<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/NCT03796884</url>
  </required_header>
  <id_info>
    <org_study_id>18F.524</org_study_id>
    <nct_id>NCT03796884</nct_id>
  </id_info>
  <brief_title>Linaclotide in Treating Patients With Stages 0-3 Colorectal Cancer</brief_title>
  <official_title>Phase II Randomized, Placebo-Controlled Trial of Linaclotide to Demonstrate Bioactivity in Patients With Sporadic Colorectal Adenomas and With Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Cancer Center at Thomas Jefferson University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Thomas Jefferson University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies the how well linaclotide works in treating patients with stages&#xD;
      0-3 colorectal cancer. Linaclotide is a very small protein that binds to receptors on&#xD;
      intestinal cells and makes them secrete water and salt.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine whether, compared to placebo, linaclotide administered as a single oral daily&#xD;
      dose x 7 days, induces a pharmacodynamics (PD) effect on cGMP levels, based on biopsy samples&#xD;
      of adenomas or resected colorectal adenocarcinomas.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To compare Ki-67, guanylin levels and GUCY2C expression in adenomas and cancers versus&#xD;
      normal tissue after exposure to linaclotide or placebo.&#xD;
&#xD;
      II. To confirm the safety and tolerability of linaclotide in sporadic adenoma and cancer&#xD;
      patients.&#xD;
&#xD;
      TRANSLATIONAL OBJECTIVE:&#xD;
&#xD;
      I. To assess the pharmacodynamic effect of linaclotide on pathway-specific biomarkers&#xD;
      relevant to GUCY2C signaling (i.e. VASP phosphorylation), markers of mutant APC-beta-catenin&#xD;
      signaling (beta-catenin levels, beta-catenin nuclear localization, axin levels, c-Myc levels,&#xD;
      guanylin levels, PCNA expression), based on adenoma/cancer and normal mucosa biopsy samples&#xD;
      obtained by endoscopy following linaclotide or placebo exposure.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 arms.&#xD;
&#xD;
      ARM I: Patients receive linaclotide orally (PO) daily on days 1-7 and undergo standard of&#xD;
      care colonoscopy or surgery on day 7.&#xD;
&#xD;
      ARM II. Patients receive placebo PO QD on days 1-7 and undergo standard of care colonoscopy&#xD;
      or surgery on day 7.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at day 14.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 30, 2019</start_date>
  <completion_date type="Anticipated">October 2023</completion_date>
  <primary_completion_date type="Anticipated">October 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacodynamics effect on cGMP levels</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Will compare cGMP levels in adenomas between study arms using a two-sample t-test (alpha=.05; two-sided) or Wilcoxon rank sum test.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events (AEs)</measure>
    <time_frame>From the time of first dose of linaclotide or placebo until resolution, if related to linaclotide, or through 30 days after occurrence</time_frame>
    <description>All participants will be evaluated for toxicity. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used to summarize adverse events associated with linaclotide.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ki-67 expression</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Wilcoxon rank sum test will be used to compare Ki-67 expression in adenomas across arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GUCY2C expression</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Wilcoxon rank sum and Fisher's exact tests will be used to compare GUCY2C expression between study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Guanylin levels</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Wilcoxon rank sum and Fisher's exact tests will be used to compare guanylin levels between study arms.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>VASP serine 239 phosphorylation</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Assessed by immunoblot analysis. Wilcoxon rank sum and Fisher's exact tests will be used to compare VASP phosphorylation between study arms.</description>
  </other_outcome>
  <other_outcome>
    <measure>Beta-catenin levels</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Assessed by immunoblot analysis. Wilcoxon rank sum and Fisher's exact tests will be used to compare beta-catenin accumulation and downstream signaling between study arms.</description>
  </other_outcome>
  <other_outcome>
    <measure>Beta-catenin nuclear localization</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Assessed by immunofluorescence. Wilcoxon rank sum and Fisher's exact tests will be used to compare beta-catenin accumulation and downstream signaling between study arms</description>
  </other_outcome>
  <other_outcome>
    <measure>Axin and c-Myc messenger ribonucleic acid (mRNA) levels</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Assessed by quantitative reverse transcriptase-polymerase chain reaction. Wilcoxon rank sum and Fisher's exact tests will be used to compare axin and c-Myc mRNA levels between study arms.</description>
  </other_outcome>
  <other_outcome>
    <measure>PCNA expression</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Assessed by immunofluorescence.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">230</enrollment>
  <condition>Colorectal Adenoma</condition>
  <condition>Stage 0 Colorectal Cancer AJCC v8</condition>
  <condition>Stage I Colorectal Cancer AJCC v8</condition>
  <condition>Stage II Colorectal Cancer AJCC v8</condition>
  <condition>Stage IIA Colorectal Cancer AJCC v8</condition>
  <condition>Stage IIB Colorectal Cancer AJCC v8</condition>
  <condition>Stage IIC Colorectal Cancer AJCC v8</condition>
  <condition>Stage III Colorectal Cancer AJCC v8</condition>
  <condition>Stage IIIA Colorectal Cancer AJCC v8</condition>
  <condition>Stage IIIB Colorectal Cancer AJCC v8</condition>
  <condition>Stage IIIC Colorectal Cancer AJCC v8</condition>
  <arm_group>
    <arm_group_label>Arm I (linaclotide)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive linaclotide PO daily on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (placebo)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients receive placebo PO QD on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Linaclotide</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm I (linaclotide)</arm_group_label>
    <other_name>851199-59-2</other_name>
    <other_name>Linzess</other_name>
    <other_name>[9-L-tyrosine]heat-stable enterotoxin (Escherichia coli)-(6-19)-peptide</other_name>
    <other_name>L-Tyrosine</other_name>
    <other_name>L-cysteinyl-L-cysteinyl-L-alpha-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L- asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteiny</other_name>
    <other_name>cyclic (1-&gt;6), (2-&gt;10), (5-&gt;13)-tris(disulfide)</other_name>
    <other_name>MD-1100</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm II (placebo)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  History of 1 or more sporadic colorectal adenoma on previous endoscopy (adenoma&#xD;
             cohort) or stage 0-3 biopsy proven colorectal cancer (CRC) (colorectal cancer cohort)&#xD;
             who are scheduled for a surgical procedure&#xD;
&#xD;
          -  Ability to understand and willingness to sign a written informed consent document and&#xD;
             follow study procedures&#xD;
&#xD;
          -  Ability to swallow capsules without difficulty&#xD;
&#xD;
          -  Ability to maintain pill diaries&#xD;
&#xD;
          -  Willingness to employ adequate contraception for men and women of childbearing&#xD;
             potential for the duration of the study. Acceptable methods include double barrier&#xD;
             methods, intrauterine device (IUD), postmenopausal status, and/or documentation of&#xD;
             surgical sterilization&#xD;
&#xD;
          -  Participants must have no chronic, clinically severe health issues which, in the&#xD;
             opinion of their physician or the research team, could preclude trial activities&#xD;
             including the one week drug exposure phase&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of gastroparesis&#xD;
&#xD;
          -  History of celiac disease&#xD;
&#xD;
          -  Inflammatory bowel disease (Crohn's disease, ulcerative colitis)&#xD;
&#xD;
          -  Microscopic colitis, including collagenous colitis&#xD;
&#xD;
          -  Has taken linaclotide within 30 days prior to consent&#xD;
&#xD;
          -  Any malignancy except colorectal cancer or any active radiotherapy or cytotoxic&#xD;
             chemotherapy within the last 6 months of baseline. Participants with a history of&#xD;
             basal cell or squamous cell skin cancer may be enrolled at the discretion of the&#xD;
             investigator&#xD;
&#xD;
          -  Participants may not be receiving any other investigational agents, or be active&#xD;
             participants in any clinical trials. If participants previously participated in a&#xD;
             clinical trial, a 30 day washout period for the investigational drug is needed before&#xD;
             the participant can be considered for this study&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to linaclotide&#xD;
&#xD;
          -  Uncontrolled current illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  History of bleeding/coagulation problems. Concurrent use of nonsteroidal&#xD;
             anti-inflammatory drugs (NSAIDs) including aspirin is acceptable&#xD;
&#xD;
          -  Any medical condition judged by the investigator to constitute a risk to safe&#xD;
             participation&#xD;
&#xD;
          -  At risk for obstructing or near-obstructing mechanical gastrointestinal obstruction&#xD;
&#xD;
          -  Chronic use of anti-coagulants or non-NSAID anti-platelet agents will serve as an&#xD;
             exclusion only when such medications cannot be safely discontinued before study&#xD;
             related endoscopy or surgery&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Scott Waldman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sidney Kimmel Cancer Center at Thomas Jefferson University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fox Chase Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sidney Kimmel Cancer Center at Thomas Jefferson University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19126</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Puget Sound Health Care Sysem</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://hospitals.jefferson.edu/</url>
    <description>Thomas Jefferson University Hospital</description>
  </link>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 7, 2019</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>March 20, 2023</last_update_submitted>
  <last_update_submitted_qc>March 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Adenoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Linaclotide</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/NCT03796884
org study id: 18F.524
nct id: NCT03796884
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies the how well linaclotide works in treating patients with stages
      0-3 colorectal cancer. Linaclotide is a very small protein that binds to receptors on
      intestinal cells and makes them secrete water and salt.
PRIMARY OBJECTIVES:

      I. To determine whether, compared to placebo, linaclotide administered as a single oral daily
      dose x 7 days, induces a pharmacodynamics (PD) effect on cGMP levels, based on biopsy samples
      of adenomas or resected colorectal adenocarcinomas.

      SECONDARY OBJECTIVES:

      I. To compare Ki-67, guanylin levels and GUCY2C expression in adenomas and cancers versus
      normal tissue after exposure to linaclotide or placebo.

      II. To confirm the safety and tolerability of linaclotide in sporadic adenoma and cancer
      patients.

      TRANSLATIONAL OBJECTIVE:

      I. To assess the pharmacodynamic effect of linaclotide on pathway-specific biomarkers
      relevant to GUCY2C signaling (i.e. VASP phosphorylation), markers of mutant APC-beta-catenin
      signaling (beta-catenin levels, beta-catenin nuclear localization, axin levels, c-Myc levels,
      guanylin levels, PCNA expression), based on adenoma/cancer and normal mucosa biopsy samples
      obtained by endoscopy following linaclotide or placebo exposure.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive linaclotide orally (PO) daily on days 1-7 and undergo standard of
      care colonoscopy or surgery on day 7.

      ARM II. Patients receive placebo PO QD on days 1-7 and undergo standard of care colonoscopy
      or surgery on day 7.

      After completion of study treatment, patients are followed up at day 14.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Pharmacodynamics effect on cGMP levels
time frame: Up to 2 years
description: Will compare cGMP levels in adenomas between study arms using a two-sample t-test (alpha=.05; two-sided) or Wilcoxon rank sum test.
measure: Incidence of adverse events (AEs)
time frame: From the time of first dose of linaclotide or placebo until resolution, if related to linaclotide, or through 30 days after occurrence
description: All participants will be evaluated for toxicity. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used to summarize adverse events associated with linaclotide.
measure: Ki-67 expression
time frame: Up to 2 years
description: Wilcoxon rank sum test will be used to compare Ki-67 expression in adenomas across arms.
measure: GUCY2C expression
time frame: Up to 2 years
description: Wilcoxon rank sum and Fisher's exact tests will be used to compare GUCY2C expression between study arms.
measure: Guanylin levels
time frame: Up to 2 years
description: Wilcoxon rank sum and Fisher's exact tests will be used to compare guanylin levels between study arms.
measure: VASP serine 239 phosphorylation
time frame: Up to 2 years
description: Assessed by immunoblot analysis. Wilcoxon rank sum and Fisher's exact tests will be used to compare VASP phosphorylation between study arms.
measure: Beta-catenin levels
time frame: Up to 2 years
description: Assessed by immunoblot analysis. Wilcoxon rank sum and Fisher's exact tests will be used to compare beta-catenin accumulation and downstream signaling between study arms.
measure: Beta-catenin nuclear localization
time frame: Up to 2 years
description: Assessed by immunofluorescence. Wilcoxon rank sum and Fisher's exact tests will be used to compare beta-catenin accumulation and downstream signaling between study arms
measure: Axin and c-Myc messenger ribonucleic acid (mRNA) levels
time frame: Up to 2 years
description: Assessed by quantitative reverse transcriptase-polymerase chain reaction. Wilcoxon rank sum and Fisher's exact tests will be used to compare axin and c-Myc mRNA levels between study arms.
measure: PCNA expression
time frame: Up to 2 years
description: Assessed by immunofluorescence.
arm group label: Arm I (linaclotide)
arm group type: Experimental
description: Patients receive linaclotide PO daily on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
arm group label: Arm II (placebo)
arm group type: Placebo Comparator
description: Patients receive placebo PO QD on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
intervention type: Drug
intervention name: Linaclotide
description: Given PO
arm group label: Arm I (linaclotide)
other name: 851199-59-2
other name: Linzess
other name: [9-L-tyrosine]heat-stable enterotoxin (Escherichia coli)-(6-19)-peptide
other name: L-Tyrosine
other name: L-cysteinyl-L-cysteinyl-L-alpha-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L- asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteiny
other name: cyclic (1->6), (2->10), (5->13)-tris(disulfide)
other name: MD-1100
intervention type: Other
intervention name: Placebo
description: Given PO
arm group label: Arm II (placebo)
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Scott Waldman, MD
role: Principal Investigator
affiliation: Sidney Kimmel Cancer Center at Thomas Jefferson University
facility: 
facility: 
facility: 
country: United States
url: http://hospitals.jefferson.edu/
description: Thomas Jefferson University Hospital
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Adenoma
mesh term: Linaclotide