Phase I Study of SGI-110 With Irinotecan Followed by Randomized Phase II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Previously Treated Metastatic Colorectal Cancer

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed adenocarcinoma of the
colon or rectum

- Patients in the phase II cohort must be amenable to having two research biopsies. This
applies to the first 36 patients enrolled to Arm A, who have both biopsiable disease
and are randomized to SGI-110 + Irinotecan.

- Archival tissue must be procured if available

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >
20 mm with conventional techniques or as > 10 mm with spiral CT scan. See section 10
for the evaluation of measureable disease.

- Patients in the phase II cohort must have progressed while receiving irinotecan
therapy in the metastatic setting. There are no limitations on number of prior
therapies in the metastatic setting.

- Age minimum of 18 years.

- Life expectancy of greater than 12 weeks.

- Eastern Cooperative Oncology Group (ECOG) performance status <1

- Participants must have normal organ and marrow function

- The effects of SGI-110 on the developing human fetus are unknown. For this reason and
because oncological agents 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, for the duration of study
participation, and for 3 months after completion of the study.

Should a woman become pregnant or suspect she is pregnant while participating in this study
or within 30 days of last dose, she should inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to enrolling in the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Participants may not be receiving any other study agents.

- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to irinotecan, decitabine or SGI-110.

- Subjects who have received prior therapy with any hypomethylating agents.

- 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.

- Pregnant women are excluded from this study because SGI-110 is a/an hypomethylating
agent with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk of adverse events in nursing infants secondary to treatment
of the mother with SGI-110, breastfeeding should be discontinued. These potential
risks may also apply to other agents used in this study.

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances: Individuals with a history of other malignancies who have
been disease-free for at least 5 years and are deemed by the investigator to be at low
risk for recurrence of that malignancy. Individuals with the following cancers are
eligible if diagnosed and treated within the past 5 years: cervical cancer in situ,
definitively treated early stage prostate cancer (confined to prostate with Gleason 6
or below), definitely treated breast ductal or lobular carcinoma in situ, and basal
cell or squamous cell carcinoma of the skin.

- HIV-positive individuals on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with SGI-110. In addition, as these
individuals are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.

- Previous treatment with regorafenib and TAS-102 (This applies to phase II only.) If
patients have previously received either regorafenib OR TAS-102, they must be able to
receive the alternate regimen if randomized to the standard of care arm).

- Hospitalization for an acute medical issue within 4 weeks prior to screening visit
that would not otherwise be managed in an infusion center or outpatient clinic setting
(e.g., a patient admitted to complete a transfusion would not be ineligible.).

- Symptomatic bowel obstruction within 6 months prior to enrollment, Patients who
undergo surgical correction of obstructing lesion will be eligible within 6 months.