Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer

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.

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; included 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 a plan to receive or must be receiving 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.

- Pre-screening must begin prior to or within the first 3 months of starting adjuvant
treatment.

- Patients must have a CT scan 3-6 weeks after completion of adjuvant therapy to confirm
no radiographic evidence of disease

- Patients must not have had 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) ≤2.5 × institutional upper limit of normal creatinine within
normal institutional limits

--- OR

- creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.

- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 6 months
after the last dose of investigational drug.

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG).

- Women must not be breastfeeding

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year.

- Women who are not of childbearing potential, ie, who are postmenopausal or surgically
sterile as well as azoospermic men, do not require contraception

- Must have documentation of microsatellite status. Immunohistochemistry (IHC) is
acceptable as is PCR. 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 per local standards.

- Patients must have sufficient tumor tissue available for molecular profiling, defined
as at least 10 x 5 micron sections of FFPE tumor tissue or the equivalent.

- Patients must have a detectable mutation on molecular profiling to be followed as per
guidelines below.

-- Tumor Sequencing:

- DNA extracted from formalin-fixed or frozen primary tumor tissue will need to be
sequenced to identify somatic mutations across all or a subset of the coding
regions for at least 50 genes. Patients must have at least 1 mutation identified
on tumor sequencing that is covered by the ctDNA assay. Tumor sequencing will be
performed at Memorial Sloan Kettering by IMPACT.

-- Circulating tumor DNA (ctDNA) analysis:

- DNA extracted from plasma will be assessed for the presence of mutations. Testing
may be performed using digital PCR or next-generation sequencing but must be able
to reliably identify genomic alterations (excluding copy number changes or
fusions) at or below a minimum allele frequency of 0.2%. If initial ctDNA assay
fails to meet minimum coverage levels patients will be excluded from the study.
Testing must be performed by ACCESS- Memorial Sloan Kettering Molecular Genetics
Laboratory, New York, NY.

-- Definition of ctDNA positive:

- In order to be eligible for the ctDNA positive cohort, patient must be ctDNA
positive following adjuvant therapy. ctDNA positive will be defined as positive
if at least one mutation is shared between the tumor and ctDNA sequence. The
mutation(s) of interest can be assessed as changes at the nucleotide or protein
level (i.e. KRAS c.35G>A vs. KRAS G12D).

- The effects on the developing human fetus are unknown. For this reason and because
5FU, Capecitabine, Oxaliplatin, Irinotecan, and Leucovorin are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. 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. Men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and 6 months after completion of any of the study
drug administration.

- 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.

- Patients who are unable to get any standard adjuvant therapy

- Patient who have received more than 3 months of standard adjuvant therapy at the time
of potential study entry

- Patients who are MSI-high are excluded

- 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