A Vaccine (PolyPEPI1018 Vaccine) and TAS-102 for the Treatment of Metastatic Colorectal Cancer

• Age >= 18 years
• Histologically confirmed metastatic adenocarcinoma originating from the colon or the rectum, microsatellite stable

• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria

  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible

• Received =\< 2 lines of prior chemotherapy regimen for mCRC

  • NOTE: Adjuvant therapy will not be considered a line of therapy for mCRC unless the patient had disease recurrence =\< 6 months of adjuvant therapy
• Provide written informed consent
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) >= 1500/mm\^3 (obtained =\< 21 days prior to registration)
• Platelet count >= 100,000/mm\^3 (obtained =\< 21 days prior to registration)
• Hemoglobin >= 9 g/dL (obtained =\< 21 days prior to registration)
• Total bilirubin =\< 1.5 x ULN (obtained =\< 21 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) =\< 3 x ULN (=\< 5 x ULN for patients with liver involvement) (obtained =\< 21 days prior to registration)
• Calculated creatinine clearance >= 30 ml/min using the Cockcroft-Gault formula (obtained =\< 21 days prior to registration)
• Anticipated life expectancy >= 6 months

• Negative urine pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only

  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of \< 1% per year) while enrolled in the study and for 3 months from the last vaccination. An effective form of contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, cervical cap or condom
• Men must agree to use an effective form of contraception (as defined above), and not donate sperm for 3 months from the last vaccination
• Willingness to provide mandatory blood and buccal swab specimens for correlative research
• Willingness to provide mandatory tissue specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study). Note: During the active monitoring phase of a study

Exclusion Criteria:

• Received continuous systemic steroid treatment =\< 2 weeks prior to registration
• Colorectal cancer with documented high microsatellite instability (MSI H)
• Pre-existing systemic autoimmune or antibody-mediated diseases or immune deficiency diseases
• Central nervous system (CNS) metastases
• Serious, non-healing wounds, ulcers or bone fractures
• Nephrotic syndrome
• Arterial thromboembolisms or severe hemorrhages =\< 6 months before registration (except bleeding tumor before tumor resection surgery)

• Any of the following prior therapies:

  • Major surgery =\< 12 weeks prior to registration or anticipation of needing such procedure during the study period
  • Radiation therapy =\< 4 weeks prior to registration
  • Received chronic systemic immune therapy or immunosuppressant medication other than steroids =\< 6 weeks prior to registration
• Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage > once every 28 days

• Participants with active malignancy (other than colorectal cancer [CRC]) or a prior malignancy =\< 12 months prior to registration

  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
• Acute or subacute intestinal obstruction or history of chronic intestinal inflammatory diseases
• Relevant toxicities of prior therapies must have resolved to =\< grade 1, except for oxaliplatin-related neuropathy or alopecia
• Participant with myocardial infarction =\< 6 months prior to registration or New York Heart Association Class III or IV, heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Administration of a live, attenuated vaccine =\< 4 weeks prior to registration or anticipation of a live attenuated vaccine will be required during the study

• Participant has or will be participating in any of the following:

  • In another clinical study involving an investigational product (IP) or investigational device =\< 30 days prior to registration or
  • Is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study or
  • Is receiving any other investigational agent which would be considered as a treatment for colorectal cancer
• Known hypersensitivity to any component of the investigational drug

• Uncontrolled intercurrent non-cardiac illness including, but not limited to:

  • Ongoing or active infection
  • Psychiatric illness/social situations
  • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
  • Any other conditions that would limit compliance with study requirements

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons
  • Men and women of childbearing potential who are unwilling to employ adequate contraception