<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/NCT01713218</url>
  </required_header>
  <id_info>
    <org_study_id>2012-003516-31</org_study_id>
    <nct_id>NCT01713218</nct_id>
  </id_info>
  <brief_title>Effect on Tumor Perfusion of a Chemotherapy Combining Gemcitabine and Vismodegib Before Surgery in Pancreatic Cancer</brief_title>
  <acronym>NEOPACHI-001</acronym>
  <official_title>Evaluation of Tumoral Perfusion Modification by Dynamic Imaging After Neoadjuvant Chemotherapy Combining Gemcitabine and a Hedgehog Inhibitor (Vismodegib) in Patients With Resectable Pancreatic Adenocarcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jean-Luc Van Laethem</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Roche Pharma AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Erasme University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all human cancers&#xD;
      and is considered as a sanctuary, resistant to most of the drugs used. Identification of new&#xD;
      molecular targets involved in its pathogenesis is urgently needed and required both proper&#xD;
      and innovative efficacy assessment.&#xD;
&#xD;
      This proof-of-concept trial is studying the &quot;dynamic&quot; tumor response after the administration&#xD;
      of a short course (4 weeks) neoadjuvant combination of gemcitabine and a Hedgehog inhibitor&#xD;
      (Vismodegib) before surgery in patients with operable pancreatic cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pancreatic cancer is characterized by a high stromal density and is a hypoperfused tumor,&#xD;
      precluding cytotoxics delivery to the epithelial tumoral compartment. There is thus a&#xD;
      rationale for combining chemotherapy and antistromal drugs like Hedgehog inhibitors.&#xD;
      Targeting the resectable primary tumor offers an appropriate setting to (1) evaluate and&#xD;
      monitor early treatment effects on the tumor, (2) correlate dynamic imaging changes&#xD;
      (perfusion and diffusion coefficient) to pre- and post-therapeutic tissue changes, (3)&#xD;
      identify specific predictive biomarkers for the drugs used (i.e. gemcitabine transporters and&#xD;
      Hedgehog pathway genes and proteins) and (4) assess if this early &quot;dynamic and biomolecular&#xD;
      response&quot; can predict treatment benefit and patient outcome.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>December 2012</start_date>
  <completion_date type="Anticipated">December 2016</completion_date>
  <primary_completion_date type="Anticipated">June 2014</primary_completion_date>
  <phase>Early 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>&quot;Dynamic&quot; tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters.</measure>
    <time_frame>4 weeks (duration of the neoadjuvant chemotherapy).</time_frame>
    <description>In order to detect changes in the tumor microenvironment and to monitor treatment efficacy, Dynamic Contrast-Enhanced-Magnetic Resonance Imaging (DCE-MRI) and Diffusion Weighted-Magnetic Resonance Imaging (DW-MRI) constitute tools more and more used. The acquired data can be analyzed using a pharmacokinetic model to obtain quantitative parameters relative to tissue perfusion and vascular permeability (Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space; Apparent Diffusion Coefficient as a surrogate marker of tissue cellularity). DCE/DW-MRI will be achieved weekly before each neoadjuvant chemotherapy treatment and before surgery. Each patient will be his/her own control by comparing serial imaging results with those of the baseline MRI.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0.</measure>
    <time_frame>End of study follow-up (up to 2 years).</time_frame>
    <description>Number of participants with (serious) adverse events will be considered as a measure of safety of the whole therapeutic sequence (gemcitabine + Hedgehog inhibitor+ surgery).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.</measure>
    <time_frame>4 weeks (duration of the neoadjuvant chemotherapy).</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Effect of treatment on selected biomarkers in tumor resection specimens.</measure>
    <time_frame>4 weeks (duration of the neoadjuvant chemotherapy).</time_frame>
    <description>The objective is to identify within pre-therapeutic samples and surgical specimens several specific biomarkers involved (1) in the Hedgehog signalling pathway (GLI1, Sonic Hedgehog, Patched, Smoothened immunohistochemical patterns protein expression) and predicting response to anti-Hh therapy, (2) in the metabolization of gemcitabine (human equilibrative nucleoside transporter 1, deoxycytidine kinase) and predicting response to gemcitabine therapy, and (3) in the relative contribution of both anti-Hh therapy and gemcitabine therapy.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">21</enrollment>
  <condition>Pancreatic Adenocarcinoma Resectable</condition>
  <arm_group>
    <arm_group_label>Gemcitabine+Vismodegib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>gemcitabine</intervention_name>
    <description>Administrated intravenously at a dose of 1000 mg/m2 over 30 minutes weekly, week 1 to 4</description>
    <arm_group_label>Gemcitabine+Vismodegib</arm_group_label>
    <other_name>GEMZAR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vismodegib</intervention_name>
    <description>150 mg capsule, oral, once daily</description>
    <arm_group_label>Gemcitabine+Vismodegib</arm_group_label>
    <other_name>GDC-0449</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Neoadjuvant chemotherapy</intervention_name>
    <description>Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery</description>
    <arm_group_label>Gemcitabine+Vismodegib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histo(cyto)logically proven ductal pancreatic adenocarcinoma&#xD;
&#xD;
          -  Resectable or potentially resectable tumor; resectability assessed during a&#xD;
             multidisciplinary meeting with expert surgeon and radiologist&#xD;
&#xD;
          -  First line chemotherapy&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  WHO performance status (PS) grade 0 or 1;&#xD;
&#xD;
          -  Absolute neutrophil count &gt; 1.5 x 10 9 / L, platelets &gt; 100 x 10 9/ L, creatinine&#xD;
             clearance (Cockcroft and Gault formula) &gt; 60 ml/min, haemoglobin level &gt; 10 g/dl&#xD;
             (transfusions authorized), bilirubin&lt;1.5 g/dl;&#xD;
&#xD;
          -  Optimal biliary drainage;&#xD;
&#xD;
          -  Women of child-bearing potential (WCBP), defined as a sexually mature woman who has&#xD;
             not undergone a hysterectomy or tubal ligation of who has not been naturally&#xD;
             postmenopausal for at least 24 consecutive months, must have a negative serum or urine&#xD;
             pregnancy test prior to treatment. All WCBP, all sexually active male patients, and&#xD;
             all partners of patients must agree to use adequate methods of birth control&#xD;
             throughout the study;&#xD;
&#xD;
          -  Signed written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Locally advanced non resectable or metastatic pancreatic adenocarcinoma&#xD;
&#xD;
          -  Previous anticancer therapy for the pancreatic adenocarcinoma&#xD;
&#xD;
          -  Biliary obstruction without endoscopic biliary drainage&#xD;
&#xD;
          -  Any contre-indication for surgery&#xD;
&#xD;
          -  Prior malignancy (except non-melanoma skin cancer, and in situ carcinoma of the&#xD;
             uterine cervix treated with a curative intent and any other tumor in complete&#xD;
             remission with a disease-free interval &gt; 3 years)&#xD;
&#xD;
          -  Uncontrolled congestive heart failure or angina pectoris, myocardial infarction within&#xD;
             1 year prior to study entry, uncontrolled hypertension (systolic pressure &gt; 160 mm or&#xD;
             diastolic pressure &gt; 100 mm under well conducted antihypertensive treatment), QT&#xD;
             prolongation&#xD;
&#xD;
          -  Major uncontrolled infection&#xD;
&#xD;
          -  Severe hepatic impairment&#xD;
&#xD;
          -  Any medical, psychological, or social condition, which, in the opinion of the&#xD;
             investigator, could hamper patient's compliance to the study protocol and/or&#xD;
             assessment/interpretation of the data&#xD;
&#xD;
          -  Pregnant or lactating women, or patients of both genders with procreative potential&#xD;
             not using adequate contraceptive methods&#xD;
&#xD;
          -  Patients receiving or having received any investigational treatment within 4 weeks&#xD;
             prior to study entry, or participating to another clinical study;Subject previously&#xD;
             enrolled into this study.&#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>Jean-Luc Van Laethem, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Erasme University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jean-Luc Van Laethem, MD, PhD</last_name>
    <email>jl.vanlaethem@erasme.ulb.ac.be</email>
  </overall_contact>
  <location>
    <facility>
      <name>Antwerp University Hospital (UZA)</name>
      <address>
        <city>Edegem</city>
        <state>Antwerpen</state>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <contact>
      <last_name>Marc Peeters, MD,PhD</last_name>
      <email>marc.peeters@uza.be</email>
    </contact>
    <investigator>
      <last_name>Marc Peeters, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Erasme University Hospital (ULB)</name>
      <address>
        <city>Brussels</city>
        <zip>1070</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <contact>
      <last_name>Jean-Luc Van Laethem, MD, PhD</last_name>
      <email>jl.vanlaethem@erasme.ulb.ac.be</email>
    </contact>
    <investigator>
      <last_name>Jean-Luc Van Laethem, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Raphaël Maréchal, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Anne Demols, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>October 2012</verification_date>
  <study_first_submitted>October 17, 2012</study_first_submitted>
  <study_first_submitted_qc>October 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>October 22, 2012</last_update_submitted>
  <last_update_submitted_qc>October 22, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 24, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Erasme University Hospital</investigator_affiliation>
    <investigator_full_name>Jean-Luc Van Laethem</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Pancreas</keyword>
  <keyword>Cancer</keyword>
  <keyword>Hedgehog inhibitor</keyword>
  <keyword>Neoadjuvant chemotherapy</keyword>
  <keyword>Dynamic imaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenocarcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</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/NCT01713218
org study id: 2012-003516-31
nct id: NCT01713218
lead sponsor: 
collaborator: 
has dmc: No
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all human cancers
      and is considered as a sanctuary, resistant to most of the drugs used. Identification of new
      molecular targets involved in its pathogenesis is urgently needed and required both proper
      and innovative efficacy assessment.

      This proof-of-concept trial is studying the "dynamic" tumor response after the administration
      of a short course (4 weeks) neoadjuvant combination of gemcitabine and a Hedgehog inhibitor
      (Vismodegib) before surgery in patients with operable pancreatic cancer.
Pancreatic cancer is characterized by a high stromal density and is a hypoperfused tumor,
      precluding cytotoxics delivery to the epithelial tumoral compartment. There is thus a
      rationale for combining chemotherapy and antistromal drugs like Hedgehog inhibitors.
      Targeting the resectable primary tumor offers an appropriate setting to (1) evaluate and
      monitor early treatment effects on the tumor, (2) correlate dynamic imaging changes
      (perfusion and diffusion coefficient) to pre- and post-therapeutic tissue changes, (3)
      identify specific predictive biomarkers for the drugs used (i.e. gemcitabine transporters and
      Hedgehog pathway genes and proteins) and (4) assess if this early "dynamic and biomolecular
      response" can predict treatment benefit and patient outcome.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: "Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters.
time frame: 4 weeks (duration of the neoadjuvant chemotherapy).
description: In order to detect changes in the tumor microenvironment and to monitor treatment efficacy, Dynamic Contrast-Enhanced-Magnetic Resonance Imaging (DCE-MRI) and Diffusion Weighted-Magnetic Resonance Imaging (DW-MRI) constitute tools more and more used. The acquired data can be analyzed using a pharmacokinetic model to obtain quantitative parameters relative to tissue perfusion and vascular permeability (Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space; Apparent Diffusion Coefficient as a surrogate marker of tissue cellularity). DCE/DW-MRI will be achieved weekly before each neoadjuvant chemotherapy treatment and before surgery. Each patient will be his/her own control by comparing serial imaging results with those of the baseline MRI.
measure: Number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0.
time frame: End of study follow-up (up to 2 years).
description: Number of participants with (serious) adverse events will be considered as a measure of safety of the whole therapeutic sequence (gemcitabine + Hedgehog inhibitor+ surgery).
measure: Tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
time frame: 4 weeks (duration of the neoadjuvant chemotherapy).
measure: Effect of treatment on selected biomarkers in tumor resection specimens.
time frame: 4 weeks (duration of the neoadjuvant chemotherapy).
description: The objective is to identify within pre-therapeutic samples and surgical specimens several specific biomarkers involved (1) in the Hedgehog signalling pathway (GLI1, Sonic Hedgehog, Patched, Smoothened immunohistochemical patterns protein expression) and predicting response to anti-Hh therapy, (2) in the metabolization of gemcitabine (human equilibrative nucleoside transporter 1, deoxycytidine kinase) and predicting response to gemcitabine therapy, and (3) in the relative contribution of both anti-Hh therapy and gemcitabine therapy.
arm group label: Gemcitabine+Vismodegib
arm group type: Experimental
description: Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery
intervention type: Drug
intervention name: gemcitabine
description: Administrated intravenously at a dose of 1000 mg/m2 over 30 minutes weekly, week 1 to 4
arm group label: Gemcitabine+Vismodegib
other name: GEMZAR
intervention type: Drug
intervention name: Vismodegib
description: 150 mg capsule, oral, once daily
arm group label: Gemcitabine+Vismodegib
other name: GDC-0449
intervention type: Procedure
intervention name: Neoadjuvant chemotherapy
description: Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery
arm group label: Gemcitabine+Vismodegib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jean-Luc Van Laethem, MD, PhD
role: Principal Investigator
affiliation: Erasme University Hospital
last name: Jean-Luc Van Laethem, MD, PhD
email: jl.vanlaethem@erasme.ulb.ac.be
facility: 
contact: 
investigator: 
facility: 
contact: 
investigator: 
investigator: 
investigator: 
country: Belgium
responsible party type: Sponsor-Investigator
investigator affiliation: Erasme University Hospital
investigator full name: Jean-Luc Van Laethem
investigator title: MD, PhD
mesh term: Adenocarcinoma
mesh term: Gemcitabine