<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/NCT02978547</url>
  </required_header>
  <id_info>
    <org_study_id>H16-02566</org_study_id>
    <nct_id>NCT02978547</nct_id>
  </id_info>
  <brief_title>The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma</brief_title>
  <acronym>Metformin 001</acronym>
  <official_title>The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>British Columbia Cancer Agency</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pancreatic Cancer Canada</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>BC Cancer Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>British Columbia Cancer Agency</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single arm, non-randomized phase II study of neoadjuvant metformin in resectable&#xD;
      PDAC. Twenty patients will be enrolled and treated with metformin 500 mg BD for a minimum of&#xD;
      7 days, until 2 days prior to surgery. Patients will undergo laboratory investigations at&#xD;
      baseline, prior to surgery and 4-10 weeks after surgery. Patients eligible for and consented&#xD;
      to the optional MRI substudy will undergo diffusion-weighted MRI 1 to 14 days before surgery.&#xD;
&#xD;
      At surgery, resected tumour and normal tissue will be collected and banked. FFPE specimens&#xD;
      will be used for sectioning, histological analysis and IHC for Ki67 (cell proliferation&#xD;
      marker), pAMPK, ACC targets, p53 and mTOR targets, apoptotic markers (Bax, Bcl-2, caspases 3,&#xD;
      8 and 9). Fresh frozen tumour and matched normal tissue samples will be used for western blot&#xD;
      analysis of insulin and IGF receptors, total and activated ERK and Akt, and RNAseq analysis.&#xD;
      Pre-metformin biopsy samples will be retrieved for molecular analysis.&#xD;
&#xD;
      Fasting blood samples at baseline and before surgery will be analyzed for glucose and insulin&#xD;
      levels. Plasma and whole blood will also be processed and banked for circulating tumour DNA&#xD;
      analysis. Urine samples will be sent for metabolomic profiling.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 2019</start_date>
  <completion_date type="Anticipated">January 2021</completion_date>
  <primary_completion_date type="Anticipated">June 2020</primary_completion_date>
  <phase>Phase 2</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>The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours</measure>
    <time_frame>6 months</time_frame>
    <description>Assessment of Ki-67 fraction as assessed by IHC of pre- and post-metformin tumour samples.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>R0 resection rates in patients undergoing curative PDAC resection</measure>
    <time_frame>6 months</time_frame>
    <description>Proportion of patients with R0 resections.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L)</measure>
    <time_frame>6 months</time_frame>
    <description>The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L)</measure>
    <time_frame>6 months</time_frame>
    <description>The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L)</measure>
    <time_frame>6 months</time_frame>
    <description>The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index</measure>
    <time_frame>6 months</time_frame>
    <description>HOMA index is calculated from serum glucose and insulin. The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg)</measure>
    <time_frame>6 months</time_frame>
    <description>The clinical marker will be reported with pre- and post-metformin values compared.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of metformin on metabolomic profile of pre- and post-metformin samples</measure>
    <time_frame>6 months</time_frame>
    <description>Serum and urine metabolomic profile.&#xD;
Comparison of metabolite levels in pre-and post-metformin samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples.</measure>
    <time_frame>6 months</time_frame>
    <description>To investigate the molecular signatures associated with metformin response&#xD;
Comparison of gene expression in pre-metformin biopsy samples and post-metformin resected tumour samples. Expression of altered genes to be validated by IHC in tumour sections.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma</measure>
    <time_frame>6 months</time_frame>
    <description>To assess the presence of ctDNA in resectable PDAC, and dynamic changes following treatment with metformin and surgical resection&#xD;
Proportion of patients with detectable plasma ctDNA at baseline. Comparison of values pre- and post-metformin and 4-10 weeks after surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between imaging and pathologic parameters</measure>
    <time_frame>6 months</time_frame>
    <description>To explore the correlation between apparent diffusion coefficient (ADC) on MRI and pathologic findings.&#xD;
ADC values will be individually compared to tumour differentiation and Ki-67 fraction on pathologic examination.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Resectable Pancreatic Ductal Adenocarcinoma</condition>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients will receive metformin 500 mg per oral twice daily with food for at least 7 days, until 2 days prior to surgery. Metformin therapy should be discontinued 2 days before surgery to reduce the risk of lactic acidosis associated with fasting.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin Hydrochloride 500Mg Tablet</intervention_name>
    <description>In the event of any grade 2 toxicities (with the exception of hyperglycemia), metformin will be withheld until improvement to ≤ grade 1, then restarted at a dose of 500 mg daily. In the event of grade ≥ 3 toxicities related to metformin, treatment will be discontinued. Metformin therapy will also be discontinued if serum lactate levels are above normal values.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater than or equal to 18 years on the day of study consent&#xD;
&#xD;
          -  Pathologic diagnosis of PDAC where 2 pre-treatment core biopsy samples are available&#xD;
             for analysis. Patients with suspected PDAC without a pathologic diagnosis must undergo&#xD;
             confirmatory biopsy under endoscopic ultrasound guidance.&#xD;
&#xD;
          -  Resectable disease based on standard imaging criteria&#xD;
&#xD;
          -  Surgery planned ≥ 2 weeks after study entry&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  Adequate hematologic, renal, and hepatic function as measured by the following&#xD;
             laboratory assessments conducted within 7 days prior to the initiation of study&#xD;
             treatment:&#xD;
&#xD;
               -  Total bilirubin &lt; 1.5 times the upper limit of normal (ULN)&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt; 2.5 times&#xD;
                  the ULN&#xD;
&#xD;
               -  Lipase &lt; 1.5 times the ULN&#xD;
&#xD;
               -  Serum creatinine &lt; 1.5 times the ULN&#xD;
&#xD;
               -  Glomerular filtration rate &gt; 30 mL/min/1.73 m2 according to the modified diet in&#xD;
                  renal disease abbreviated formula&#xD;
&#xD;
               -  International normalized ratio (INR) or prothrombin time (PT; PT-INR) and partial&#xD;
                  thromboplastin time (PTT) &lt; 1.5 times the ULN&#xD;
&#xD;
               -  Platelet count &gt; 100000 /mm3, hemoglobin (&gt; 9 g/dL, absolute neutrophil count &gt;&#xD;
                  1500/mm3.&#xD;
&#xD;
          -  Baseline fasting glucose &lt;13.9 mmol/L&#xD;
&#xD;
          -  No prior chemotherapy or radiotherapy for PDAC&#xD;
&#xD;
          -  Serum lactate levels within normal range assessed within 7 days prior to the&#xD;
             initiation of study treatment&#xD;
&#xD;
        MRI sub-study:&#xD;
&#xD;
          -  Signed informed consent for the optional MRI substudy&#xD;
&#xD;
          -  No contraindications to MRI&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of locally unresectable disease or distant metastases&#xD;
&#xD;
          -  Treatment with metformin or any other anti-hyperglycemic agent within the previous 6&#xD;
             months&#xD;
&#xD;
          -  Known allergy or contraindication to metformin&#xD;
&#xD;
          -  Not fit for surgery&#xD;
&#xD;
          -  Planned for, or received, neoadjuvant treatment of any type&#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>Daniel J Renouf, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>British Columbia Cancer Agency</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Daniel J Renouf, MD</last_name>
    <phone>6048776000</phone>
    <phone_ext>2445</phone_ext>
    <email>drenouf@bccancer.bc.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hui-li Wong, MD</last_name>
    <phone>6048776000</phone>
    <phone_ext>2445</phone_ext>
    <email>HuiLi.Wong@bccancer.bc.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>BC Cancer Agency - Vancouver Cancer Centre</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 4E6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
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  <verification_date>January 2018</verification_date>
  <study_first_submitted>November 2, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 1, 2016</study_first_posted>
  <last_update_submitted>January 16, 2018</last_update_submitted>
  <last_update_submitted_qc>January 16, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Resectable pancreatic ductal adenocarcinoma</keyword>
  <keyword>PDAC</keyword>
  <keyword>Metformin</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>Metformin</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/NCT02978547
org study id: H16-02566
nct id: NCT02978547
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a single arm, non-randomized phase II study of neoadjuvant metformin in resectable
      PDAC. Twenty patients will be enrolled and treated with metformin 500 mg BD for a minimum of
      7 days, until 2 days prior to surgery. Patients will undergo laboratory investigations at
      baseline, prior to surgery and 4-10 weeks after surgery. Patients eligible for and consented
      to the optional MRI substudy will undergo diffusion-weighted MRI 1 to 14 days before surgery.

      At surgery, resected tumour and normal tissue will be collected and banked. FFPE specimens
      will be used for sectioning, histological analysis and IHC for Ki67 (cell proliferation
      marker), pAMPK, ACC targets, p53 and mTOR targets, apoptotic markers (Bax, Bcl-2, caspases 3,
      8 and 9). Fresh frozen tumour and matched normal tissue samples will be used for western blot
      analysis of insulin and IGF receptors, total and activated ERK and Akt, and RNAseq analysis.
      Pre-metformin biopsy samples will be retrieved for molecular analysis.

      Fasting blood samples at baseline and before surgery will be analyzed for glucose and insulin
      levels. Plasma and whole blood will also be processed and banked for circulating tumour DNA
      analysis. Urine samples will be sent for metabolomic profiling.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The effect of neoadjuvant metformin treatment on tumour cell proliferation in PDAC tumours
time frame: 6 months
description: Assessment of Ki-67 fraction as assessed by IHC of pre- and post-metformin tumour samples.
measure: R0 resection rates in patients undergoing curative PDAC resection
time frame: 6 months
description: Proportion of patients with R0 resections.
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting GGT (mmol/L)
time frame: 6 months
description: The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting glucose (mmol/L)
time frame: 6 months
description: The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, fasting insulin (mU/L)
time frame: 6 months
description: The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.
measure: The effect of metformin on glucose and insulin metabolism as assessed by serum marker, HOMA index
time frame: 6 months
description: HOMA index is calculated from serum glucose and insulin. The marker of glucose and insulin metabolism will be reported with pre- and post-metformin values compared.
measure: The effect of metformin on glucose and insulin metabolism as assessed by clinical marker, weight (kg)
time frame: 6 months
description: The clinical marker will be reported with pre- and post-metformin values compared.
measure: The effect of metformin on metabolomic profile of pre- and post-metformin samples
time frame: 6 months
description: Serum and urine metabolomic profile.
Comparison of metabolite levels in pre-and post-metformin samples.
measure: Transcriptome sequencing (RNAseq) of pre- and post-treatment tumour samples.
time frame: 6 months
description: To investigate the molecular signatures associated with metformin response
Comparison of gene expression in pre-metformin biopsy samples and post-metformin resected tumour samples. Expression of altered genes to be validated by IHC in tumour sections.
measure: Plasma ctDNA, measured as percentage of mutant to total DNA fragments in plasma
time frame: 6 months
description: To assess the presence of ctDNA in resectable PDAC, and dynamic changes following treatment with metformin and surgical resection
Proportion of patients with detectable plasma ctDNA at baseline. Comparison of values pre- and post-metformin and 4-10 weeks after surgery.
measure: Correlation between imaging and pathologic parameters
time frame: 6 months
description: To explore the correlation between apparent diffusion coefficient (ADC) on MRI and pathologic findings.
ADC values will be individually compared to tumour differentiation and Ki-67 fraction on pathologic examination.
arm group label: Metformin
arm group type: Experimental
description: All patients will receive metformin 500 mg per oral twice daily with food for at least 7 days, until 2 days prior to surgery. Metformin therapy should be discontinued 2 days before surgery to reduce the risk of lactic acidosis associated with fasting.
intervention type: Drug
intervention name: Metformin Hydrochloride 500Mg Tablet
description: In the event of any grade 2 toxicities (with the exception of hyperglycemia), metformin will be withheld until improvement to ≤ grade 1, then restarted at a dose of 500 mg daily. In the event of grade ≥ 3 toxicities related to metformin, treatment will be discontinued. Metformin therapy will also be discontinued if serum lactate levels are above normal values.
arm group label: Metformin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Daniel J Renouf, MD
role: Principal Investigator
affiliation: British Columbia Cancer Agency
last name: Daniel J Renouf, MD
phone: 6048776000
phone ext: 2445
email: drenouf@bccancer.bc.ca
last name: Hui-li Wong, MD
phone: 6048776000
phone ext: 2445
email: HuiLi.Wong@bccancer.bc.ca
facility: 
country: Canada
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responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Metformin