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

This is a randomized, double-blind, placebo-controlled, multicenter Phase iii study designed
to evaluate and compare the safety and efficacy of regorafenib vs. placebo in subjects with
CRC after curative resection of liver metastasis and completion of all planned chemotherapy.
The study is planned to be conducted at study sites located in north america, Brazil, europe,
asia, israel, and australia.
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.4
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 prior to submitting for central radiology review.9
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 10 weeks since
a) the completion of the last dose of chemotherapy or b) the date of surgery, whichever came
later.8
The estimated sample size is approximately 750 subjects (see Section 8.6). Subjects meeting
the study entry criteria (including all of the inclusion criteria and none of the exclusion criteria
[see Section 5.1]) will be randomly assigned in a 1:1 ratio to treatment with regorafenib or
placebo (see Section 6.3):
* Regorafenib 160 mg (4 tablets), given once daily, on a 3-weeks-on/1-week-off dosing
schedule
* Placebo (4 tablets, matching regorafenib tablets in appearance), given on the same schedule

Treatment will continue for up to 2 years (a maximum of 26 cycles) or until disease
recurrence (see Section 7.3.2), or until withdrawal for other reasons (see Section 5.2).

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)
The synchronous presence of primary colon cancer and liver metastasis may indicate a
more disseminated disease status. Synchronous disease has been demonstrated to be
an independent prognostic factor that influences DFS (HR 1.636
[Ci[?]1.02-2.623]).[13]
* Time since last surgery for any CRC lesion to randomization: [LessThanorequalTo] 6 months vs.
[Greater Than] 6 months
This factor takes into account a potential effect of the time interval between surgery
and randomization on the clinical outcome.

a computer-generated randomization list will be prepared by the Bayer Randomization
Manager. The randomization number will be used to link the subject to a treatment group and
to a medication package.

The investigator or a designated associate will obtain the randomization number and the
medication package numbers assigned to a subject by accessing the iVRS/iWRS after
confirming that the subject meets all the inclusion criteria and does not meet any of the
exclusion criteria.

Participant Eligibility

1. Be male or female, and >= 18 years of age
2. Have a history of a primary adenocarcinoma of the colon and / or rectum4
3. Have a history of Stage IV CRC with metastases to the liver only4
4. Have received at least 3 monthsf,5 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 monthsh,5 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 monthsh,5 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.
Radiofrequency ablation and chemoembolization are not permitted. Subjects undergoing
a planned 2-stage resection of liver metastases may be enrolled into the study.
5. 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).
6. Prior to randomization, have histological confirmation that CRC lesions were
adenocarcinoma (subtypes of adenocarcinoma, eg, mucinous adenocarcinoma, are
allowed). Subjects with CRC lesions of other histologic types, including mixed type
with predominant adenocarcinoma, will not be eligible to be randomized to study
treatment.
7. 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.
8. 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
* )
9. 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.
10. 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)
11. 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 <= 1.5 times the upper limit of normal (ULN)

* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3 times the
ULN

* Lipase <= 1.5 times the ULN

* Serum creatinine <= 1.5 times the ULN

* Carcinoembryonic antigen (CEA) <= 3 times the ULN Subjects who are
therapeutically 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
(ANC) >= 1500/mm3 without transfusions or granulocyte-colony stimulating factor
(G-CSF) and other hematopoietic growth factors (see Sections 7.1.2 and 7.5.3)

* Alkaline phosphatase <= 2.5 times the ULN 12. Understand, be willing to give consent, and sign the written informed consent form (ICF)
prior to undergoing any study-specific procedure.
13. Be willing to give consent and sign the ICF for tumor tissue collection (primary tumor and
liver metastases).
14. 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)
15. 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.
16. 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.