<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/NCT03803553</url>
  </required_header>
  <id_info>
    <org_study_id>18-397</org_study_id>
    <nct_id>NCT03803553</nct_id>
  </id_info>
  <brief_title>Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer</brief_title>
  <official_title>Early Identification and Treatment of Occult Metastatic Disease in Stage III Colon Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Stand Up To Cancer</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</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 research study is comparing two standard of care treatment options based on blood test&#xD;
      results for participants who have metastatic colorectal cancer.&#xD;
&#xD;
      The names of the potential treatments involved in this study are:&#xD;
&#xD;
        -  Active surveillance&#xD;
&#xD;
        -  FOLFIRI treatment&#xD;
&#xD;
        -  Nivolumab treatment&#xD;
&#xD;
        -  Encorafenib/Binimetinib/Cetuximab treatment&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The FDA (the U.S. Food and Drug Administration) has approved FOLFIRI, comprised of&#xD;
      Irinotecan, Leucovorin, and 5-Fluorouracil, as a treatment option for metastatic colorectal&#xD;
      cancer in the Stage IV setting.&#xD;
&#xD;
        -  After diagnosis and surgical removal of tumors, individuals with metastatic colorectal&#xD;
           cancer commonly receive what is called adjuvant chemotherapy treatment, commonly&#xD;
           utilizing treatment plans called FOLFOX, CAPOX, or therapy with 5-Fluorouracil.&#xD;
&#xD;
        -  If all the cancer is not killed, the investigators may be able to detect tumor in the&#xD;
           blood called circulating tumor DNA (ctDNA). This is genetic material unique to&#xD;
           metastatic colorectal cancer that may be present in the blood stream, and it can be&#xD;
           identified through a ctDNA blood test. If ctDNA is present in the blood stream, it is&#xD;
           commonly called micro-metastatic disease (meaning disease that can't be seen detected by&#xD;
           CT scans but may be there in the blood). Cancer researchers believe that ctDNA in the&#xD;
           blood stream may be an indicator that cancer is more likely to recur.&#xD;
&#xD;
        -  After initial adjuvant chemotherapy, it is standard for individuals to begin active&#xD;
           surveillance, where they do not receive further treatment but instead undergo frequent&#xD;
           tumor imaging scans to see if their cancer is stable, growing, or coming back. The&#xD;
           investigators plan to see if additional therapy, where FOLFIRI (comprised of Irinotecan,&#xD;
           Leucovorin, and 5-Fluorouracil) is administered can decrease recurrence. Typically,&#xD;
           FOLFIRI is given when the disease is visibly recurrent.&#xD;
&#xD;
             -  In addition, the investigators plan to include study groups of adjuvant nivolumab&#xD;
                treatment and adjuvant Encorafenib/Binimetinib/Cetuximab treatment to see if these&#xD;
                treatments can decrease recurrence. The FDA has not approved either of these as a&#xD;
                treatment options for metastatic colorectal cancer in the Stage IV setting.&#xD;
&#xD;
             -  Patients who have a greater than normal number of genetic markers called&#xD;
                microsatellites are called MSI-H. Because tumor cells with these features tend to&#xD;
                have more genetic mutations than tumor cells without them, they are more likely to&#xD;
                be recognized by the immune system. Nivolumab is an anti-PD-1 antibody. It works by&#xD;
                attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present&#xD;
                on different types of cells in your immune system and controls parts of your immune&#xD;
                system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1&#xD;
                from shutting down the immune system, thus potentially allowing immune cells to&#xD;
                recognize and destroy cancer cells.&#xD;
&#xD;
             -  Encorafenib in combination with binimetinib and cetuximab is one of the first&#xD;
                effective regimens to target the BRAF V600E-mutation in colorectal cancer. When&#xD;
                this mutation is present, it switches on pathway called the MAPK pathway which&#xD;
                stimulates cell division and leads to uncontrolled cell growth. Encorafenib,&#xD;
                binimetinib and cetuximab target different parts of this important signaling&#xD;
                pathway in tumor cells with this mutation and slows down their growth and&#xD;
                communication&#xD;
&#xD;
      However, in this research study, the investigators are&#xD;
&#xD;
        -  determining whether there are differences in cancer recurrence in ctDNA positive&#xD;
           participants treated with additional therapy versus put on active surveillance.&#xD;
&#xD;
        -  determining whether there are differences in health in ctDNA positive participants&#xD;
           treated with additional therapy versus put on active surveillance.&#xD;
&#xD;
        -  examining whether patients who undergo further therapy experience changes in the ctDNA&#xD;
           levels.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 16, 2020</start_date>
  <completion_date type="Anticipated">April 2026</completion_date>
  <primary_completion_date type="Anticipated">April 2025</primary_completion_date>
  <phase>Phase 3</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease-free survival (DFS)</measure>
    <time_frame>5 years</time_frame>
    <description>Disease-free survival (DFS) between ctDNA-positive patients treated with additional treatment of FOLFIRI and ctDNA-positive patients who are untreated</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clearance rate of ctDNA</measure>
    <time_frame>7 Months</time_frame>
    <description>Compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional treatment of FOLFIRI and those who are untreated</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) Rate</measure>
    <time_frame>5 years</time_frame>
    <description>Overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy (Arm 1) and ctDNA-positive patients who are untreated (Arm 2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clearance rate of ctDNA of Arm 4: Nivolumab Treatment</measure>
    <time_frame>13 months</time_frame>
    <description>Determine clearance rate of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-free survival (DFS) of Arm 4: Nivolumab Treatment</measure>
    <time_frame>5 years</time_frame>
    <description>Determine the disease-free survival (DFS) of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clearance rate of ctDNA of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment</measure>
    <time_frame>7 months</time_frame>
    <description>Determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-free survival (DFS) of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment</measure>
    <time_frame>5 years</time_frame>
    <description>Determine the disease-free survival DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ctDNA clearance as Marker</measure>
    <time_frame>13 Months</time_frame>
    <description>Examine the correlation of ctDNA clearance as a surrogate marker for disease burden</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lead time to recurrence</measure>
    <time_frame>5 years</time_frame>
    <description>Compare lead time to recurrence and sensitivity of predicting recurrence between ctDNA and tumor markers</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">500</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <condition>Stage III Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>ctDNA-POSITIVE: FOLFIRI Protocol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance&#xD;
- ctDNA-POSITIVE: FOLFIRI Protocol&#xD;
FOLFIRI chemotherapy via intravenous infusion on days 1-3 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).&#xD;
infusions will consist of the drugs&#xD;
5-Fluorouracil&#xD;
Irinotecan&#xD;
Leucovorin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ctDNA-POSITIVE: ACTIVE SURVEILLANCE</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance&#xD;
-- Active surveillance.&#xD;
Observation and monitoring with imaging (every 3 months), tumor markers, and ctDNA draws every 1 month for the initial 6 months.&#xD;
After 6 months, followed with ctDNA, tumor markers, and scans every 3 months for the first 3 years and every 6 months thereafter.&#xD;
Additional scans and tumor markers will be at the discretion of the clinician. .</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ctDNA-NEGATIVE: ACTIVE SURVEILLANCE</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance&#xD;
- Observation and monitoring with imaging, tumor markers, and ctDNA collections every 3 months for the first 3 years and every 6 months thereafter.&#xD;
Additional scans and tumor markers will be at the discretion of the clinician</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ctDNA-POSITIVE MSI-H: NIVOLUMAB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.&#xD;
If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and MSI-H, the participant will not be randomized and will be placed into the group: ctDNA positive, MSI-H: Nivolumab&#xD;
-ctDNA-Positive, MSI-H: Nivolumab Protocol&#xD;
Nivolumab treatment via intravenous infusion on day 1 of each cycle. Cycle is 28 days long. This will occur for up to 12 cycles (48 weeks).&#xD;
infusions will consist of the drug Nivolumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ctDNA-POSITIVE BRAF Mutant: ENCORAFENIB/BINIMETINIB/CETUXIMAB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.&#xD;
If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and has a BRAF mutation, the participant will not be randomized and will be placed into the group: ctDNA positive, BRAF mutant: Encorafenib/Binimetinib/Cetuximab&#xD;
-ctDNA-Positive, MSI-H: Encorafenib/Binimetinib/Cetuximab Protocol&#xD;
Encorafenib/Binimetinib treatment is received orally every day and Cetuximab via intravenous infusion on day 1 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).&#xD;
infusions will consist of the drug Cetuximab</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>FOLFIRI Protocol</intervention_name>
    <description>FOLFIRI cycle will be two weeks (14 days) long, with FOLFIRI administered on Days 1-3. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of FOLFIRI chemotherapy.</description>
    <arm_group_label>ctDNA-POSITIVE: FOLFIRI Protocol</arm_group_label>
    <other_name>FOLinic acid-Fluorouracil-IRInotecan regimen</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>ACTIVE SURVEILLANCE</intervention_name>
    <description>Will be followed with observation and monitoring with imaging, tumor markers, and ctDNA collections</description>
    <arm_group_label>ctDNA-NEGATIVE: ACTIVE SURVEILLANCE</arm_group_label>
    <arm_group_label>ctDNA-POSITIVE: ACTIVE SURVEILLANCE</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab Protocol</intervention_name>
    <description>Nivolumab cycle will be four weeks (28 days) long, with Nivolumab administered on day 1. Participants will receive up to 12 four-week cycles (for a total of 48 weeks) of Nivolumab treatment.</description>
    <arm_group_label>ctDNA-POSITIVE MSI-H: NIVOLUMAB</arm_group_label>
    <other_name>Nivolumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Encorafenib/Binimetinib/Cetuximab Protocol</intervention_name>
    <description>Encorafenib/Binimetinib will be taken orally every day and Cetuximab will be administered intravenously on day 1 of each cycle. Cycles are 14 days long. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of Encorafenib/Binimetinib/Cetuximab.</description>
    <arm_group_label>ctDNA-POSITIVE BRAF Mutant: ENCORAFENIB/BINIMETINIB/CETUXIMAB</arm_group_label>
    <other_name>Enco/Bini/Cetux</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must have histologically confirmed resected Stage III adenocarcinoma of&#xD;
             colorectal. Any T [Tx, T1, T2, T3, or T4-], N1-2MO; including NC.&#xD;
&#xD;
          -  Patient must have completed resected disease. In patients with tumor adherent to&#xD;
             adjacent structures, en block RO resection must be documented.&#xD;
&#xD;
          -  Entire tumor must be in the colon (rectal involvement is excluded).&#xD;
&#xD;
          -  Patients must have completed standard adjuvant chemotherapy per the discretion of the&#xD;
             treating physician. Standard therapy includes FOLFOX, CAPOX, or therapy with 5FU&#xD;
             analog alone will be permitted if it constitutes appropriate standard therapy in the&#xD;
             opinion of the treating physician.&#xD;
&#xD;
          -  Patients must not have received prior neoadjuvant chemotherapy.&#xD;
&#xD;
          -  Age ≥18 years.&#xD;
&#xD;
          -  ECOG performance status ≤1.&#xD;
&#xD;
          -  Life expectancy of greater than 3 months.&#xD;
&#xD;
          -  Participants must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  leukocytes ≥3,000/mcL&#xD;
&#xD;
               -  absolute neutrophil count ≥1,500/mcL&#xD;
&#xD;
               -  platelets ≥100,000/ mcL&#xD;
&#xD;
               -  total bilirubin within normal institutional limits&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) ≤3 (AST) or ≤ 3 (ALT) × institutional upper limit of normal&#xD;
&#xD;
               -  creatinine within normal institutional limits OR&#xD;
&#xD;
               -  creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels&#xD;
                  above institutional normal by Cockroft-Gault formula.&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             (minimum sensitivity 25 IU/L or equivalent units of HCG).&#xD;
&#xD;
          -  The effects on the developing human fetus are unknown. For this reason and because&#xD;
             5FU, Capecitabine, Oxaliplatin, Irinotecan, Leucovorin, Nivolumab, and cetuximab are&#xD;
             known to be teratogenic, females of child-bearing potential (FOCBP) and males must be&#xD;
             willing to abstain from heterosexual activity or use 2 forms of effective&#xD;
             contraception (fail rate of less than 1% per year, hormonal or barrier method of birth&#xD;
             control) from time of informed consent until 5 months (FOCBP) and 7 months (males)&#xD;
             after the last dose of study treatment. Should a woman become pregnant or suspect she&#xD;
             is pregnant while she or her partner is participating in this study, she should inform&#xD;
             her treating physician immediately. Women who are not of childbearing potential, ie,&#xD;
             who are postmenopausal or surgically sterile as well as azoospermic men, do not&#xD;
             require contraception.&#xD;
&#xD;
          -  Patient must have documentation of mismatch repair deficiency (dMMR). Abnormal&#xD;
             immunohistochemistry (IHC) staining for dMMR (MMR protein expression (MLH1, MSH2,&#xD;
             MSH6, PMS2) where loss of one or more protein indicated dMMR) is acceptable as is MSI&#xD;
             assessment via PCR. This may be done locally per local standards.&#xD;
&#xD;
          -  Patient's circulating tumor DNA (ctDNA) assay (LUNAR-Guardant Health) must satisfy&#xD;
             assay specific quality control metrics to generate a result.&#xD;
&#xD;
          -  In order to be eligible for the ctDNA positive cohort, patient must be ctDNA positive&#xD;
             following adjuvant therapy using the CLIA certified Guardant Health LUNAR assay. ctDNA&#xD;
             positive will be defined as positive based on having a tumor derived signal in the&#xD;
             cfDNA that passes calling threshold (&quot;ctDNA detected&quot;).&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are receiving additional investigational therapy or on another&#xD;
             investigational protocol&#xD;
&#xD;
          -  Patients who have confirmed metastatic disease per CT.&#xD;
&#xD;
          -  Patients who are unable to get any standard adjuvant therapy&#xD;
&#xD;
          -  Patient who have received more than 3-6 months of standard adjuvant therapy at the&#xD;
             time of study entry&#xD;
&#xD;
          -  Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic&#xD;
             biologic therapy (e.g., cetuximab, bevacizumab etc.), within 30 days prior to start of&#xD;
             study treatment.&#xD;
&#xD;
          -  Patients who are MSI-high or have a BRAF V600E mutation are excluded from Arm 1&#xD;
             (FOLFIRI) and Arm 2 (Active Surveillance).&#xD;
&#xD;
          -  Patients with a BRAFV600E mutation and who are MSI-high are excluded from Arm 5&#xD;
             (ENCO/BINI/CETUX).&#xD;
&#xD;
          -  Has uncontrolled intercurrent 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;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 6 months for woman and 6 months for men, after the last dose of trial&#xD;
             treatment.&#xD;
&#xD;
          -  Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer.&#xD;
&#xD;
          -  Has an active infection requiring systemic therapy.&#xD;
&#xD;
        Nivolumab Specific Inclusion Criteria for MSI-H Cohort:&#xD;
&#xD;
          -  Must have documentation of microsatellite instability status. Both PCR based&#xD;
             assessment and Immunohistochemistry (IHC) are acceptable. Presence of deficient (d)&#xD;
             DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1,&#xD;
             MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done&#xD;
             locally.&#xD;
&#xD;
          -  Patients must have detectable ctDNA (Guardant Health LUNAR assay) post standard&#xD;
             adjuvant therapy in order to be in this cohort.&#xD;
&#xD;
        Nivolumab Specific Exclusion Criteria for MSI-H Cohort:&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any&#xD;
             other forms of immunosuppressive therapy within 7 days prior to the first dose of&#xD;
             nivolumab treatment. Subject requiring systemic steroids are excluded from the trial.&#xD;
             The use of physiologic doses of corticosteroids may be approved after discussion with&#xD;
             the sponsor.&#xD;
&#xD;
          -  Has a known history of active TB (Bacillus tuberculosis)&#xD;
&#xD;
          -  Hypersensitivity to nivolumab or any of is excipients&#xD;
&#xD;
          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study&#xD;
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events&#xD;
             due to agents administered more than 4 weeks earlier.&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment.&#xD;
&#xD;
          -  Patients that require supplemental oxygen are excluded.&#xD;
&#xD;
          -  Patients who are known HIV+ positive are eligible if their CD4+ count is ≥ 350/μL for&#xD;
             at least 3 months and they have an undetectable viral load. In addition, patient must&#xD;
             be currently receiving Highly Active Antiretroviral Therapy (HAART) and have been on&#xD;
             therapy for at least 3 months prior to study entry, under the care of an Infectious&#xD;
             Diseases specialist. Patients should have no history of an AIDS-defining opportunistic&#xD;
             infection.&#xD;
&#xD;
          -  Patients known hepatitis B and hepatitis C must be under the care of viral hepatitis&#xD;
             expert consultant. Patients with hepatitis B are required to be treated with anti-HBV&#xD;
             treatment (e.g., entecavir) and have an HBV viral load &lt;100 IU/mL. Patients with&#xD;
             hepatitis C need to have received prior and/or ongoing hepatitis C treatment.&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy. Note:&#xD;
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and&#xD;
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live&#xD;
             attenuated vaccines, and are not allowed.&#xD;
&#xD;
        Encorafenib, binimetinib, and cetuximab Specific Inclusion Criteria for BRAF mutant Cohort&#xD;
&#xD;
          -  Presence of BRAFV600E in tumor tissue previously determined by IMPACT at any time&#xD;
             prior to Screening.&#xD;
&#xD;
          -  Patients must have detectable ctDNA (Guardant Health LUNAR assay) post standard&#xD;
             adjuvant therapy in order to be in this cohort.&#xD;
&#xD;
          -  Participants must have normal organ, marrow, and hematologic function as defined&#xD;
             below:&#xD;
&#xD;
               -  Hemoglobin ≥9 g/dL (5.58 mmol/L)&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 (25.65 μmol/L)&#xD;
&#xD;
               -  Platelets ≥100,000/μL&#xD;
&#xD;
        Encorafenib, binimetinib, and cetuximab Specific Exclusion Criteria for BRAF V600E mutant&#xD;
        Cohort:&#xD;
&#xD;
          -  Patients with a BRAFV600E mutation and who are MSI-H are excluded from Arm 5&#xD;
             (ENCO/BINI/CETUX)&#xD;
&#xD;
          -  Prior therapy with a BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib)&#xD;
             and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).&#xD;
&#xD;
          -  Known hypersensitivity or contraindication to any component of binimetinib or&#xD;
             encorafenib or their excipients.&#xD;
&#xD;
          -  The patient has a history of allergic reactions attributed to compounds of chemical or&#xD;
             biologic composition similar to those of cetuximab, or has red meat allergy or tick&#xD;
             bit history.&#xD;
&#xD;
          -  Inability to swallow and retain study drug.&#xD;
&#xD;
          -  Participants who have undergone major surgery (e.g., in-patient procedures) ≤ 6 weeks&#xD;
             prior to start of study treatment or who have not recovered from side effects of such&#xD;
             procedure.&#xD;
&#xD;
          -  Participants who have had radiotherapy ≤ 14 days prior to start of study treatment or&#xD;
             who have not recovered from side effects of such procedure. Note: Palliative radiation&#xD;
             therapy must be complete 7 days prior to the first dose of study treatment.&#xD;
&#xD;
          -  Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before&#xD;
             starting study treatment.&#xD;
&#xD;
        Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as&#xD;
        neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and&#xD;
        may enroll.&#xD;
&#xD;
          -  Impaired cardiovascular function or clinically significant cardiovascular disease&#xD;
             including, but not limited to, any of the following:&#xD;
&#xD;
               -  History of acute coronary syndromes (including myocardial infarction, unstable&#xD;
                  angina, coronary artery bypass grafting, coronary angioplasty or stenting) &lt; 6&#xD;
                  months prior to Screening;&#xD;
&#xD;
               -  Congestive heart failure requiring treatment (New York Heart Association Grade ≥&#xD;
                  2);&#xD;
&#xD;
               -  Left ventricular ejection fraction (LVEF) &lt; 50% as determined by MUGA or ECHO;&#xD;
&#xD;
               -  Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150&#xD;
                  mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy;&#xD;
&#xD;
               -  History or presence of clinically significant cardiac arrhythmias (including&#xD;
                  resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal&#xD;
                  supraventricular tachycardia);&#xD;
&#xD;
               -  Triplicate average baseline QTc interval ≥ 480 ms.&#xD;
&#xD;
          -  Impairment of gastrointestinal function or disease which may significantly alter the&#xD;
             absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or&#xD;
             diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal&#xD;
             absorption), or recent (≤ 3 months) history of a partial or complete bowel&#xD;
             obstruction, or other conditions that will interfere significantly with the absorption&#xD;
             of oral drugs.&#xD;
&#xD;
          -  Known history of acute or chronic pancreatitis.&#xD;
&#xD;
          -  Concurrent neuromuscular disorder that is associated with elevated CK (e.g.,&#xD;
             inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal&#xD;
             muscular atrophy).&#xD;
&#xD;
          -  History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled&#xD;
             glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability&#xD;
             syndromes); history of retinal degenerative disease.&#xD;
&#xD;
          -  Current use of a prohibited medication (including herbal medications, supplements, or&#xD;
             foods), as described in Section 5.5, or use of a prohibited medication ≤ 1 week prior&#xD;
             to the start of study treatment.&#xD;
&#xD;
          -  History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first dose&#xD;
             of study treatment. Examples include transient ischemic attacks, cerebrovascular&#xD;
             accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein&#xD;
             thrombosis or pulmonary emboli.&#xD;
&#xD;
        Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in&#xD;
        hemodynamic instability are allowed to enroll as long as they are on a stable dose of&#xD;
        anticoagulants for at least 4 weeks.&#xD;
&#xD;
        Note: Patients with thromboembolic events related to indwelling catheters or other&#xD;
        procedures may be enrolled.&#xD;
&#xD;
          -  Concurrent or previous other malignancy within 2 years of study entry, except&#xD;
             adequately treated basal or squamous cell skin cancer, prostate intraepithelial&#xD;
             neoplasm, carcinoma in-situ of the cervix, Bowen's disease and Gleason 6 prostate&#xD;
             cancer.&#xD;
&#xD;
          -  Known history of positive test for human immunodeficiency virus (HIV) or known&#xD;
             acquired immunodeficiency syndrome (AIDS).&#xD;
&#xD;
          -  Evidence of Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Note:&#xD;
             Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled.&#xD;
&#xD;
        Note: Patients with no prior history of HBV infection who have been vaccinated against HBV&#xD;
        and who have a positive antibody against hepatitis B surface antigen as the only evidence&#xD;
        of prior exposure may be enrolled.&#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>Aparna Parikh, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Aparna Parikh, MD</last_name>
    <phone>617-724-4000</phone>
    <email>Aparna.Parikh@MGH.HARVARD.EDU</email>
  </overall_contact>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aparna Parikh, MD</last_name>
      <email>aparna.parikh@mgh.harvard.edu</email>
    </contact>
    <investigator>
      <last_name>Aparna Parikh, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marios Giannakis, MD</last_name>
      <email>MGIANNAKIS@PARTNERS.ORG</email>
    </contact>
    <investigator>
      <last_name>Marios Giannakis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>January 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>June 16, 2023</last_update_submitted>
  <last_update_submitted_qc>June 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Aparna Parikh</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Metastatic colorectal cancer</keyword>
  <keyword>Stage III Colorectal Cancer</keyword>
  <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>Fluorouracil</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
    <mesh_term>Cetuximab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data can be shared no earlier than 1 year following the date of publication</ipd_time_frame>
    <ipd_access_criteria>MGH - Contact the Partners Innovations team at http://www.partners.org/innovation</ipd_access_criteria>
  </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/NCT03803553
org study id: 18-397
nct id: NCT03803553
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is comparing two standard of care treatment options based on blood test
      results for participants who have metastatic colorectal cancer.

      The names of the potential treatments involved in this study are:

        -  Active surveillance

        -  FOLFIRI treatment

        -  Nivolumab treatment

        -  Encorafenib/Binimetinib/Cetuximab treatment
The FDA (the U.S. Food and Drug Administration) has approved FOLFIRI, comprised of
      Irinotecan, Leucovorin, and 5-Fluorouracil, as a treatment option for metastatic colorectal
      cancer in the Stage IV setting.

        -  After diagnosis and surgical removal of tumors, individuals with metastatic colorectal
           cancer commonly receive what is called adjuvant chemotherapy treatment, commonly
           utilizing treatment plans called FOLFOX, CAPOX, or therapy with 5-Fluorouracil.

        -  If all the cancer is not killed, the investigators may be able to detect tumor in the
           blood called circulating tumor DNA (ctDNA). This is genetic material unique to
           metastatic colorectal cancer that may be present in the blood stream, and it can be
           identified through a ctDNA blood test. If ctDNA is present in the blood stream, it is
           commonly called micro-metastatic disease (meaning disease that can't be seen detected by
           CT scans but may be there in the blood). Cancer researchers believe that ctDNA in the
           blood stream may be an indicator that cancer is more likely to recur.

        -  After initial adjuvant chemotherapy, it is standard for individuals to begin active
           surveillance, where they do not receive further treatment but instead undergo frequent
           tumor imaging scans to see if their cancer is stable, growing, or coming back. The
           investigators plan to see if additional therapy, where FOLFIRI (comprised of Irinotecan,
           Leucovorin, and 5-Fluorouracil) is administered can decrease recurrence. Typically,
           FOLFIRI is given when the disease is visibly recurrent.

             -  In addition, the investigators plan to include study groups of adjuvant nivolumab
                treatment and adjuvant Encorafenib/Binimetinib/Cetuximab treatment to see if these
                treatments can decrease recurrence. The FDA has not approved either of these as a
                treatment options for metastatic colorectal cancer in the Stage IV setting.

             -  Patients who have a greater than normal number of genetic markers called
                microsatellites are called MSI-H. Because tumor cells with these features tend to
                have more genetic mutations than tumor cells without them, they are more likely to
                be recognized by the immune system. Nivolumab is an anti-PD-1 antibody. It works by
                attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present
                on different types of cells in your immune system and controls parts of your immune
                system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1
                from shutting down the immune system, thus potentially allowing immune cells to
                recognize and destroy cancer cells.

             -  Encorafenib in combination with binimetinib and cetuximab is one of the first
                effective regimens to target the BRAF V600E-mutation in colorectal cancer. When
                this mutation is present, it switches on pathway called the MAPK pathway which
                stimulates cell division and leads to uncontrolled cell growth. Encorafenib,
                binimetinib and cetuximab target different parts of this important signaling
                pathway in tumor cells with this mutation and slows down their growth and
                communication

      However, in this research study, the investigators are

        -  determining whether there are differences in cancer recurrence in ctDNA positive
           participants treated with additional therapy versus put on active surveillance.

        -  determining whether there are differences in health in ctDNA positive participants
           treated with additional therapy versus put on active surveillance.

        -  examining whether patients who undergo further therapy experience changes in the ctDNA
           levels.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease-free survival (DFS)
time frame: 5 years
description: Disease-free survival (DFS) between ctDNA-positive patients treated with additional treatment of FOLFIRI and ctDNA-positive patients who are untreated
measure: Clearance rate of ctDNA
time frame: 7 Months
description: Compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional treatment of FOLFIRI and those who are untreated
measure: Overall Survival (OS) Rate
time frame: 5 years
description: Overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy (Arm 1) and ctDNA-positive patients who are untreated (Arm 2)
measure: Clearance rate of ctDNA of Arm 4: Nivolumab Treatment
time frame: 13 months
description: Determine clearance rate of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort
measure: Disease-free survival (DFS) of Arm 4: Nivolumab Treatment
time frame: 5 years
description: Determine the disease-free survival (DFS) of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort
measure: Clearance rate of ctDNA of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment
time frame: 7 months
description: Determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort.
measure: Disease-free survival (DFS) of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment
time frame: 5 years
description: Determine the disease-free survival DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort.
measure: ctDNA clearance as Marker
time frame: 13 Months
description: Examine the correlation of ctDNA clearance as a surrogate marker for disease burden
measure: Lead time to recurrence
time frame: 5 years
description: Compare lead time to recurrence and sensitivity of predicting recurrence between ctDNA and tumor markers
arm group label: ctDNA-POSITIVE: FOLFIRI Protocol
arm group type: Experimental
description: Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance
- ctDNA-POSITIVE: FOLFIRI Protocol
FOLFIRI chemotherapy via intravenous infusion on days 1-3 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).
infusions will consist of the drugs
5-Fluorouracil
Irinotecan
Leucovorin
arm group label: ctDNA-POSITIVE: ACTIVE SURVEILLANCE
arm group type: Active Comparator
description: Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance
-- Active surveillance.
Observation and monitoring with imaging (every 3 months), tumor markers, and ctDNA draws every 1 month for the initial 6 months.
After 6 months, followed with ctDNA, tumor markers, and scans every 3 months for the first 3 years and every 6 months thereafter.
Additional scans and tumor markers will be at the discretion of the clinician. .
arm group label: ctDNA-NEGATIVE: ACTIVE SURVEILLANCE
arm group type: Active Comparator
description: Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance
- Observation and monitoring with imaging, tumor markers, and ctDNA collections every 3 months for the first 3 years and every 6 months thereafter.
Additional scans and tumor markers will be at the discretion of the clinician
arm group label: ctDNA-POSITIVE MSI-H: NIVOLUMAB
arm group type: Experimental
description: Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.
If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and MSI-H, the participant will not be randomized and will be placed into the group: ctDNA positive, MSI-H: Nivolumab
-ctDNA-Positive, MSI-H: Nivolumab Protocol
Nivolumab treatment via intravenous infusion on day 1 of each cycle. Cycle is 28 days long. This will occur for up to 12 cycles (48 weeks).
infusions will consist of the drug Nivolumab
arm group label: ctDNA-POSITIVE BRAF Mutant: ENCORAFENIB/BINIMETINIB/CETUXIMAB
arm group type: Experimental
description: Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.
If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and has a BRAF mutation, the participant will not be randomized and will be placed into the group: ctDNA positive, BRAF mutant: Encorafenib/Binimetinib/Cetuximab
-ctDNA-Positive, MSI-H: Encorafenib/Binimetinib/Cetuximab Protocol
Encorafenib/Binimetinib treatment is received orally every day and Cetuximab via intravenous infusion on day 1 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).
infusions will consist of the drug Cetuximab
intervention type: Drug
intervention name: FOLFIRI Protocol
description: FOLFIRI cycle will be two weeks (14 days) long, with FOLFIRI administered on Days 1-3. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of FOLFIRI chemotherapy.
arm group label: ctDNA-POSITIVE: FOLFIRI Protocol
other name: FOLinic acid-Fluorouracil-IRInotecan regimen
intervention type: Other
intervention name: ACTIVE SURVEILLANCE
description: Will be followed with observation and monitoring with imaging, tumor markers, and ctDNA collections
arm group label: ctDNA-NEGATIVE: ACTIVE SURVEILLANCE
arm group label: ctDNA-POSITIVE: ACTIVE SURVEILLANCE
intervention type: Drug
intervention name: Nivolumab Protocol
description: Nivolumab cycle will be four weeks (28 days) long, with Nivolumab administered on day 1. Participants will receive up to 12 four-week cycles (for a total of 48 weeks) of Nivolumab treatment.
arm group label: ctDNA-POSITIVE MSI-H: NIVOLUMAB
other name: Nivolumab
intervention type: Drug
intervention name: Encorafenib/Binimetinib/Cetuximab Protocol
description: Encorafenib/Binimetinib will be taken orally every day and Cetuximab will be administered intravenously on day 1 of each cycle. Cycles are 14 days long. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of Encorafenib/Binimetinib/Cetuximab.
arm group label: ctDNA-POSITIVE BRAF Mutant: ENCORAFENIB/BINIMETINIB/CETUXIMAB
other name: Enco/Bini/Cetux
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Aparna Parikh, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Aparna Parikh, MD
phone: 617-724-4000
email: Aparna.Parikh@MGH.HARVARD.EDU
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Aparna Parikh
investigator title: Principal Investigator
mesh term: Colorectal Neoplasms
mesh term: Fluorouracil
mesh term: Nivolumab
mesh term: Irinotecan
mesh term: Cetuximab
sharing ipd: Yes
ipd description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data can be shared no earlier than 1 year following the date of publication
ipd access criteria: MGH - Contact the Partners Innovations team at http://www.partners.org/innovation