<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/NCT01719926</url>
  </required_header>
  <id_info>
    <org_study_id>NL40487.041.12</org_study_id>
    <nct_id>NCT01719926</nct_id>
  </id_info>
  <brief_title>Phase I Platinum Based Chemotherapy Plus Indomethacin</brief_title>
  <acronym>PIFA</acronym>
  <official_title>Phase I Study Evaluating Indomethacin in Combination With Platinum-based Chemotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Mesenchymal stem cells (MSCs) are present in the circulation of cancer patients, and are&#xD;
      recruited to the stroma of both the primary tumor and metastasis. Recent preclinical research&#xD;
      has shown that in response to platinum-based chemotherapy, MSCs secrete two specific&#xD;
      platinum-induced fatty acids (PIFAs) which induce resistance to a broad spectrum of&#xD;
      chemotherapies. The secreted PIFAs are the fatty acid oxo-heptadecatetraenoic acid (KHT) and&#xD;
      the omega-3 fatty acid hexadecatetraenoic acid (16:4). These PIFAs are produced via the COX-1&#xD;
      pathway. COX inhibitors, including indomethacin. This phase 1 study explores the safety of&#xD;
      combining indomethacin with platinum containing chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">August 2017</completion_date>
  <primary_completion_date type="Actual">August 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of dose limiting toxicities at each dosage cohort</measure>
    <time_frame>From first dose of indomethacin until 28 days after last dose of indomethacin</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics</measure>
    <time_frame>During first 2 cycles of 3 weeks each</time_frame>
    <description>Serum levels of mesenchymal stem cells and platinum induced fatty acids at T = pre-chemotherapy, one, two and four hours expressed in pmol/L.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>From baseline to date of progressive disease according RECIST 1.1, approximately 9 to 18 weeks</time_frame>
    <description>Efficacy will be assessed according RECIST 1.1 criteria. Progression free survival is defined as time from baseline CT scan to progressive disease according RECIST 1.1 criteria.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Colorectal Neoplasms</condition>
  <condition>Esophageal Neoplasms</condition>
  <condition>Ovarian Neoplasms</condition>
  <arm_group>
    <arm_group_label>Capecitabine/Oxaliplatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receiving Capecitabine/Oxaliplatin chemotherapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cisplatin + Xeloda(Capecitabine) or Gemcitabine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receiving Cisplatin regimen</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Indomethacin</intervention_name>
    <description>3 times per day from 2 days before until 5 days after chemotherapy. Escalating dosage each cohort.</description>
    <arm_group_label>Capecitabine/Oxaliplatin</arm_group_label>
    <arm_group_label>Cisplatin + Xeloda(Capecitabine) or Gemcitabine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects with a histological proven malignancy receiving cisplatin combined with&#xD;
             gemcitabine or 5FU/capecitabine. (cisplatin dose range 60-80 mg/m2) (Arm I) or CAPOX&#xD;
             (oxaliplatin, capecitabine) (Arm II) in a 21 day cycle.&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Platinum-based chemotherapy naïve for at least 6 months.&#xD;
&#xD;
          -  Subjects with at least one evaluable lesion.&#xD;
&#xD;
          -  WHO Performance Status of 0 or 1.&#xD;
&#xD;
          -  Female participants should be of non-child bearing potential either physiologic or by&#xD;
             using adequate contraception, have a negative serum pregnancy test, and refrain from&#xD;
             breast feeding.&#xD;
&#xD;
          -  Written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known or suspected allergy or hypersensitivity to indomethacin or any agent given in&#xD;
             association with this trial, in particular subjects who have a history of severe&#xD;
             hypersensitivity reactions to anti-emetics (5-HT3 antagonists, metoclopramide or&#xD;
             corticosteroids) and acetylsalicylic acid or other prostaglandin synthetase&#xD;
             inhibitors.&#xD;
&#xD;
          -  Symptomatic brain or meningeal tumors&#xD;
&#xD;
          -  Subjects with seizure disorder requiring medication (such as corticosteroids or&#xD;
             anti-epileptics).&#xD;
&#xD;
          -  Any of the following concurrent severe and/or uncontrolled medical conditions which&#xD;
             could compromise participation in the study:&#xD;
&#xD;
          -  Uncontrolled high blood pressure, history of labile hypertension, or history of poor&#xD;
             compliance with an antihypertensive regimen&#xD;
&#xD;
          -  Unstable angina pectoris&#xD;
&#xD;
          -  Symptomatic congestive heart failure NYHA class ≥ 3 (see appendix 13.6)&#xD;
&#xD;
          -  Myocardial infarction ≤ 6 months prior to randomization&#xD;
&#xD;
          -  Serious uncontrolled cardiac arrhythmia&#xD;
&#xD;
          -  Active peptic ulcer disease, gastritis, inflammatory bowel disease.&#xD;
&#xD;
          -  History of active gastrointestinal bleeding&#xD;
&#xD;
          -  History of cerebrovascular disease&#xD;
&#xD;
          -  Bleeding diathesis&#xD;
&#xD;
          -  Chronic renal disease defined as GFR (MDRD) &lt;60 ml/min&#xD;
&#xD;
          -  Absolute Neutrophil Count (ANC) &lt; 1.5 x 109/L (&lt; 1500/mm3)&#xD;
&#xD;
          -  Platelets (PLT) &lt; 100 x 109/L (&lt; 100,000/mm3)&#xD;
&#xD;
          -  Hemoglobin (Hgb) &lt; 6.0 mmol/l (patients may be transfused to achieve adequate Hb)&#xD;
&#xD;
          -  Partial thromboplastin time (PTT) &gt; 1,5 x ULN&#xD;
&#xD;
          -  Serum bilirubin &gt; 1.5 ULN&#xD;
&#xD;
          -  Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) &gt; 3.0 x&#xD;
             ULN (&gt; 5 x ULN if liver metastases present)&#xD;
&#xD;
          -  Patients who are unable or unwilling to comply with the protocol&#xD;
&#xD;
          -  Chronic treatment with a corticosteroid agent (nebulized corticosteroids are allowed)&#xD;
&#xD;
          -  Patients who received radiation therapy within 4 weeks of the start of the study&#xD;
&#xD;
          -  Patients who received an experimental agent less than 4 weeks before start of the&#xD;
             study.&#xD;
&#xD;
          -  Patients who used Omega-3/omega-6 containing products, including fish oil products&#xD;
             less than 2 weeks before start of the study.&#xD;
&#xD;
          -  Chronic use of NSAID's and/or acetylsalicylic acid and/or other prostaglandin&#xD;
             synthetase inhibitors.&#xD;
&#xD;
          -  Use of anticoagulant therapy&#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>F.Y.F.L. de Vos, MD/PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Meander Medisch Centrum</name>
      <address>
        <city>Amersfoort</city>
        <state>Utrecht</state>
        <zip>3813TZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>the Netherlands Cancer Institute</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UMC Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3584CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Institute of Southern Switzerland</name>
      <address>
        <city>Bellinzona</city>
        <zip>CH-6500</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>October 30, 2012</study_first_submitted>
  <study_first_submitted_qc>October 30, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 1, 2012</study_first_posted>
  <last_update_submitted>August 15, 2017</last_update_submitted>
  <last_update_submitted_qc>August 15, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>Dr. F.Y.F.L. de Vos</investigator_full_name>
    <investigator_title>MD/PhD</investigator_title>
  </responsible_party>
  <keyword>Colorectal</keyword>
  <keyword>Esophageal</keyword>
  <keyword>Indomethacin</keyword>
  <keyword>PIFA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Ovarian Neoplasms</mesh_term>
    <mesh_term>Esophageal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Indomethacin</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/NCT01719926
org study id: NL40487.041.12
nct id: NCT01719926
lead sponsor: 
has dmc: No
Mesenchymal stem cells (MSCs) are present in the circulation of cancer patients, and are
      recruited to the stroma of both the primary tumor and metastasis. Recent preclinical research
      has shown that in response to platinum-based chemotherapy, MSCs secrete two specific
      platinum-induced fatty acids (PIFAs) which induce resistance to a broad spectrum of
      chemotherapies. The secreted PIFAs are the fatty acid oxo-heptadecatetraenoic acid (KHT) and
      the omega-3 fatty acid hexadecatetraenoic acid (16:4). These PIFAs are produced via the COX-1
      pathway. COX inhibitors, including indomethacin. This phase 1 study explores the safety of
      combining indomethacin with platinum containing chemotherapy.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Number of dose limiting toxicities at each dosage cohort
time frame: From first dose of indomethacin until 28 days after last dose of indomethacin
measure: Pharmacodynamics
time frame: During first 2 cycles of 3 weeks each
description: Serum levels of mesenchymal stem cells and platinum induced fatty acids at T = pre-chemotherapy, one, two and four hours expressed in pmol/L.
measure: Efficacy
time frame: From baseline to date of progressive disease according RECIST 1.1, approximately 9 to 18 weeks
description: Efficacy will be assessed according RECIST 1.1 criteria. Progression free survival is defined as time from baseline CT scan to progressive disease according RECIST 1.1 criteria.
arm group label: Capecitabine/Oxaliplatin
arm group type: Experimental
description: Patients receiving Capecitabine/Oxaliplatin chemotherapy
arm group label: Cisplatin + Xeloda(Capecitabine) or Gemcitabine
arm group type: Experimental
description: Patients receiving Cisplatin regimen
intervention type: Drug
intervention name: Indomethacin
description: 3 times per day from 2 days before until 5 days after chemotherapy. Escalating dosage each cohort.
arm group label: Capecitabine/Oxaliplatin
arm group label: Cisplatin + Xeloda(Capecitabine) or Gemcitabine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: F.Y.F.L. de Vos, MD/PhD
role: Principal Investigator
affiliation: UMC Utrecht
facility: 
facility: 
facility: 
facility: 
country: Netherlands
country: Switzerland
responsible party type: Principal Investigator
investigator affiliation: UMC Utrecht
investigator full name: Dr. F.Y.F.L. de Vos
investigator title: MD/PhD
mesh term: Neoplasms
mesh term: Colorectal Neoplasms
mesh term: Ovarian Neoplasms
mesh term: Esophageal Neoplasms
mesh term: Indomethacin