Guadecitabine and Irinotecan Hydrochloride or Regorafenib or TAS-102 Alone in Treating Patients with Previously Treated Metastatic Colorectal Cancer

Inclusion Criteria

• Participants must have histologically or cytologically confirmed adenocarcinoma of the colon or rectum
• Patients in the phase I cohort must have biopsiable disease and be amenable to having two research biopsies
• 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 computed tomography (CT) scan
• 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
• Life expectancy of greater than 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal with or without liver metastases
• Creatinine < 1.5 x institutional upper limit of normal or creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
• 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 and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, 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 entering 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; or individuals with another malignancy that are deemed by the investigator to be at low risk for clinically meaningful recurrence (example [ex.] 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, basal cell or squamous cell carcinoma of the skin)
• Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible, 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 otherwise not be managed in an infusion center or outpatient clinic setting (i.e., a patient admitted to complete a transfusion would not be ineligible)
• Symptomatic bowel obstruction within 6 months prior to screening visit enrollment; patients who undergo surgical correction of obstructing lesion will be eligible within 6 months