Inclusion Criteria:

- Histologically confirmed metastatic colorectal cancer

- Measurable disease

- Patient has failed ≥ 2 prior chemotherapy regimens

- Not a candidate for curative resection

- No CNS metastases within ≤ 2 years

- Treatment for brain metastasis and whole brain disease that has remained stable
for > 3 months allowed

- Patients who have not been treated with steroid therapy may be allowed

- ECOG performance status 0-1

- Life expectancy ≥ 12 weeks

- Leukocytes ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Sensory neuropathy ≤ grade 2 allowed

- Willing to provide tissue and blood samples

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to entinostat, azacitidine, mannitol, or other agents used in
the study

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- NYHA class II-IV symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness and/or social situations that would limit compliance with
study requirements

- No history of severe bleeding without thrombocytopenia

- No concurrent radiotherapy including palliative treatment

- Toxicities from prior therapy have resolved to ≤ grade 1

- More than 4 weeks since prior chemotherapy (> 6 weeks for nitrosoureas or mitomycin
C)

- More than 4 weeks since prior major surgical procedure

- No prior histone deacetylase inhibitors (including valproic acid) or demethylating
agents

- No concurrent investigational agents

- No concurrent combination antiretroviral therapy in HIV-positive patients

- No concurrent investigational or commercial anticancer agents or therapies