actual">January 2013</start_date>
  <completion_date type="Actual">April 16, 2021</completion_date>
  <primary_completion_date type="Actual">December 12, 2019</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>Maximal Tolerated Dose</measure>
    <time_frame>day 43</time_frame>
    <description>maximal tolerated dose 3x3 patients inclusion(modified Fibonnacci dose escalation )</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>MGMT gene re-methylation</measure>
    <time_frame>day 43</time_frame>
    <description>MGMT gene re-methylation in tumoral and blood samples</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Year 1</time_frame>
    <description>Progression-free survival (PFS)</description>
  </other_outcome>
  <other_outcome>
    <measure>Folic acid and Temozolomide combination Toxicity evaluation</measure>
    <time_frame>day 43</time_frame>
    <description>Acute toxicity: Common toxicity criteria version 4.03</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Grade IV Astrocytoma</condition>
  <condition>Glioblastoma</condition>
  <arm_group>
    <arm_group_label>Folinic Acid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Folinic acid is given orally every day during the radiation therapy (47 days), then 5 days at each of the 6 maintenance cycle of temozolomide. The dose is escalated in a &quot;3x3&quot; method and the levels are: 5mg, 10mg, 15mg, 30mg, 60mg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Temozolomide</intervention_name>
    <description>All the Patients are treated by oral Temozolomide 75 mg/m²/day every day during 42 days, 30 minutes after Folinic acid and 120 min before the radiation dose to the brain tumor. After one month rest, the maintenance phase consists of:Temozolomide is given orally (30 min after Folinic acid), at 200 mg/m²/day every day during 5 days: one course every month during 6 months (6 maintenance course).</description>
    <arm_group_label>Folinic Acid</arm_group_label>
    <other_name>Temodal</other_name>
    <other_name>capsule dosage available: 5, 20, 10, 180 and 250 mg</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>folinic acid at pharmacological dose is the escalated drug</intervention_name>
    <arm_group_label>Folinic Acid</arm_group_label>
    <other_name>Folinate de Calcium, Lederfoline</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>High voltage radiation therapy (linear accelerator)</intervention_name>
    <description>Brain tumor field is irradiated Five days a week, during Stupp regimen during 6 weeks. During the sams time, Folinic acid and Temozolomide are given orally every days (six weeks).</description>
    <arm_group_label>Folinic Acid</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Operated GBM (complete or near complete resection)&#xD;
&#xD;
          -  Un-methylated MGMT gene&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non operable GBM&#xD;
&#xD;
          -  Methylated MGMT&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mario CAMPONE, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Cancerologie de l'Ouest</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut de Cacerologie de l'ouest - site Paul Papin</name>
      <address>
        <city>Angers</city>
        <zip>49055</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Lyon</name>
      <address>
        <city>Bron</city>
        <zip>69677</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ICO site Gauducheau</name>
      <address>
        <city>Nantes</city>
        <zip>44805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CLCC Antoine Lacassagne</name>
      <address>
        <city>Nice</city>
        <zip>06189</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.</citation>
    <PMID>15758009</PMID>
  </reference>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>September 12, 2012</study_first_submitted>
  <study_first_submitted_qc>October 2, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <last_update_submitted>February 20, 2023</last_update_submitted>
  <last_update_submitted_qc>February 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>high-grade</keyword>
  <keyword>glioma</keyword>
  <keyword>epigenetic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Temozolomide</mesh_term>
    <mesh_term>Levoleucovorin</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/NCT01700569
org study id: ICO 2012-02
secondary id: 2012-000774-31
nct id: NCT01700569
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
O6-méthylguanine méthyltransférase (MGMT) is the main repair gene after DNA lesion induced by
      Temozolomide in combination with radiation therapy of Glioblastoma (GBM) in Stupp.R et al
      published regimen. In preclinical models, it has been demonstrated that MGMT methylation
      (which is silencing the DNA repair process) is achievable by folic acid. About half of the
      patients with operated GBM have an un-methylated MGMT gene status and therefore a poorer
      prognosis. A phase-1 dose escalation study is proposed with pharmacologic doses of folinic
      acid in combination with temozolomide and radiotherapy of operated GBM.
Glioblastoma treated by Stupp regimen (Temozolomide + radiation therapy) have a different
      outcome depending on the methylation status of MGMT gene: when the gene is unmethylated, the
      repair process is active and the prognostic poor. In pre-clinical models, it has been
      demonstrated that Folic acid could re-methylate the MGMT gene and therefore the repair
      process to radiation and temozolomide could be limited, allowing a better prognosis. The
      proposed phase-1 study will explore the safety and efficacy of escalated doses of oral
      Folinic acid concomitantly with Stupp regimen. To determine the MTD is the main objective of
      the study, then the toxicty profile, the RDP2 and the methylation process efficacy at the
      MGMT gene level.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximal Tolerated Dose
time frame: day 43
description: maximal tolerated dose 3x3 patients inclusion(modified Fibonnacci dose escalation )
measure: MGMT gene re-methylation
time frame: day 43
description: MGMT gene re-methylation in tumoral and blood samples
measure: Progression-free survival (PFS)
time frame: Year 1
description: Progression-free survival (PFS)
measure: Folic acid and Temozolomide combination Toxicity evaluation
time frame: day 43
description: Acute toxicity: Common toxicity criteria version 4.03
arm group label: Folinic Acid
arm group type: Experimental
description: Folinic acid is given orally every day during the radiation therapy (47 days), then 5 days at each of the 6 maintenance cycle of temozolomide. The dose is escalated in a "3x3" method and the levels are: 5mg, 10mg, 15mg, 30mg, 60mg.
intervention type: Drug
intervention name: Temozolomide
description: All the Patients are treated by oral Temozolomide 75 mg/m²/day every day during 42 days, 30 minutes after Folinic acid and 120 min before the radiation dose to the brain tumor. After one month rest, the maintenance phase consists of:Temozolomide is given orally (30 min after Folinic acid), at 200 mg/m²/day every day during 5 days: one course every month during 6 months (6 maintenance course).
arm group label: Folinic Acid
other name: Temodal
other name: capsule dosage available: 5, 20, 10, 180 and 250 mg
intervention type: Drug
intervention name: folinic acid at pharmacological dose is the escalated drug
arm group label: Folinic Acid
other name: Folinate de Calcium, Lederfoline
intervention type: Radiation
intervention name: High voltage radiation therapy (linear accelerator)
description: Brain tumor field is irradiated Five days a week, during Stupp regimen during 6 weeks. During the sams time, Folinic acid and Temozolomide are given orally every days (six weeks).
arm group label: Folinic Acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Mario CAMPONE, MD, PhD
role: Principal Investigator
affiliation: Institut Cancerologie de l'Ouest
facility: 
facility: 
facility: 
facility: 
country: France
citation: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
PMID: 15758009
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Astrocytoma
mesh term: Leucovorin
mesh term: Folic Acid
mesh term: Temozolomide
mesh term: Levoleucovorin