A Randomized, Double-blind, Placebo-controlled Phase-III Study of Adjuvant Regorafenib Versus Placebo for Patients with Stage IV Colorectal Cancer After Curative Treatment of Liver Metastases

Summary

at the time of study entry, all subjects will have received surgery with curative intent for the primary lesion(s) and surgery with curative intent for liver lesions, as well as at least 3 months, and no more than a planned 6 months, of neoadjuvant, adjuvant, or perioperative chemotherapy. The timing of the pre-study interventions depends upon the timing of the diagnosis of primary and metastatic disease and the preference of the treating physician.

at no time may a subject have had extra-hepatic metastatic disease. Suspicious lesions should be rigorously evaluated with other imaging techniques and/or biopsy to exclude extra-hepatic metastatic disease.

Subjects are to be disease-free at study entry as assessed by the investigator via computed tomography (CT) or magnetic resonance imaging (MRi) scan obtained within 4 weeks prior to randomization and confirmed by central radiology review as defined by the imaging charter. Pathology-proven complete removal of all CRC lesions will be required, as will confirmation of tumor histology.

a subject MaY noT be randomized into the study if it has been longer than 8 weeks since a) the completion of the last dose of chemotherapy or b) the date of surgery, whichever came later.

Stratification
Subjects will be stratified at randomization as follows:
* Pre-operative number of liver metastases [Less Than] 4 or [GreaterThanorequalTo] 4
* Time of diagnosis of CRC tumor to time of occurrence of liver metastases [LessThanorequalTo] 6 months (synchronous) vs. [Greater Than] 6 months (metachronous)

Participant Eligibility

1. Be male or female, and >= 18 years of age

2. Have a diagnosis of Stage IV CRC with metastases to the liver only and have undergone
one of the following three treatment scenarios:

* A primary CRC lesion(s) in the colon and/or rectum and synchronous liver metastases,
which were treated with surgery with curative intent for both primary and metastatic
lesions and at least 3 months of neoadjuvant, adjuvant, or perioperative chemotherapy
including a fluoropyrimidine and either oxaliplatin or irinotecan. Total chemotherapy
administered, including that administered prior to and after liver resection, should not
exceed 6 months.

3. Have tumor tissue (of primary tumor and liver metastases or at least one of the two)
available for biomarker analysis (to be collected as soon as possible before or after
randomization).

4. Prior to randomization, have histological confirmation that all CRC lesions were
adenocarcinoma. Subjects with CRC lesions of other histologic types, including mixed
type with predominant adenocarcinoma, will not be eligible to be randomized to study
treatment.

5. Prior to randomization, have pathology-proven complete removal of all primary and liver
metastatic CRC lesions. Subjects with positive margins will not be eligible for the study.

6. 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
* ).

7. Have absence of disease on the eligibility scan (CT/MRI) as assessed by the investigator
and confirmed by central radiology review as defined in the imaging charter.

8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
within 14 days prior to the initiation of study treatment (see Section 14.1).

9. Have adequate bone marrow function, liver function, and renal function, as measured by
the laboratory assessments outlined in the protocol conducted within 7 days prior to the initiation of
study treatment.

10.Understand, be willing to give consent, and sign the written informed consent form (ICF)
prior to undergoing any study-specific procedure.

11. Be willing to give consent and sign the ICF for tumor tissue collection (primary tumor and
liver metastases).

12. Be willing to give consent and sign the ICF for the genetic testing unless precluded by
local guidelines (eg, Independent Ethics Committee [IEC]/Institutional Review Board
[IRB] or Regulatory Authority).

13. If female and of childbearing potential, have a negative result on a pregnancy test
performed a maximum of 7 days before initiation of study treatment.

14. If female and of childbearing potential, or if male, agree to use adequate contraception
(eg, 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.