A Randomized Phase 2 Trial of Fruquintinib and TAS-102 as Compared to Fruquintinib in Patients With Refractory Advanced/Metastatic Colorectal Cancer

1. Provision to sign and date the consent form 2. Able to comply with all study procedures and be available for the duration of the study in the investigator's judgment 3. Age ≥18 4. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 5. Histologically or cytologically confirmed advanced or metastatic colorectal adenocarcinoma 6. Prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab (unless contraindicated) and cetuximab/panitumumab (for RAS-wild type disease) for the treatment of advanced or metastatic colorectal cancer and had demonstrated progressive disease or intolerance to their last regimen. 1. Patients who progressed on irinotecan- and oxaliplatin-based regimens previously for metastatic disease should not be retreated with these agents prior to enrolling on this study. 2. Patients who developed locally advanced/metastatic disease during or within 6 months of completing adjuvant therapy are eligible and the adjuvant/neoadjuvant therapy can be counted as one regimen of chemotherapy for advanced disease. Patients who developed locally advanced/metastatic disease \> 6 months after completion of adjuvant therapy must be treated with the above therapies in the advanced setting to be eligible. 7. Mismatch repair proficient (MMRp) status documented by local IHC testing 8. RAS and BRAF status documented 9. Measurable disease according to RECIST v1.1 10. Able to swallow and absorb oral medication 11. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 72 hours prior to first dose of study drug treatment: 1. ANC ≥ 1.5 × 109/L 2. Platelet count ≥ 70 × 109/L 3. Hemoglobin ≥ 9 g/dL in the previous week 4. Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN); patients with known Gilbert's disease may have a bilirubin ≤ 3.0 ×ULN 5. Aspartate aminotransferase (AST) and alanine aminotransferase ALT) \< 3 × upper limit of normal (ULN) (in the presence of liver metastases ≤ 5 × ULN) 6. Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault Equation (or similar formula) or as calculated using a timed urine collection 12. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. 13. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 180 days after the last dose of study treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Exclusion criteria: 1. Patients with known MSI-high or mismatch repair deficient (dMMR) status or in whom the status of both are unknown 2. Patients with BRAF V600 mutations 3. Prior treatment with regorafenib, trifluridine-tipiracil (TAS-102), or fruquintinib. 4. Major surgery within 14 days of C1D1. Minor procedures (e.g. biopsies, central venous catheters) are not considered major surgery. 5. Patients must have recovered from clinically significant AEs of their most recent prior therapy/intervention prior to enrollment as determined by relevant clinical and laboratory parameters. 6. Untreated CNS metastases or known leptomeningeal disease. Patients with treated CNS metastases (either by surgical or radiation techniques) are eligible provided there is no evidence of progression for at least 4 weeks after CNS-directed therapy as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. 7. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessments of the investigational regimen. Patients whose prior or concurrent malignancy natural history and/or treatment does NOT have the potential to impact safety or study assessments are eligible. 8. Uncontrolled intercurrent illness (defined as but not limited to others in the opinion of the treating investigator): 1. Uncontrolled pleural effusion, pericardial effusion or ascites defined as requiring recurrent drainage procedures within 3 weeks of C1D1 2. Uncontrolled arrhythmia or any ventricular arrhythmia requiring treatment 3. Uncontrolled hypertension (≥ 160 mmHg systolic or ≥ 100mmHg diastolic in spite of maximal medical therapy) 4. Urine dipstick or urinalysis with protein ≥ 2+ or 24-hour urine protein ≥ 1.0g/24 hours. Patients with 1+ proteinuria must undergo a urine protein creatinine ratio (UPCR) or 24-hour urine collecti