Regorafenib in Subjects With Antiangiogenic-naive and Chemotherapy-refractory Advanced Colorectal Cancer

An Uncontrolled, Open-label Phase IIb Trial of Regorafenib in Subjects With Antiangiogenic-naive and Chemotherapy-refractory Advanced Colorectal Cancer

To determine the efficacy (as measured by progression-free survival [PFS] rate at 8 weeks) of regorafenib in subjects with metastatic colorectal cancer (CRC) whose disease is refractory to standard therapies and who were never exposed to antiangiogenic therapy.

Inclusion Criteria:

• Male or female subjects ≥18 years of age;
• Histological or cytological confirmation of adenocarcinoma of the colon or/and rectum;
• Subjects with metastatic colorectal cancer (CRC) whose disease progressed or who were intolerant to standard chemotherapy based on fluoropyrimidine, oxaliplatin, irinotecan, and an anti-EGFR therapy if RAS wild-type. This progression must be during or within 4 months following the last administration of standard therapies.
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate bone-marrow, liver, and renal function
• Women of childbearing potential and men must agree to use adequate contraception when sexually active during the study and for at least 8 weeks after the last study drug administration.

Exclusion Criteria:

• Prior treatment with an antiangiogenic agent;
• Congestive heart failure of New York Heart Association (NYHA) class 2 or worse;
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of study drug;
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
• Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management);
• Ongoing acute or chronic infection (> Grade 2 NCI-CTCAE v 4.03);
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication) events within 6 months of study enrollment. Subjects being treated with low-weight heparin are allowed to participate as long as dose is limited to prophylactic use.
• Any history of or currently known brain metastases (head CT/MRI will be performed during screening period if brain metastases are suspected)
• Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years before study entry, except for curatively treated cervical cancer in situ, in situ ductal breast cancer, non-melanoma skin cancer and superficial bladder tumors;
• Last chemotherapy dose or any other anti-cancer therapy administered in less than 4 weeks from start of study treatment;
• Use of therapeutic anticoagulation;
• Proteinuria > 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (Grade 3, NCI-CTCAE v 4.03) on urinalysis screening result. If there is medical history of proteinuria, previous urinalysis results should be considered and/or performed so at least 2 results separated by at least 2 weeks are available;
• History of interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
• Non-healing wound, non-healing ulcer, or non-healing bone fracture;
• Subjects with evidence or history of any bleeding diathesis, irrespective of severity;
• Any hemorrhage or bleeding event ≥ Grade 3 NCI-CTCAE v 4.03 within 4 weeks prior to the start of study medication;
• Known history of human immunodeficiency virus (HIV) infection;
• History of active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy;
• Pregnancy or breastfeeding.