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.
Inclusion Criteria:
- Participants must have histologically confirmed resected Stage III adenocarcinoma of
colorectal. Any T [Tx, T1, T2, T3, or T4-], N1-2MO; including NC.
- Patient must have completed resected disease. In patients with tumor adherent to
adjacent structures, en block RO resection must be documented.
- Entire tumor must be in the colon (rectal involvement is excluded).
- Patients must have completed standard adjuvant chemotherapy per the discretion of the
treating physician. Standard therapy includes FOLFOX, CAPOX, or therapy with 5FU
analog alone will be permitted if it constitutes appropriate standard therapy in the
opinion of the treating physician.
- Patients must not have received prior neoadjuvant chemotherapy.
- Age ≥18 years.
- ECOG performance status ≤1.
- Life expectancy of greater than 3 months.
- Participants must have normal organ and marrow function as defined below:
- leukocytes ≥3,000/mcL
- absolute neutrophil count ≥1,500/mcL
- platelets ≥100,000/ mcL
- total bilirubin within normal institutional limits
- AST(SGOT)/ALT(SGPT) ≤3 (AST) or ≤ 3 (ALT) × institutional upper limit of normal
- creatinine within normal institutional limits OR
- creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal by Cockroft-Gault formula.
- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG).
- The effects on the developing human fetus are unknown. For this reason and because
5FU, Capecitabine, Oxaliplatin, Irinotecan, Leucovorin, Nivolumab, and cetuximab are
known to be teratogenic, females of child-bearing potential (FOCBP) and males must be
willing to abstain from heterosexual activity or use 2 forms of effective
contraception (fail rate of less than 1% per year, hormonal or barrier method of birth
control) from time of informed consent until 5 months (FOCBP) and 7 months (males)
after the last dose of study treatment. Should a woman become pregnant or suspect she
is pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Women who are not of childbearing potential, ie,
who are postmenopausal or surgically sterile as well as azoospermic men, do not
require contraception.
- Patient must have documentation of mismatch repair deficiency (dMMR). Abnormal
immunohistochemistry (IHC) staining for dMMR (MMR protein expression (MLH1, MSH2,
MSH6, PMS2) where loss of one or more protein indicated dMMR) is acceptable as is MSI
assessment via PCR. This may be done locally per local standards.
- Patient's circulating tumor DNA (ctDNA) assay (LUNAR-Guardant Health) must satisfy
assay specific quality control metrics to generate a result.
- In order to be eligible for the ctDNA positive cohort, patient must be ctDNA positive
following adjuvant therapy using the CLIA certified Guardant Health LUNAR assay. ctDNA
positive will be defined as positive based on having a tumor derived signal in the
cfDNA that passes calling threshold ("ctDNA detected").
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Patients who are receiving additional investigational therapy or on another
investigational protocol
- Patients who have confirmed metastatic disease per CT.
- Patients who are unable to get any standard adjuvant therapy
- Patient who have received more than 3-6 months of standard adjuvant therapy at the
time of study entry
- Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic
biologic therapy (e.g., cetuximab, bevacizumab etc.), within 30 days prior to start of
study treatment.
- Patients who are MSI-high or have a BRAF V600E mutation are excluded from Arm 1
(FOLFIRI) and Arm 2 (Active Surveillance).
- Patients with a BRAFV600E mutation and who are MSI-high are excluded from Arm 5
(ENCO/BINI/CETUX).
- Has uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 6 months for woman and 6 months for men, after the last dose of trial
treatment.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
- Has an active infection requiring systemic therapy.
Nivolumab Specific Inclusion Criteria for MSI-H Cohort:
- 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.
Nivolumab Specific Exclusion Criteria for MSI-H Cohort:
- 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/μL 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 μmol/L)
- Platelets ≥100,000/μL
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.
