This phase II trial studies how well TAS-102 and oxaliplatin work in treating patients with stage IV colon cancer. Drugs used in chemotherapy, such as TAS-102 and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

PRIMARY OBJECTIVE:

I. Overall response rate (ORR).

SECONDARY OBJECTIVES:

I. Progression free survival (PFS). II. Overall survival (OS). III. Disease control rate (DCR). IV. Duration of response. V. Safety and tolerability.

OUTLINE:

Patients receive trifluridine and tipiracil hydrochloride (TAS-102) orally (PO) twice daily (BID) on days 1-5 and oxaliplatin intravenously (IV) over 2 hours on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days.

Inclusion Criteria:

• Histologically confirmed stage IV colon cancer (American Joint Committee on Cancer [AJCC] 7th edition) that has progressed after standard therapy that included fluorouracil (5-FU), irinotecan, oxaliplatin, bevacizumab (unless contraindicated) and an anti-EGFR antibody, if RAS wild type. Patients who could not tolerate standard agents because of unacceptable, but reversible toxicity necessitating their discontinuation will be allowed to participate
• Patients who had received adjuvant chemotherapy and had recurrence during or within 6 months of completion of the adjuvant chemotherapy will be allowed to count the adjuvant therapy as one chemotherapy regimen
• Progression of disease must be documented on the most recent scan
• Presence of measurable disease
• RAS mutation and mismatch repair deficiency (MMR) status must be determined (or tissue availability for testing if not already determined)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy of at least 3 months
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Hemoglobin >= 9 g/dL
• Platelets (PLT) >= 75 x 10^9/L
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5 x upper limit of normal (ULN)
• Adequate contraception if applicable
• Women who are nursing and discontinue nursing prior to enrollment in the program
• Ability to take oral medication (i.e., no feeding tube)
• Patient able and willing to comply with study procedures as per protocol
• Patient able to understand and willing to sign and date the written voluntary informed consent form (ICF) at screening visit prior to any protocol-specific procedures

Exclusion Criteria:

• Patients who have previously received TAS-102
• Grade 2 or higher peripheral neuropathy (functional impairment)
• Symptomatic central nervous system (CNS) metastases requiring treatment
• Other active malignancy within the last 3 years (except for non-melanoma skin cancer or a non-invasive/in situ cancer)
• Pregnancy or breast feeding
• Current therapy with other investigational agents
• Active infection with body temperature >= 38 degree Celsius (C) due to infection
• Major surgery within prior 4 weeks (the surgical incision should be fully healed prior to drug administration)
• Any anticancer therapy within prior 3 weeks of first dose of study drug
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS-102
• Current therapy with other investigational agents or participation in another clinical study or any investigational agent received within prior 4 weeks
• Grade 3 or higher hypersensitivity reaction to oxaliplatin, or grade 1-2 hypersensitivity reaction to oxaliplatin not controlled with pre-medication
• Has unresolved toxicity of greater than or equal to Common Terminology Criteria for Adverse (CTCAE) grade 2 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum-induced neurotoxicity)