<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/NCT04418895</url>
  </required_header>
  <id_info>
    <org_study_id>LCCC 1933</org_study_id>
    <nct_id>NCT04418895</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Therapy for Localized Rectal Adenocarcinoma</brief_title>
  <official_title>Biomarkers and Clinical Outcomes in Localized Rectal Adenocarcinoma Treated With Neoadjuvant Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UNC Lineberger Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>UNC Lineberger Comprehensive Cancer Center</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 study is a prospective, single-arm, single-center study of investigator's choice of&#xD;
      total neoadjuvant therapy (TNT) or neoadjuvant chemoradiation in locally advanced rectal&#xD;
      cancer. The standard of care for rectal adenocarcinomas that are triiodothyronine-thyroxine&#xD;
      (T3-T4) or node positive has generally been comprised of neoadjuvant chemoradiation, followed&#xD;
      by surgical resection and then adjuvant chemotherapy. More recently, TNT, comprised of&#xD;
      neoadjuvant chemotherapy and chemoradiation followed by surgical resection, has been&#xD;
      increasingly used as a standard therapy approach. While the use of TNT is increasingly&#xD;
      common, prospective study of outcomes following TNT has been limited. Moreover, there are not&#xD;
      any biomarkers known at this time that impact clinical decision-making or personalization of&#xD;
      therapy in the treatment of rectal cancer. In this study, we will collect pre-treatment&#xD;
      rectal adenocarcinoma specimens and determine clinical outcome, including pathologic complete&#xD;
      response rate, post-treatment pathologic downstaging rate, recurrence-free survival (RFS),&#xD;
      overall survival (OS) and neoadjuvant rectal score, among patients who are treated with&#xD;
      standard neoadjuvant chemoradiation or TNT, with an aim to investigate how baseline&#xD;
      biomarkers and changes in biomarkers with standard therapies may be associated with, and&#xD;
      modulate, clinical outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      At enrollment, subjects should be planned to receive either neoadjuvant chemoradiation or&#xD;
      total neoadjuvant therapy, with the choice of regimen at the discretion of treating&#xD;
      investigators. Subjects will have been staged as deemed consistent with standard of care,&#xD;
      including either a pelvic Magnetic resonance imaging (MRI) and/or an endorectal ultrasound,&#xD;
      and deemed to have either T3-T4 primary tumor or node-positive tumor.&#xD;
&#xD;
      Neoadjuvant Chemoradiation Subjects will undergo endoscopic tumor biopsy within 6 weeks of&#xD;
      the start of standard of care chemoradiation. Subjects will also have a baseline peripheral&#xD;
      blood sample collected.&#xD;
&#xD;
      Subjects will receive neoadjuvant chemoradiation per standard of care. This is typically&#xD;
      comprised of radiotherapy with concurrent capecitabine 825 mg/m2 by mouth (po) two times&#xD;
      daily (bid) (typically rounded to the nearest 500 mg dose) or infusional 5-fluorouracil&#xD;
      (5FU). However, dosing and administration are at the discretion of the treating medical and&#xD;
      radiation oncologist.&#xD;
&#xD;
      An acceptable alternative approach is short-course radiation therapy per standard of care,&#xD;
      which is typically comprised of radiotherapy, with surgery within 1 week of completion of&#xD;
      therapy or delayed for 6-8 weeks. Selection of the optimal radiation therapy approach is at&#xD;
      the discretion of the treating medical oncologist, radiation oncologist, and surgical&#xD;
      oncologist. However, generally, short-course radiation therapy is not recommended for&#xD;
      low-lying tumors less than 5 centimeters (cm) from the anal verge.&#xD;
&#xD;
      Occasionally patients with inadequate response after neoadjuvant chemoradiation may be&#xD;
      recommended to proceed with subsequent consolidative chemotherapy with 5-Fluorouracil,&#xD;
      leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) for 16-18&#xD;
      weeks before surgical resection. This treatment is at the discretion of the treating medical&#xD;
      oncologist, radiation oncologist, and surgical oncologist. These subjects will be allowed to&#xD;
      remain on study.&#xD;
&#xD;
      Surgery will occur approximately 4-8 weeks after chemoradiation or consolidative&#xD;
      chemotherapy, depending on clinical factors (i.e. resectability, presence or absence of&#xD;
      metastatic disease), although it may occur as soon as 1 week after completing short-course&#xD;
      radiation therapy. The timing of surgical resection after completion of neoadjuvant therapy&#xD;
      is at the discretion of the treating surgical oncologist. At the time of surgery, tumor&#xD;
      samples and peripheral blood samples for correlative studies will be collected.&#xD;
&#xD;
      Subjects who do not receive preoperative mFOLFOX6 or CAPOX typically receive postoperative&#xD;
      adjuvant chemotherapy with a fluoropyrimidine +/- oxaliplatin for an additional 16-18 weeks&#xD;
      of therapy, if permitted based on recovery after surgical resection and post-surgical&#xD;
      performance status. This treatment is at the discretion of the treating medical oncologist.&#xD;
      Subjects will remain on study regardless of postoperative therapy administration or duration.&#xD;
&#xD;
      Total Neoadjuvant Therapy Subjects will undergo endoscopic tumor biopsy within 6 weeks of the&#xD;
      start of standard of care treatment with chemotherapy. Subjects will also have a baseline&#xD;
      peripheral blood sample collected.&#xD;
&#xD;
      Subjects who are intended to receive total neoadjuvant therapy will typically receive&#xD;
      chemotherapy with mFOLFOX6 or CAPOX for 16-18 weeks, followed by chemoradiation. Dosing and&#xD;
      administration are at the discretion of the primary medical and radiation oncologist.&#xD;
      Alternative subsequent approaches such as short-course radiotherapy are also acceptable at&#xD;
      the discretion of the treating medical and radiation oncologist.&#xD;
&#xD;
      Surgery will occur approximately 4-8 weeks after chemoradiation depending on clinical factors&#xD;
      (i.e. resectability, presence or absence of metastatic disease), although it may occur as&#xD;
      soon as 1 week after completing short-course radiation therapy. The timing of surgical&#xD;
      resection after completion of neoadjuvant therapy is at the discretion of the treating&#xD;
      surgical oncologist. At the time of surgery, tumor samples and peripheral blood samples for&#xD;
      correlative studies will be collected.&#xD;
&#xD;
      Duration of Therapy&#xD;
&#xD;
      The duration of therapy should be defined per the subject's standard of care. Reasons to&#xD;
      discontinue treatment may include:&#xD;
&#xD;
        -  Disease progression&#xD;
&#xD;
        -  Inter-current illness that prevents further administration of treatment&#xD;
&#xD;
        -  Unacceptable adverse event(s)&#xD;
&#xD;
        -  Pregnancy&#xD;
&#xD;
        -  Subject decides to withdraw from study treatment, or&#xD;
&#xD;
        -  General or specific changes in the subject's condition render the subject unacceptable&#xD;
           for further treatment in the judgment of the investigator.&#xD;
&#xD;
        -  Subject has completed the treatment regimen&#xD;
&#xD;
        -  Subject is lost to follow up&#xD;
&#xD;
      Duration of Follow Up After surgery, subjects will be followed with routine surveillance at&#xD;
      the discretion of treating investigators. Subjects will be followed for survival and disease&#xD;
      status for at least 3 years after surgery or until death, whichever occurs first.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    lack of resources&#xD;
  </why_stopped>
  <start_date type="Actual">August 13, 2021</start_date>
  <completion_date type="Anticipated">May 2025</completion_date>
  <primary_completion_date type="Anticipated">May 2022</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>complete pathologic response (pCR) rate</measure>
    <time_frame>At time of surgery (1- 26 weeks after completion of standard of care neoadjuvant treatment)</time_frame>
    <description>Anatomic stage for rectal cancer uses the American Joint Committee on Cancer (AJCC) Tumor/Node/Metastasis (TNM) system, which is based on:Size of primary tumor (T) and whether it has grown into nearby areas. Spread to regional lymph nodes (N). Spread (metastasis; M) to other organs of the body. Once the T, N, and M categories have been determined, this information is combined into a prognostic group. Higher numbers mean the cancer is more advanced. Stage prefixes include &quot;c&quot; for clinical stage, &quot;p&quot; for pathological stage, and &quot;y&quot; to indicate that the clinical or pathologic classification has been determined after preoperative therapy&#xD;
Complete pathologic response is defined as no disease on pathology at resection (ypT0N0).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>pathologic down staging rate</measure>
    <time_frame>At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)</time_frame>
    <description>Defined as a decrease in Tumor (T) and/or Nodal (N) stage from baseline to pathologic post-treatment determination, without any increase in T, N, or M stage.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>near pathological complete response (near-pCR) rate</measure>
    <time_frame>At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)</time_frame>
    <description>Near-pCR will be defined as minimal tumor on pathology at resection (ypT0-1 N0).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>R0 resection rate</measure>
    <time_frame>At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)</time_frame>
    <description>R0 resection will be defined as resection of all appreciable disease with a margin &gt; 1 millimeter (mm) distally, proximally, and radially/circumferentially.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recurrence Free Survival (RFS) rate</measure>
    <time_frame>3 years after surgical resection</time_frame>
    <description>Defined as the time from day 1 of neoadjuvant chemotherapy until definitive local or metastatic disease recurrence or death as a result of any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) rate</measure>
    <time_frame>3 years after surgical resection</time_frame>
    <description>Defined as the time from day 1 of neoadjuvant chemotherapy until death as a result of any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Neoadjuvant Rectal Score (NAR)</measure>
    <time_frame>At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)</time_frame>
    <description>With clinical T stage (cT) comprised of 1, 2, 3, or 4; pathologic T stage (pT) comprised of 0, 1, 2, 3, or 4; and pathologic N stage (pN) comprised of 0, 1, or 2 (according to AJCC clinical rectal staging criteria)., the Neoadjuvant rectal score (NAR)will be calculated after resection as follows:&#xD;
NAR = [5 pN - 3 (cT-pT) + 12]2 / 9.61&#xD;
A higher score indicates poorer prognosis</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Rectal Adenocarcinoma</condition>
  <arm_group>
    <arm_group_label>Single Arm: Standard of Care</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Investigator's choice of total neoadjuvant therapy (TNT) comprised of neoadjuvant chemotherapy and chemoradiation followed by surgical resection; or neoadjuvant chemoradiation followed by surgical resection and then adjuvant chemotherapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Chemoradiation</intervention_name>
    <description>Subjects will receive neoadjuvant chemoradiation per standard of care. This is typically comprised of radiotherapy of 5040 cGy (centigray) with concurrent capecitabine 825 mg/m2 by mouth (po) two times daily (bid) (typically rounded to the nearest 500 mg dose) or infusional 5-fluorouracil (5FU). However, dosing and administration are at the discretion of the treating medical and radiation oncologist.</description>
    <arm_group_label>Single Arm: Standard of Care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>short course radiation therapy</intervention_name>
    <description>An acceptable alternative approach is short-course radiation therapy per standard of care, which is typically comprised of radiotherapy of 25 Gy (gray) in 5 fractions, with surgery within 1 week of completion of therapy or delayed for 6-8 weeks. Selection of the optimal radiation therapy approach is at the discretion of the treating medical oncologist, radiation oncologist, and surgical oncologist. However, generally, short-course radiation therapy is not recommended for low-lying tumors less than 5 centimeters (cm) from the anal verge.</description>
    <arm_group_label>Single Arm: Standard of Care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mFOLFOX6</intervention_name>
    <description>possible consolidative neo-adjuvant chemotherapy. This treatment is at the discretion of the treating medical oncologist, radiation oncologist, and surgical oncologist.</description>
    <arm_group_label>Single Arm: Standard of Care</arm_group_label>
    <other_name>leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CAPOX</intervention_name>
    <description>possible consolidative neo-adjuvant chemotherapy. This treatment is at the discretion of the treating medical oncologist, radiation oncologist, and surgical oncologist.</description>
    <arm_group_label>Single Arm: Standard of Care</arm_group_label>
    <other_name>Capecitabine, Oxaliplatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>fluoropyrimidine +/- oxaliplatin</intervention_name>
    <description>possible adjuvant chemotherapy regimen. Subjects who do not receive preoperative mFOLFOX6 or CAPOX typically receive postoperative adjuvant chemotherapy with a fluoropyrimidine +/- oxaliplatin for an additional 16-18 weeks of therapy, if permitted based on recovery after surgical resection and post-surgical performance status. This treatment is at the discretion of the treating medical oncologist. Subjects will remain on study regardless of postoperative therapy administration or duration.</description>
    <arm_group_label>Single Arm: Standard of Care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent obtained to participate in the study and HIPAA authorization&#xD;
             for release of personal health information.&#xD;
&#xD;
          -  Age ≥ 18 years at the time of consent.&#xD;
&#xD;
          -  ECOG (Eastern Cooperative Oncology Group) Performance Status of 0-2 (See Appendix A.&#xD;
             ECOG Performance Status Scale).&#xD;
&#xD;
          -  Histological or cytological confirmation of rectal adenocarcinoma.&#xD;
&#xD;
          -  Planned to receive treatment with neoadjuvant therapy, comprised of either 1)&#xD;
             chemoradiation with concurrent fluoropyrimidine or short-course radiotherapy, or 2)&#xD;
             total neoadjuvant therapy with fluoropyrimidine +oxaliplatin followed by&#xD;
             chemoradiation or short-course radiotherapy. Rectal adenocarcinoma patients deemed&#xD;
             candidates for neoadjuvant therapy include:&#xD;
&#xD;
               1. Tumor staged as T3-4 or node-positive by pelvic MRI or endorectal ultrasound, or&#xD;
                  node-positive by CT scan; OR&#xD;
&#xD;
               2. Tumor fixed to extra colonic structures as determined by digital rectal&#xD;
                  examination; OR&#xD;
&#xD;
               3. Tumor &lt; 5 cm from sphincter mechanism.&#xD;
&#xD;
          -  Willing and able to undergo baseline rectal tumor biopsy, and willing and able to&#xD;
             donate blood for research purposes.&#xD;
&#xD;
          -  Females of childbearing potential must be willing to abstain from heterosexual&#xD;
             activity or to use 2 forms of effective methods of contraception from the time of&#xD;
             informed consent until 12 weeks after treatment discontinuation. The two contraception&#xD;
             methods can be comprised of two barrier methods, or a barrier method plus a hormonal&#xD;
             method or an intrauterine device that meets &lt;1% failure rate for protection from&#xD;
             pregnancy in the product label.&#xD;
&#xD;
          -  Male subjects with female partners must have had a prior vasectomy or agree to use an&#xD;
             adequate method of contraception (i.e., double barrier method: condom plus spermicidal&#xD;
             agent) starting with the first dose of study therapy through 12 weeks after the last&#xD;
             dose of study therapy.&#xD;
&#xD;
          -  Subjects are willing and able to comply with study procedures based on the judgement&#xD;
             of the investigator or protocol designee.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with colon carcinomas that are too proximal to receive neoadjuvant therapy&#xD;
             per routine clinical practice (i.e. with primary tumor proximal to or at the sigmoid&#xD;
             colon).&#xD;
&#xD;
          -  Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the&#xD;
             mother is being treated on study).&#xD;
&#xD;
          -  Has a known additional malignancy that is active and/or progressive and is requiring&#xD;
             treatment; exceptions include basal cell or squamous cell skin cancer, in situ&#xD;
             cervical or bladder cancer, or other cancer for which the subject Is not currently&#xD;
             receiving anti-cancer therapy such as chemotherapy, radiation therapy, targeted&#xD;
             therapy, immunotherapy, or hormonal therapy.&#xD;
&#xD;
          -  Patients who are not candidates at the discretion of their treating physicians to&#xD;
             receive neoadjuvant chemoradiation or total neoadjuvant therapy (e.g. poor performance&#xD;
             status, significant comorbidities, clinically significant organ dysfunction).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael S Lee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UNC Lineberger Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599-7295</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://unclineberger.org/patientcare/clinical-trials/clinical-trials</url>
    <description>University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials</description>
  </link>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>June 2, 2020</study_first_submitted>
  <study_first_submitted_qc>June 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>November 2, 2021</last_update_submitted>
  <last_update_submitted_qc>November 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 10, 2021</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>Adenocarcinoma</mesh_term>
    <mesh_term>Rectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Levoleucovorin</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/NCT04418895
org study id: LCCC 1933
nct id: NCT04418895
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study is a prospective, single-arm, single-center study of investigator's choice of
      total neoadjuvant therapy (TNT) or neoadjuvant chemoradiation in locally advanced rectal
      cancer. The standard of care for rectal adenocarcinomas that are triiodothyronine-thyroxine
      (T3-T4) or node positive has generally been comprised of neoadjuvant chemoradiation, followed
      by surgical resection and then adjuvant chemotherapy. More recently, TNT, comprised of
      neoadjuvant chemotherapy and chemoradiation followed by surgical resection, has been
      increasingly used as a standard therapy approach. While the use of TNT is increasingly
      common, prospective study of outcomes following TNT has been limited. Moreover, there are not
      any biomarkers known at this time that impact clinical decision-making or personalization of
      therapy in the treatment of rectal cancer. In this study, we will collect pre-treatment
      rectal adenocarcinoma specimens and determine clinical outcome, including pathologic complete
      response rate, post-treatment pathologic downstaging rate, recurrence-free survival (RFS),
      overall survival (OS) and neoadjuvant rectal score, among patients who are treated with
      standard neoadjuvant chemoradiation or TNT, with an aim to investigate how baseline
      biomarkers and changes in biomarkers with standard therapies may be associated with, and
      modulate, clinical outcomes.
At enrollment, subjects should be planned to receive either neoadjuvant chemoradiation or
      total neoadjuvant therapy, with the choice of regimen at the discretion of treating
      investigators. Subjects will have been staged as deemed consistent with standard of care,
      including either a pelvic Magnetic resonance imaging (MRI) and/or an endorectal ultrasound,
      and deemed to have either T3-T4 primary tumor or node-positive tumor.

      Neoadjuvant Chemoradiation Subjects will undergo endoscopic tumor biopsy within 6 weeks of
      the start of standard of care chemoradiation. Subjects will also have a baseline peripheral
      blood sample collected.

      Subjects will receive neoadjuvant chemoradiation per standard of care. This is typically
      comprised of radiotherapy with concurrent capecitabine 825 mg/m2 by mouth (po) two times
      daily (bid) (typically rounded to the nearest 500 mg dose) or infusional 5-fluorouracil
      (5FU). However, dosing and administration are at the discretion of the treating medical and
      radiation oncologist.

      An acceptable alternative approach is short-course radiation therapy per standard of care,
      which is typically comprised of radiotherapy, with surgery within 1 week of completion of
      therapy or delayed for 6-8 weeks. Selection of the optimal radiation therapy approach is at
      the discretion of the treating medical oncologist, radiation oncologist, and surgical
      oncologist. However, generally, short-course radiation therapy is not recommended for
      low-lying tumors less than 5 centimeters (cm) from the anal verge.

      Occasionally patients with inadequate response after neoadjuvant chemoradiation may be
      recommended to proceed with subsequent consolidative chemotherapy with 5-Fluorouracil,
      leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) for 16-18
      weeks before surgical resection. This treatment is at the discretion of the treating medical
      oncologist, radiation oncologist, and surgical oncologist. These subjects will be allowed to
      remain on study.

      Surgery will occur approximately 4-8 weeks after chemoradiation or consolidative
      chemotherapy, depending on clinical factors (i.e. resectability, presence or absence of
      metastatic disease), although it may occur as soon as 1 week after completing short-course
      radiation therapy. The timing of surgical resection after completion of neoadjuvant therapy
      is at the discretion of the treating surgical oncologist. At the time of surgery, tumor
      samples and peripheral blood samples for correlative studies will be collected.

      Subjects who do not receive preoperative mFOLFOX6 or CAPOX typically receive postoperative
      adjuvant chemotherapy with a fluoropyrimidine +/- oxaliplatin for an additional 16-18 weeks
      of therapy, if permitted based on recovery after surgical resection and post-surgical
      performance status. This treatment is at the discretion of the treating medical oncologist.
      Subjects will remain on study regardless of postoperative therapy administration or duration.

      Total Neoadjuvant Therapy Subjects will undergo endoscopic tumor biopsy within 6 weeks of the
      start of standard of care treatment with chemotherapy. Subjects will also have a baseline
      peripheral blood sample collected.

      Subjects who are intended to receive total neoadjuvant therapy will typically receive
      chemotherapy with mFOLFOX6 or CAPOX for 16-18 weeks, followed by chemoradiation. Dosing and
      administration are at the discretion of the primary medical and radiation oncologist.
      Alternative subsequent approaches such as short-course radiotherapy are also acceptable at
      the discretion of the treating medical and radiation oncologist.

      Surgery will occur approximately 4-8 weeks after chemoradiation depending on clinical factors
      (i.e. resectability, presence or absence of metastatic disease), although it may occur as
      soon as 1 week after completing short-course radiation therapy. The timing of surgical
      resection after completion of neoadjuvant therapy is at the discretion of the treating
      surgical oncologist. At the time of surgery, tumor samples and peripheral blood samples for
      correlative studies will be collected.

      Duration of Therapy

      The duration of therapy should be defined per the subject's standard of care. Reasons to
      discontinue treatment may include:

        -  Disease progression

        -  Inter-current illness that prevents further administration of treatment

        -  Unacceptable adverse event(s)

        -  Pregnancy

        -  Subject decides to withdraw from study treatment, or

        -  General or specific changes in the subject's condition render the subject unacceptable
           for further treatment in the judgment of the investigator.

        -  Subject has completed the treatment regimen

        -  Subject is lost to follow up

      Duration of Follow Up After surgery, subjects will be followed with routine surveillance at
      the discretion of treating investigators. Subjects will be followed for survival and disease
      status for at least 3 years after surgery or until death, whichever occurs first.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: complete pathologic response (pCR) rate
time frame: At time of surgery (1- 26 weeks after completion of standard of care neoadjuvant treatment)
description: Anatomic stage for rectal cancer uses the American Joint Committee on Cancer (AJCC) Tumor/Node/Metastasis (TNM) system, which is based on:Size of primary tumor (T) and whether it has grown into nearby areas. Spread to regional lymph nodes (N). Spread (metastasis; M) to other organs of the body. Once the T, N, and M categories have been determined, this information is combined into a prognostic group. Higher numbers mean the cancer is more advanced. Stage prefixes include "c" for clinical stage, "p" for pathological stage, and "y" to indicate that the clinical or pathologic classification has been determined after preoperative therapy
Complete pathologic response is defined as no disease on pathology at resection (ypT0N0).
measure: pathologic down staging rate
time frame: At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)
description: Defined as a decrease in Tumor (T) and/or Nodal (N) stage from baseline to pathologic post-treatment determination, without any increase in T, N, or M stage.
measure: near pathological complete response (near-pCR) rate
time frame: At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)
description: Near-pCR will be defined as minimal tumor on pathology at resection (ypT0-1 N0).
measure: R0 resection rate
time frame: At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)
description: R0 resection will be defined as resection of all appreciable disease with a margin > 1 millimeter (mm) distally, proximally, and radially/circumferentially.
measure: Recurrence Free Survival (RFS) rate
time frame: 3 years after surgical resection
description: Defined as the time from day 1 of neoadjuvant chemotherapy until definitive local or metastatic disease recurrence or death as a result of any cause.
measure: Overall Survival (OS) rate
time frame: 3 years after surgical resection
description: Defined as the time from day 1 of neoadjuvant chemotherapy until death as a result of any cause.
measure: Median Neoadjuvant Rectal Score (NAR)
time frame: At time of surgery (1-26 weeks after completion of standard of care neoadjuvant treatment)
description: With clinical T stage (cT) comprised of 1, 2, 3, or 4; pathologic T stage (pT) comprised of 0, 1, 2, 3, or 4; and pathologic N stage (pN) comprised of 0, 1, or 2 (according to AJCC clinical rectal staging criteria)., the Neoadjuvant rectal score (NAR)will be calculated after resection as follows:
NAR = [5 pN - 3 (cT-pT) + 12]2 / 9.61
A higher score indicates poorer prognosis
arm group label: Single Arm: Standard of Care
arm group type: Experimental
description: Investigator's choice of total neoadjuvant therapy (TNT) comprised of neoadjuvant chemotherapy and chemoradiation followed by surgical resection; or neoadjuvant chemoradiation followed by surgical resection and then adjuvant chemotherapy.
intervention type: Other
intervention name: Chemoradiation
description: Subjects will receive neoadjuvant chemoradiation per standard of care. This is typically comprised of radiotherapy of 5040 cGy (centigray) with concurrent capecitabine 825 mg/m2 by mouth (po) two times daily (bid) (typically rounded to the nearest 500 mg dose) or infusional 5-fluorouracil (5FU). However, dosing and administration are at the discretion of the treating medical and radiation oncologist.
arm group label: Single Arm: Standard of Care
intervention type: Radiation
intervention name: short course radiation therapy
description: An acceptable alternative approach is short-course radiation therapy per standard of care, which is typically comprised of radiotherapy of 25 Gy (gray) in 5 fractions, with surgery within 1 week of completion of therapy or delayed for 6-8 weeks. Selection of the optimal radiation therapy approach is at the discretion of the treating medical oncologist, radiation oncologist, and surgical oncologist. However, generally, short-course radiation therapy is not recommended for low-lying tumors less than 5 centimeters (cm) from the anal verge.
arm group label: Single Arm: Standard of Care
intervention type: Drug
intervention name: mFOLFOX6
description: possible consolidative neo-adjuvant chemotherapy. This treatment is at the discretion of the treating medical oncologist, radiation oncologist, and surgical oncologist.
arm group label: Single Arm: Standard of Care
other name: leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin
intervention type: Drug
intervention name: CAPOX
description: possible consolidative neo-adjuvant chemotherapy. This treatment is at the discretion of the treating medical oncologist, radiation oncologist, and surgical oncologist.
arm group label: Single Arm: Standard of Care
other name: Capecitabine, Oxaliplatin
intervention type: Drug
intervention name: fluoropyrimidine +/- oxaliplatin
description: possible adjuvant chemotherapy regimen. Subjects who do not receive preoperative mFOLFOX6 or CAPOX typically receive postoperative adjuvant chemotherapy with a fluoropyrimidine +/- oxaliplatin for an additional 16-18 weeks of therapy, if permitted based on recovery after surgical resection and post-surgical performance status. This treatment is at the discretion of the treating medical oncologist. Subjects will remain on study regardless of postoperative therapy administration or duration.
arm group label: Single Arm: Standard of Care
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Michael S Lee, MD
role: Principal Investigator
affiliation: UNC Lineberger Comprehensive Cancer Center
facility: 
country: United States
url: http://unclineberger.org/patientcare/clinical-trials/clinical-trials
description: University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Rectal Neoplasms
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Capecitabine
mesh term: Oxaliplatin
mesh term: Levoleucovorin
sharing ipd: No