<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/NCT02239952</url>
  </required_header>
  <id_info>
    <org_study_id>2013.465</org_study_id>
    <nct_id>NCT02239952</nct_id>
  </id_info>
  <brief_title>HGG-TCP (High Grade Glioma - Tumor Concentrations of Protein Kinase Inhibitors)</brief_title>
  <official_title>Pilot Study on the Determination of Tumor Concentrations of Protein Kinase Inhibitors in Patients With Newly Diagnosed High-grade Glioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amsterdam UMC, location VUmc</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Amsterdam UMC, location VUmc</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine intratumoral concentration of kinase inhibitors&#xD;
      upon 2 weeks of treatment in tumor tissue (in the brain) of patients with high-grade gliomas&#xD;
      (HGG).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In clinical trials for HGG, multiple agents targeting various oncogenic signaling pathways&#xD;
      that play an important role in the biology of HGG have been studied, but unfortunately only a&#xD;
      small number of patients seem to benefit from these treatment strategies. Whether these&#xD;
      disappointing results are due to a restricted drug delivery through the blood-brain barrier,&#xD;
      or due to differential biological characteristics of these HGGs, remains unknown. To better&#xD;
      understand these clinical observations and to find potential insight how to overcome them, we&#xD;
      intend to measure tumor concentrations of PKIs after approximately two weeks treatment and to&#xD;
      determine whether these tumor concentrations correlate with plasma- and CSF concentrations of&#xD;
      PKIs. Subsequently, we intend to determine the (phospho)proteomic profiles and kinase&#xD;
      inhibitory activity in tumor tissue from these HGG patients after approximately two weeks of&#xD;
      treatment with a PKI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>November 2014</start_date>
  <completion_date type="Anticipated">November 2021</completion_date>
  <primary_completion_date type="Anticipated">November 2021</primary_completion_date>
  <phase>N/A</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PKI and active metabolites concentrations in tumor tissue</measure>
    <time_frame>2 weeks</time_frame>
    <description>PKI concentrations and active metabolites in tumor tissue after approximately two weeks of PKI treatment will be determined.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation of PKI and active metabolites concentrations in tumor.</measure>
    <time_frame>2 weeks</time_frame>
    <description>Venous blood sampling will be performed to determine plasma drug and active metabolites concentrations after approximately one and two weeks of PKI treatment and during surgery. CSF samples will be drawn during surgery. Plasma- and CSF drug concentrations will be correlated to tumor drug concentrations. Plasma samples for pharmacodynamics will be simultaneously drawn with the on- and after treatment hematology and chemistry analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue and CSF.</measure>
    <time_frame>2 weeks</time_frame>
    <description>Kinome wide and quantitative (phospho)proteomic profiles will be determined in tumor tissue of study patients and in tumor tissue of matched controled patients. We anticipate that these profiles will reveal information on the effect of treatment on kinase abundances, phosphopeptide levels and on phosphorylation sites. Differences in levels of phosphopeptides and fold-change of phosphorylation sites will be quantified. In an exploratory design, we will determine whether observed profile differences can be correlated to drug concentrations in tumor tissue. Kinase inhibition profiles will be measured according to standard methods as developed and modified in our laboratory.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Significant difference of the (phospho)proteomic profiles and kinase activities of tumor tissue in study patients and control group.</measure>
    <time_frame>2 weeks</time_frame>
    <description>The (phospho)proteomic profiles and kinase activity profiles will be determined in tumor tissue of study patients and in tumor tissue of patients in a control group.&#xD;
Kinase inhibition profiles will be measured according to standard methods as developed and modified in our laboratory.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Cancer</condition>
  <condition>High-grade Glioma</condition>
  <arm_group>
    <arm_group_label>sunitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>vandetanib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Erlotinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sunitinib</intervention_name>
    <description>50 mg once daily, oral use for 14 days</description>
    <arm_group_label>sunitinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>vandetanib</intervention_name>
    <description>300 mg, once daily, oral use for 14 days</description>
    <arm_group_label>vandetanib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Erlotinib</intervention_name>
    <description>150 mg, once daily, oral use for 14 days</description>
    <arm_group_label>Erlotinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients without a history of brain tumor&#xD;
&#xD;
          2. Initial brain MR-scan suggesting a high grade glioma, according to the interpretation&#xD;
             of an expert neuroradiologist&#xD;
&#xD;
          3. On initial MR-scan a tumor localisation that is deemed resectable without major&#xD;
             neurological deficits&#xD;
&#xD;
          4. Patients must have a Karnofsky Performance Score ≥ 70%&#xD;
&#xD;
          5. Patients must have a RTOG Neurologic Function Status of 0-2&#xD;
&#xD;
          6. Patients need to have adequate hematological, renal and hepatic function as assessed&#xD;
             by the following laboratory requirements to be conducted within seven days prior to&#xD;
             start study treatment: - Hemoglobin &gt; 7.0 mmol/l - Absolute neutrophil count (ANC)&#xD;
             &gt;1,5 x 10*9/l - Platelet count &gt; 100 x 10*9/l - ALT and AST&lt; 2.5 x ULN - Alkaline&#xD;
             phosphatase &lt; 4 x ULN - Serum creatinine eGFR &gt; 50 ml/min&#xD;
&#xD;
          7. Patients are 18 years of older&#xD;
&#xD;
          8. Male and female patients with reproductive potential must use an approved&#xD;
             contraceptive method during and for three months after discontinuation of study&#xD;
             treatment&#xD;
&#xD;
          9. Patients need to give informed consent&#xD;
&#xD;
         10. Patients should be able to swallow oral medication&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients receiving prior chemotherapy, radiotherapy or anti-angiogenic therapy&#xD;
&#xD;
          2. Use of anti-coagulant therapy&#xD;
&#xD;
          3. Use of CYP3A4 enzyme-inducing drugs, other than dexamethasone (including&#xD;
             Carbamazepine, Phenytoine, Phenobarbital)&#xD;
&#xD;
          4. Initial MR-scan of the brain showing tumor hemorrhage or intracerebral hemorrhage&#xD;
&#xD;
          5. Patients with progressive neurological symptoms despite dexamethasone&#xD;
&#xD;
          6. Inability to comply with protocol or study procedures&#xD;
&#xD;
          7. Pregnancy&#xD;
&#xD;
          8. Patients with uncontrolled arterial hypertension. Blood pressure must be ≤160/95 mmHg&#xD;
             at the time of screening on a stable antihypertensive regimen.&#xD;
&#xD;
          9. Patients with a history of cardiac arrhythmias requiring anti-arrhythmic therapy (beta&#xD;
             blockers or digoxin are permitted)&#xD;
&#xD;
         10. Patients with evidence or history of bleeding diathesis&#xD;
&#xD;
         11. Patients with a history of venous or arterial thrombo-embolic events or hemorrhagic&#xD;
             disease during the past six months&#xD;
&#xD;
         12. Patients with a history of congestive heart failure (NYHA III, IV)&#xD;
&#xD;
         13. Patients with a history of peripheral vascular disease (Fontaine stage III and IV)&#xD;
&#xD;
         14. Patients with stroke or myocardial infarction during the past six months&#xD;
&#xD;
         15. Patients with a history of a recent peptic ulcer disease (endoscopically-proven&#xD;
             gastric ulcer, duodenal ulcer of esophageal ulcer) during the past six months&#xD;
&#xD;
         16. Patients with uncontrolled infections (&gt; grade 2 NCI-CTC version 4.0)&#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_contact>
    <last_name>M.E. Van Linde, MD</last_name>
    <phone>+31 (0)20 4444321</phone>
    <email>dm-onc@vumc.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>VU University Medical Center</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord-Holland</state>
        <zip>1081 HV</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>M.E. Van Linde, MD</last_name>
      <phone>+31 (0)20 4444321</phone>
      <email>dm-onc@vumc.nl</email>
    </contact>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>August 28, 2014</study_first_submitted>
  <study_first_submitted_qc>September 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 15, 2014</study_first_posted>
  <last_update_submitted>October 6, 2020</last_update_submitted>
  <last_update_submitted_qc>October 6, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Amsterdam UMC, location VUmc</investigator_affiliation>
    <investigator_full_name>M.E. van Linde</investigator_full_name>
    <investigator_title>Medical Oncologist</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Erlotinib Hydrochloride</mesh_term>
    <mesh_term>Sunitinib</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/NCT02239952
org study id: 2013.465
nct id: NCT02239952
lead sponsor: 
has dmc: Yes
The purpose of this study is to determine intratumoral concentration of kinase inhibitors
      upon 2 weeks of treatment in tumor tissue (in the brain) of patients with high-grade gliomas
      (HGG).
In clinical trials for HGG, multiple agents targeting various oncogenic signaling pathways
      that play an important role in the biology of HGG have been studied, but unfortunately only a
      small number of patients seem to benefit from these treatment strategies. Whether these
      disappointing results are due to a restricted drug delivery through the blood-brain barrier,
      or due to differential biological characteristics of these HGGs, remains unknown. To better
      understand these clinical observations and to find potential insight how to overcome them, we
      intend to measure tumor concentrations of PKIs after approximately two weeks treatment and to
      determine whether these tumor concentrations correlate with plasma- and CSF concentrations of
      PKIs. Subsequently, we intend to determine the (phospho)proteomic profiles and kinase
      inhibitory activity in tumor tissue from these HGG patients after approximately two weeks of
      treatment with a PKI.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: PKI and active metabolites concentrations in tumor tissue
time frame: 2 weeks
description: PKI concentrations and active metabolites in tumor tissue after approximately two weeks of PKI treatment will be determined.
measure: Correlation of PKI and active metabolites concentrations in tumor.
time frame: 2 weeks
description: Venous blood sampling will be performed to determine plasma drug and active metabolites concentrations after approximately one and two weeks of PKI treatment and during surgery. CSF samples will be drawn during surgery. Plasma- and CSF drug concentrations will be correlated to tumor drug concentrations. Plasma samples for pharmacodynamics will be simultaneously drawn with the on- and after treatment hematology and chemistry analysis.
measure: Feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue and CSF.
time frame: 2 weeks
description: Kinome wide and quantitative (phospho)proteomic profiles will be determined in tumor tissue of study patients and in tumor tissue of matched controled patients. We anticipate that these profiles will reveal information on the effect of treatment on kinase abundances, phosphopeptide levels and on phosphorylation sites. Differences in levels of phosphopeptides and fold-change of phosphorylation sites will be quantified. In an exploratory design, we will determine whether observed profile differences can be correlated to drug concentrations in tumor tissue. Kinase inhibition profiles will be measured according to standard methods as developed and modified in our laboratory.
measure: Significant difference of the (phospho)proteomic profiles and kinase activities of tumor tissue in study patients and control group.
time frame: 2 weeks
description: The (phospho)proteomic profiles and kinase activity profiles will be determined in tumor tissue of study patients and in tumor tissue of patients in a control group.
Kinase inhibition profiles will be measured according to standard methods as developed and modified in our laboratory.
arm group label: sunitinib
arm group type: Experimental
arm group label: vandetanib
arm group type: Experimental
arm group label: Erlotinib
arm group type: Experimental
intervention type: Drug
intervention name: Sunitinib
description: 50 mg once daily, oral use for 14 days
arm group label: sunitinib
intervention type: Drug
intervention name: vandetanib
description: 300 mg, once daily, oral use for 14 days
arm group label: vandetanib
intervention type: Drug
intervention name: Erlotinib
description: 150 mg, once daily, oral use for 14 days
arm group label: Erlotinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: M.E. Van Linde, MD
phone: +31 (0)20 4444321
email: dm-onc@vumc.nl
facility: 
status: Recruiting
contact: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Amsterdam UMC, location VUmc
investigator full name: M.E. van Linde
investigator title: Medical Oncologist
mesh term: Glioma
mesh term: Erlotinib Hydrochloride
mesh term: Sunitinib