TAS-102, Irinotecan, and Bevacizumab for the Treatment of Pre-treated Metastatic or Unresectable Colorectal Cancer, the TABAsCO Study

Inclusion Criteria:

* Advanced colorectal cancer (metastatic or unresectable): Histologically or cytological proven adenocarcinoma of the colon or rectum which is metastatic or otherwise incurable
* Prior treatment with a fluoropyrimidine (5-fluorouracil \[5-FU\] or capecitabine) and oxaliplatin in the metastatic/unresectable setting OR, recurrence within 12 months of adjuvant therapy with a regimen that included oxaliplatin
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Hemoglobin \>= 9 g/dL
* Absolute neutrophil count \>= 1500/mm\^3
* Platelet count \>= 100,000/mm\^3
* Creatinine \< 1.5 upper limit of normal (ULN) or if \>= 1.5 x ULN creatinine clearance (CRCL) \>= 30 mL/min (by Cockcroft-Gault)
* Bilirubin \< 1.5 x ULN
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5 x ULN or =\< 5 x ULN if with hepatic metastases
* Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present
* Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. 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
* Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

* Prior treatment with TAS-102 or irinotecan
* Anti-cancer therapy within 2 weeks of the planned first dose of study medication
* Unresolved toxicities from prior therapy of \> grade 1, excluding alopecia or similar toxicities which are not deemed to be clinically significant or put the participant at greater risk. Grade 2 neuropathy is permitted
* Major surgery within 4 weeks of anticipated start of therapy
* Uncontrolled hypertension: systolic blood pressure \>= 150, diastolic blood pressure \>= 100
* Unstable angina, symptomatic congestive heart failure or cardiac arrhythmia requiring anti-arrhythmic therapy (beta-blockers, calcium channel blockers and digoxin are allowed)
* Arterial or venous thrombotic or embolic events within 3 months of study initiation, unless well controlled on stable anti-coagulation for \>= 2 weeks. This excludes uncomplicated catheter associated venous thrombosis
* History of cerebrovascular or myocardial ischemia within 6 months of initiation
* National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 grade 3 or greater hemorrhage within the past 4 weeks
* Proteinuria \>= 2+, unless 24 hour urine collection demonstrates =\< 1 g of protein OR spot protein: creatinine demonstrates a ratio of =\< 1
* Untreated brain metastases
* History of abnormal glucuronidation of bilirubin (Gilbert's syndrome)
* History of second primary malignancy within 3 years prior to enrollment, excluding in-situ cervical carcinoma, non-melanoma skin cancer or malignancy of equivalent risk which is highly unlikely to require systemic treatment in the next 2 years
* Have known active infection which would heighten the risk of complications
* Pregnant or nursing female participants
* Unwilling or unable to follow protocol requirements
* Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug