This is multinational, double-blind, two-arm, parallel, randomized Phase 3 comparison study evaluating the efficacy and safety of TAS-102 vs. placebo in patientws with refractory metastatic colotrectal cancer. Patients will be randomly assigned (2:1) to TAS-102 (experimental arm) or placebo (control arm). Randomization will take place once the consented patient has completed all the necessary Baseline procedures and is deemed eligible for study entry. Treatment assignement will be done centrally using a dynamic allocation method (biased coin) via an Interactive Voice/Web Response System (IXRS) stratified by:

KRAS gene type (wild, mutant)

Time since diagnosis of first metastasis

Geographical region (Region 1:Asia/Japan, Region 2: Western/USA and Europe

Inclusion Criteria

A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study:

1. Has provided written informed consent prior to performance of any study procedure.

2. Is ≥18 years of age.

3. Has definitive histologically or cytologically confirmed adenocarcinoma of the colon or rectum.

a. KRAS status must have been determined (mutant or wild).

4. Has received at least 2 prior regimens of standard chemotherapies for metastatic colorectal cancer

and is refractory to or failing those chemotherapies.

a. Standard chemotherapy must include ALL of the following agents approved in each country:

i. Fluoropyrimidines, irinotecan and oxaliplatin

ii. An anti-VEGF monoclonal antibody (bevacizumab)

iii. At least one of the anti-EGFR monoclonal antibodies (cetuximab or panitumumab)

for KRAS wild-type patients.

b. Patients who have progressed based on imaging during or within 3 months of the last

administration of each standard chemotherapy.

c. Patients who have withdrawn from standard treatment due to unacceptable toxicity

warranting discontinuation of treatment and precluding retreatment with the same agent prior

to progression of disease will also be eligible to enter the study.

d. Patients who had received adjuvant chemotherapy and had recurrence during or within

6 months of completion of the adjuvant chemotherapy are allowed to count the adjuvant

therapy as one regimen of chemotherapy.

5. Has Eastern Cooperative Group (ECOG) performance status of 0 or 1 (see Appendix A) in the

Baseline period and on Cycle 1, Day 1.

6. Is able to take medications orally (ie, no feeding tube).

7. Has measurable or non-measurable metastatic lesion(s), as defined by RECIST version 1.1.

8. Has adequate organ function as defined by the following laboratory values obtained within 7 days

prior to study drug administration on Day 1 of Cycle 1:

a. Hemoglobin value of ≥9.0 g/dL.

b. Absolute neutrophil count of ≥1,500/mm3 (ie, ≥1.5 × 109/L by International Units [IU]).

c. Platelet count ≥100,000/mm3 (IU: ≥100 × 109/L).

d. Total serum bilirubin of ≤1.5 mg/dL (except for Grade 1 hyperbilirubinemia due solely to a

medical diagnosis of Gilbert’s syndrome).

e. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT)

≤3.0 × upper limit of normal (ULN); if liver function abnormalities are due to underlying

liver metastasis, AST and ALT ≤5 × ULN.

f. Serum creatinine of ≤1.5 mg/dL.

9. Women of childbearing potential must have a negative pregnancy test (urine or serum) within

7 days prior to randomization. Females must agree to adequate birth control if conception is

possible during the study and up to 6 months after the discontinuation of study medication; and

males must agree to adequate birth control during the study and up to 6 months after the

discontinuation of study medication.

10. Is willing and able to comply with scheduled visits and study procedures.