Colorectal Cancer Treated With Adjuvant Regorafenib Versus Placebo After Curative Treatment of Liver Metastases in a Randomized, Double-blind, Placebo‑Controlled Phase-III STudy

Inclusion Criteria:

- Have a history of a primary adenocarcinoma of the colon and / or rectum

- Have a history of Stage IV Colorectal Cancer (CRC) with metastases to the liver only

- Have received at least 3 months ,of neoadjuvant, adjuvant, or perioperative
chemotherapy, including a fluoropyrimidine and either oxaliplatin or irinotecan or
both for subjects with initial Stage IV CRC which were treated with surgery with
curative intent for both primary and metastatic lesions. The total chemotherapy
administered, including that administered prior to and after liver resection, should
not exceed 9 months. OR Have received surgery with curative intent for primary CRC and
at least 3 months ,of neoadjuvant, adjuvant, or perioperative chemotherapy for the
primary tumor, including a fluoropyrimidine or a fluoropyrimidine and either
oxaliplatin or irinotecan or both

- For subjects with liver metastases developing > 6 months after completing
treatment for primary CRC and having undergone surgery with curative intent for
liver metastases, a second course of chemotherapy lasting at least 3 months needs
to be administered, including a fluoropyrimidine and either oxaliplatin or
irinotecan or both. The second course of chemotherapy should not exceed 9 months.

- For subjects who developed liver metastases >/=6 months after completing treatment for
primary CRC and having undergone surgery with curative intent for liver metastases, a
second course of chemotherapy is not permitted unless initial adjuvant therapy
consisted of fluoropyrimidine monotherapy. Subjects who received fluoropyrimidine
alone must have received a second course of chemotherapy with fluoropyrimidine and
either oxaliplatin or irinotecan or both, which should not exceed 9 months.For
subjects with initial Stage I or II disease, no chemotherapy is required for a primary
CRC lesion treated with surgery with curative intent. These subjects must receive
chemotherapy for the treatment of liver metastases (which were also treated with
surgery with curative intent), which must last at least 3 months, including a
fluoropyrimidine and either oxaliplatin or irinotecan or both. The total course of
chemotherapy should not exceed 9 months.

- Prior to randomization, have histological confirmation that CRC lesions were
adenocarcinoma (subtypes of adenocarcinoma, e.g. mucinous adenocarcinoma are allowed).
Subjects with CRC lesions of other histological types, including mixed type with
predominant adenocarcinoma, will not be eligible to be randomized to study treatment.

- Have pathology-proven complete removal of all primary and liver metastatic CRC
lesions. Subjects with positive margins will not be eligible for the study.

- Have adequate bone marrow function, liver function, and renal function, as measured by
the following laboratory assessments conducted within 7 days prior to the initiation
of study treatment:

- Total bilirubin
- Alanine aminotransferase and aspartate aminotransferase
- Lipase
- Serum creatinine
- Carcinoembryonic antigen (CEA)
- Glomerular filtration rate>/=30 mL/min/1.73 m2 according to the Modified Diet in
Renal Disease abbreviated formula

- International normalized ratio of prothrombin time and activated partial
thromboplastic time treated with an agent such as warfarin or heparin will be allowed to participate
if no underlying abnormality in coagulation parameters exists per medical
history.

- Platelet count >/=100,000 /mm3, hemoglobin >/=9 g/dL, absolute neutrophil count
>/= 1500/mm3 without transfusions or granulocyte colony stimulating factor and
other hematopoietic growth factors

- Alkaline phosphatase ≤ 2.5 times the ULN

- Have had a CT or MRI scan (chest, abdomen, pelvis and other suspected sites as
applicable) to determine eligibility for randomization within 4 weeks prior to
randomization (hereafter referred to as the "eligibility scan")

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within
14 days prior to the initiation of study treatment

- If female and of childbearing potential, or if male, agree to use adequate
contraception (e.g., abstinence, intrauterine device, oral contraceptive, or double
barrier method) based on the judgment of the investigator or a designated associate
from the date on which the ICF is signed until 8 weeks after the last dose of study
drug.

Exclusion Criteria:

- Are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir,
saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine,
phenobarbital, phenytoin, rifampin, St. John's Wort).

- Have used biologic response modifiers, such as granulocyte-colony stimulating factor,
within 3 weeks prior to signing the ICF.

- Have had prior treatment with regorafenib or any other (vascular endothelial growth
factor receptor) VEGFR-targeting kinase inhibitor.

- Have had anti-cancer treatment following liver resection that exceeded a duration of 6
months.

- Have been treated with biologics (eg, antibodies targeting VEGFR or EGFR) after liver
resection unless the administration of the biologic started prior to liver resection
and continued after liver resection only to complete a pre-specified number of cycles.

- Completed their last dose of chemotherapy or had their last cancer surgery more than
10 weeks, whichever came later, prior to randomization.

- Have extra-hepatic metastatic disease. Suspicious lesions should be rigorously
evaluated with other imaging techniques and/or biopsy to exclude extra-hepatic
metastatic disease prior to submitting for central radiology review.

- Have had systemic anticancer therapy including cytotoxic therapy, signal transduction
inhibitors, immunotherapy, and/or hormonal therapy within 4 weeks prior to initiation
of study treatment.

- Are pregnant and or breast feeding.

- Have had prior or concurrent cancer distinct in primary site or histology from CRC
within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in
situ, nonmelanoma skin cancer, Stage 0 intramucosal gastric cancer after endoscopic
complete removal, or superficial bladder tumors classified as noninvasive tumor (Ta),
carcinoma in situ (Tis), or tumor invades lamina propria (T1).

- Have congestive heart failure classified as New York Heart Association Class 2 or
higher.Have had unstable angina (angina symptoms at rest) or new-onset angina ≤ 3
months prior to screening. Have had a myocardial infarction < 6 months prior to
initiation of study treatment.

- Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta
blockers or digoxin.

- Have uncontrolled hypertension (systolic blood pressure [SBP] greater than140 mmHg or
diastolic blood pressure [DBP] greater than 90 mmHg) despite optimal medical
management.

- Have pheochromocytoma.

- Have had arterial or venous thrombotic or embolic events such as cerebrovascular
accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary
embolism within 6 months prior to the initiation of study treatment.

- Have a known history of human immunodeficiency virus infection.

- Have either active or chronic hepatitis B or C requiring treatment with antiviral
therapy.

- Have a seizure disorder requiring medication.

- Have evidence or history of any bleeding diathesis (including mild hemophilia),
irrespective of severity.

- Have had a hemorrhage or a bleeding event >/=Grade 3 (NCI-CTCAE v 4.0) within 4 weeks
prior to the initiation of study treatment.

- Have any other serious or unstable illness, or medical, social, or psychological
condition, that could jeopardize the safety of the subject and/or his/her compliance
with study procedures, or may interfere with the subject's participation in the study
or evaluation of the study results.