<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/NCT03748680</url>
  </required_header>
  <id_info>
    <org_study_id>KFE-1803</org_study_id>
    <nct_id>NCT03748680</nct_id>
  </id_info>
  <brief_title>IMPROVE Intervention Trial Implementing Non-invasive Circulating Tumor DNA Analysis to Optimize the Operative and Postoperative Treatment for Patients With Colorectal Cancer</brief_title>
  <acronym>IMPROVE-IT</acronym>
  <official_title>Implementing Non-invasive Circulating Tumor DNA Analysis to Optimize the Operative and Postoperative Treatment for Patients With Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Karen-Lise Garm Spindler</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Aarhus University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A open label 1:1 randomized phase II exploratory study investigating adjuvant therapy in&#xD;
      patients with molecular biologically detectable residual disease after primary resection for&#xD;
      localized colorectal tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main clinical hypothesis is that patients having undergone radical resection from CRC do&#xD;
      not present with detectable tumor DNA in the plasma, whereas patients with detectable tumor&#xD;
      DNA two weeks' post surgery have residual microscopic disease, and consequently a high risk&#xD;
      of diseases recurrence which can be prevented with adjuvant chemotherapy.&#xD;
&#xD;
      The primary aim of the present study is to investigate - in a randomized trial - if use of&#xD;
      standard adjuvant chemotherapy therapy improves the disease free survival in patients with&#xD;
      molecular biological residual disease where adjuvant chemotherapy is not standard treatment .&#xD;
&#xD;
      Secondary aims include investigating molecular biological response to adjuvant chemotherapy&#xD;
      in patients with post-operative ctDNA.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 1, 2018</start_date>
  <completion_date type="Anticipated">October 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">October 1, 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>
    <intervention_model_description>A open label 1:1 randomized phase II exploratory study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>DFS</measure>
    <time_frame>3 years</time_frame>
    <description>Disease free survival</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Molecular biological response</measure>
    <time_frame>6 months</time_frame>
    <description>Molecular biological response at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MB-DFS</measure>
    <time_frame>1 year</time_frame>
    <description>Molecular biological disease free survival at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TT-MBR</measure>
    <time_frame>3 years</time_frame>
    <description>Time to molecular biological recurrence</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TTR</measure>
    <time_frame>3 years</time_frame>
    <description>Time to radiological recurrence</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LRR</measure>
    <time_frame>3 years</time_frame>
    <description>Local recurrence rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DRR</measure>
    <time_frame>3 years</time_frame>
    <description>Distant recurrence rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS</measure>
    <time_frame>5 years</time_frame>
    <description>Overall survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TR</measure>
    <time_frame>3 years</time_frame>
    <description>Translational research exploratory</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">64</enrollment>
  <condition>Colorectal Cancer</condition>
  <condition>Circulating Tumor DNA</condition>
  <condition>Adjuvant Chemotherapy</condition>
  <condition>Progression Free Survival</condition>
  <arm_group>
    <arm_group_label>A</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intensified follow-up schedule</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Adjuvant chemotherapy + intensified follow-up schedule</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capox (or FOLFOX) including flouropyrimidine and oxaliplatin combination chemotherapy</intervention_name>
    <description>Six months of adjuvant combination chemotherapy with Capox (or FOLFOX) Patients will receive adjuvant chemotherapy with eight cycles of CAPOX (oxaliplatin 130 mg/m2 day 1 and capecitabine 1000 mg/m2 b.i.d. days 1-14, repeated every 3 weeks.&#xD;
(Patients with an ileostomy are only eligible for FOLFOX and will be treated with 12 cycles of FOLFOX (oxaliplatin 85 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1 and 5FU 2400 mg/ m2 over 46-48 hours day 1-3, repeated every second weeks)</description>
    <arm_group_label>B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Intensified Follow-up Schedule</intervention_name>
    <description>Close monitoring with Imaging during follow-up Patients included in this trial will undergo intensified follow-up with CT-chest and abdomen every four months after surgery for the first 2 years, then every 6 months for 1 years and finally once yearly for the last 2 years up to 5 years follow-up is completed.</description>
    <arm_group_label>A</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Surgically removed Adenocarcinoma of the colon or rectum&#xD;
&#xD;
          -  Pathologically stage I or II disease, and radical resection&#xD;
&#xD;
          -  Detectable ctDNA in two weeks postoperative plasma sample&#xD;
&#xD;
          -  No indication for adjuvant chemotherapy according to DCCG guidelines (website)&#xD;
&#xD;
          -  Age at least 18 years&#xD;
&#xD;
          -  ECOG performance status 0-2&#xD;
&#xD;
          -  Clinically eligible for adjuvant chemotherapy at investigators decision.&#xD;
&#xD;
          -  Adequate bone marrow, liver and renal function allowing systemic chemotherapy&#xD;
             (Absolute neutrophil count ≥1.5x109/l and thrombocytes ≥ 100x109/l. Bilirubin ≤ 1.5 x&#xD;
             upper normal value and alanine aminotransferase ≤ 3 x upper normal value, and&#xD;
             Calculated or measured renal glomerular filtration rate at least 30 mL/min)&#xD;
&#xD;
          -  Anticonception for fertile women and for male patients with a fertile partner.&#xD;
             Intrauterine device, vasectomy of a female subject's male partner or hormonal&#xD;
             contraceptive are acceptable •&#xD;
&#xD;
          -  Written and verbally informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Radiological evidence of distant metastasis, by CT- chest and abdomen&#xD;
&#xD;
          -  Incapacity, frailty, disability and comorbidity to a degree that according to the&#xD;
             investigator is not compatible with combination chemotherapy&#xD;
&#xD;
          -  Previous treatment with 5FU or oxaliplatin&#xD;
&#xD;
          -  Neuropathy NCI grade &gt; 1&#xD;
&#xD;
          -  Other malignant tumor within 5 years except non-melanoma skin cancer or carcinoma in&#xD;
             situ cervicis uteri&#xD;
&#xD;
          -  Pregnant (positive pregnancy test) or breast feeding women&#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>Karen-Lise G Spindler, Professor</last_name>
    <phone>0045 7846 2535</phone>
    <phone_ext>+4578462535</phone_ext>
    <email>k.g.spindler@rm.dk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Karen-Lise G Spindler, Professor</last_name>
    <phone>+4578462535</phone>
    <phone_ext>+4578462535</phone_ext>
    <email>k.g.spindler@rm.dk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Aalborg University Hospital</name>
      <address>
        <city>Aalborg</city>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Aarhus University Hospital</name>
      <address>
        <city>Aarhus</city>
        <zip>8000</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Karen-Lise G Spindler, Prof.</last_name>
      <phone>+457846 2535</phone>
      <email>k.g.spindler@rm.dk</email>
    </contact>
    <contact_backup>
      <last_name>Line M Sparvath, CRN</last_name>
      <phone>457846 2610</phone>
      <email>linspa@rm.dk</email>
    </contact_backup>
    <investigator>
      <last_name>Søren Lauerberg, Prof.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Claus L Andersen, Prof.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Herlev Hospital</name>
      <address>
        <city>Herlev</city>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Odense University Hospital</name>
      <address>
        <city>Odense</city>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>November 19, 2018</study_first_submitted>
  <study_first_submitted_qc>November 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <last_update_submitted>February 24, 2022</last_update_submitted>
  <last_update_submitted_qc>February 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Aarhus University Hospital</investigator_affiliation>
    <investigator_full_name>Karen-Lise Garm Spindler</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Oxaliplatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03748680
org study id: KFE-1803
nct id: NCT03748680
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
A open label 1:1 randomized phase II exploratory study investigating adjuvant therapy in
      patients with molecular biologically detectable residual disease after primary resection for
      localized colorectal tumors.
The main clinical hypothesis is that patients having undergone radical resection from CRC do
      not present with detectable tumor DNA in the plasma, whereas patients with detectable tumor
      DNA two weeks' post surgery have residual microscopic disease, and consequently a high risk
      of diseases recurrence which can be prevented with adjuvant chemotherapy.

      The primary aim of the present study is to investigate - in a randomized trial - if use of
      standard adjuvant chemotherapy therapy improves the disease free survival in patients with
      molecular biological residual disease where adjuvant chemotherapy is not standard treatment .

      Secondary aims include investigating molecular biological response to adjuvant chemotherapy
      in patients with post-operative ctDNA.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A open label 1:1 randomized phase II exploratory study
primary purpose: Treatment
masking: None (Open Label)
measure: DFS
time frame: 3 years
description: Disease free survival
measure: Molecular biological response
time frame: 6 months
description: Molecular biological response at 6 months
measure: MB-DFS
time frame: 1 year
description: Molecular biological disease free survival at 1 year
measure: TT-MBR
time frame: 3 years
description: Time to molecular biological recurrence
measure: TTR
time frame: 3 years
description: Time to radiological recurrence
measure: LRR
time frame: 3 years
description: Local recurrence rate
measure: DRR
time frame: 3 years
description: Distant recurrence rate
measure: OS
time frame: 5 years
description: Overall survival
measure: TR
time frame: 3 years
description: Translational research exploratory
arm group label: A
arm group type: Active Comparator
description: Intensified follow-up schedule
arm group label: B
arm group type: Experimental
description: Adjuvant chemotherapy + intensified follow-up schedule
intervention type: Drug
intervention name: Capox (or FOLFOX) including flouropyrimidine and oxaliplatin combination chemotherapy
description: Six months of adjuvant combination chemotherapy with Capox (or FOLFOX) Patients will receive adjuvant chemotherapy with eight cycles of CAPOX (oxaliplatin 130 mg/m2 day 1 and capecitabine 1000 mg/m2 b.i.d. days 1-14, repeated every 3 weeks.
(Patients with an ileostomy are only eligible for FOLFOX and will be treated with 12 cycles of FOLFOX (oxaliplatin 85 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1 and 5FU 2400 mg/ m2 over 46-48 hours day 1-3, repeated every second weeks)
arm group label: B
intervention type: Other
intervention name: Intensified Follow-up Schedule
description: Close monitoring with Imaging during follow-up Patients included in this trial will undergo intensified follow-up with CT-chest and abdomen every four months after surgery for the first 2 years, then every 6 months for 1 years and finally once yearly for the last 2 years up to 5 years follow-up is completed.
arm group label: A
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Karen-Lise G Spindler, Professor
phone: 0045 7846 2535
phone ext: +4578462535
email: k.g.spindler@rm.dk
last name: Karen-Lise G Spindler, Professor
phone: +4578462535
phone ext: +4578462535
email: k.g.spindler@rm.dk
facility: 
status: Recruiting
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
facility: 
status: Recruiting
facility: 
status: Recruiting
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Aarhus University Hospital
investigator full name: Karen-Lise Garm Spindler
investigator title: Professor
mesh term: Colorectal Neoplasms
mesh term: Oxaliplatin
sharing ipd: No