Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer

  • STATUS
    Recruiting
  • End date
    Feb 1, 2023
  • participants needed
    500
  • sponsor
    Massachusetts General Hospital
Updated on 25 February 2022
oxaliplatin
neutrophil count
capecitabine
leucovorin
irinotecan
folfox regimen
cetuximab
adjuvant therapy
nivolumab
adenocarcinoma
adjuvant chemotherapy
folfiri regimen

Summary

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

Description

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.

Details
Condition Metastatic Colorectal Cancer, Stage III Colorectal Cancer
Treatment active surveillance, FOLFIRI Protocol, Nivolumab Protocol, Encorafenib/Binimetinib/Cetuximab Protocol
Clinical Study IdentifierNCT03803553
SponsorMassachusetts General Hospital
Last Modified on25 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Must have documentation of microsatellite instability status. Both PCR based assessment and Immunohistochemistry (IHC) are acceptable. Presence of deficient (d) DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done locally
Patients must have detectable ctDNA (Guardant Health LUNAR assay) post standard adjuvant therapy in order to be in this cohort

Exclusion Criteria

Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other forms of immunosuppressive therapy within 7 days prior to the first dose of nivolumab treatment. Subject requiring systemic steroids are excluded from the trial. The use of physiologic doses of corticosteroids may be approved after discussion with the sponsor
Has a known history of active TB (Bacillus tuberculosis)
Hypersensitivity to nivolumab or any of is excipients
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
Patients that require supplemental oxygen are excluded
Patients who are known HIV+ positive are eligible if their CD4+ count is 350/L for at least 3 months and they have an undetectable viral load. In addition, patient must be currently receiving Highly Active Antiretroviral Therapy (HAART) and have been on therapy for at least 3 months prior to study entry, under the care of an Infectious Diseases specialist. Patients should have no history of an AIDS-defining opportunistic infection
Patients known hepatitis B and hepatitis C must be under the care of viral hepatitis expert consultant. Patients with hepatitis B are required to be treated with anti-HBV treatment (e.g., entecavir) and have an HBV viral load <100 IU/mL. Patients with hepatitis C need to have received prior and/or ongoing hepatitis C treatment
Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Encorafenib, binimetinib, and cetuximab Specific Inclusion Criteria for BRAF
mutant Cohort
Presence of BRAFV600E in tumor tissue previously determined by IMPACT at any time prior to Screening
Patients must have detectable ctDNA (Guardant Health LUNAR assay) post standard adjuvant therapy in order to be in this cohort
Participants must have normal organ, marrow, and hematologic function as defined
below
Hemoglobin 9 g/dL (5.58 mmol/L)
Total bilirubin 1.5 (25.65 mol/L)
Platelets 100,000/L
Encorafenib, binimetinib, and cetuximab Specific Exclusion Criteria for BRAF
V600E mutant
Cohort
Patients with a BRAFV600E mutation and who are MSI-H are excluded from Arm 5 (ENCO/BINI/CETUX)
Prior therapy with a BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib)
Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients
The patient has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or has red meat allergy or tick bit history
Inability to swallow and retain study drug
Participants who have undergone major surgery (e.g., in-patient procedures) 6 weeks prior to start of study treatment or who have not recovered from side effects of such procedure
Participants who have had radiotherapy 14 days prior to start of study treatment or who have not recovered from side effects of such procedure. Note: Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment
Patient has not recovered to Grade 1 from toxic effects of prior therapy before starting study treatment
Note: Stable chronic conditions ( Grade 2) that are not expected to resolve
(such as neuropathy, myalgia, alopecia, prior therapy-related
endocrinopathies) are exceptions and may enroll
Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, any of the following
History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to Screening
Congestive heart failure requiring treatment (New York Heart Association Grade 2)
Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or ECHO
Uncontrolled hypertension defined as persistent systolic blood pressure 150 mmHg or diastolic blood pressure 100 mmHg despite current therapy
History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia)
Triplicate average baseline QTc interval 480 ms
Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent ( 3 months) history of a partial or complete bowel obstruction, or other conditions that will interfere significantly with the absorption of oral drugs
Known history of acute or chronic pancreatitis
Concurrent neuromuscular disorder that is associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease
Current use of a prohibited medication (including herbal medications, supplements, or foods), as described in Section 5.5, or use of a prohibited medication 1 week prior to the start of study treatment
History of thromboembolic or cerebrovascular events 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli
Note: Patients with either deep vein thrombosis or pulmonary emboli that does
not result in hemodynamic instability are allowed to enroll as long as they
are on a stable dose of anticoagulants for at least 4 weeks
Note: Patients with thromboembolic events related to indwelling catheters or
other procedures may be enrolled
Concurrent or previous other malignancy within 2 years of study entry, except adequately treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen's disease and Gleason 6 prostate cancer
Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
Evidence of Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Note: Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled
Note: Patients with no prior history of HBV infection who have been vaccinated
against HBV and who have a positive antibody against hepatitis B surface
antigen as the only evidence of prior exposure may be enrolled
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