This clinical study evaluates and compares the efficacy and safety of Regorafenib versus placebo in patients with coloreactal cancer after curative resection of liver metastasis and completion of all planned chemotherapy.

Phase 1

• Conditions: MedDRA version: 17.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864; Metastatic Colorectal cancer; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-004369-42-BE
• Lead Sponsor: Bayer HealthCare AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2013-09-03
• Last Update Posted: 23 January 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 750

Inclusion Criteria

Eligible subjects must:

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

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

3. Have a history of Stage IV CRC with metastases to the liver only

4.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.

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 ra

Exclusion Criteria

1.Are taking strong CYP3A4 inhibitors(eg,clarithromycin,indinavir,itraconazole,ketoconazole,nefazod one,nelfinavir,posaconazole,ritonavir,saquinavir,telithromycin,voriconazole)or strong CYP3A4 inducers (eg,carbamazepine,phenobarbital,phenytoin,rifampin,St. John's Wort).
2.Have used biologic response modifiers,such as granulocyte-colony stimulating factor,within 3 weeks prior to signing the ICF
3.Have had prior treatment with regorafenib or any other VEGFRtargeting kinase inhibitor.
4.Have had anti-cancer treatment following liver resection that exceeded a duration of 6 months.
5.Have been treated with biologics(eg,antibodies targeting VEGFR or EFGR)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.
6.Completed their last dose of chemotherapy or had their last cancer surgery more than 10 weeks,whichever came later,prior to randomisation.
7.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.
8.Have been previously assigned to treatment during this study(subjects permanently withdrawn from study treatment will not be allowed to reenter the study).
9.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).
10.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.
11.Have unresolved toxicity higher than National Cancer Institute-
Common Terminology for Adverse Events version 4.0(NCI-CTCAE v 4.0)Grade 1 attributed to any prior therapy/procedure,excluding alopecia and/or oxaliplatin-induced neurotoxicity=Grade 2 and hemoglobin=9g/dL as per inclusion criteria.
12.Have had a major surgical procedure,open biopsy,or significant traumatic injury within 28 days prior to initiation of study treatment.
13.Are pregnant.
14.Are breastfeeding.
15.Are unable to swallow oral tablets(crushing of study treatment tablets is not allowed).
16.Have congestive heart failure classified as New York Heart Association Class 2 or higher.
17.Have had unstable angina(angina symptoms at rest)or new-onset angina =3months prior to screening.
18.Have had a myocardial infarction <6 months prior to initiation of study treatment.
19.Have cardiac arrhythmias requiring anti-arrhythmic therapy,with the exception of beta blockers or digoxin.
20.Have uncontrolled hypertension(systolic blood pressure >140 mmHg or diastolic blood pressure >90mmHg)despite optimal medical management.
21.Have pheochromocytoma.
22.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.
23.Have an ongoing infection with severity of Grade 2 or above(NCICTCAE
v4.0).
24.Have a known history of human immunodeficiency virus infection.
25.Have eithe

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate and compare the efficacy and safety of regorafenib versus placebo in subjects with colorectal cancer (CRC) after curative resection of liver metastasis and completion of all planned chemotherapy.<br>;Secondary Objective: Not Applicable;Primary end point(s): Disease-free survival (DFS) <br>;Timepoint(s) of evaluation of this end point: The primary endpoint, disease-free survival (DFS) as assessed by the investigator, will be measured by CT/MRI scans obtained at screening and every 3 months during the first 3 years of the study, then 6-monthly for a further year, then yearly until disease recurrence.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Overall survival;Timepoint(s) of evaluation of this end point: All subjects will be followed until death (unless consent for Overall Survival follow-up is withdrawn).