[18F]FLT-PET as a Predictive Imaging Biomaker of Treatment Responses to Regorafenib

Inclusion Criteria

• Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum.
• Progressed after 3 active cytotoxic chemotherapy including fluoropyrimidines, oxaliplatin and irinotecan during or within 6 months of their administrations with or without targeted agents (bevacizumab or cetuximab).
• Extrahepatic measurable lesion(s) by RECIST 1.1.
• Unresectable metastatic disease.
• Age over 20 years old.
• Have a life expectancy of at least 3 months.
• ECOG performance status of 1 or lower.
• Adequate organ functions.
• Be willing and able to comply with the protocol for the duration of the study.
• Give written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw the study at any time, without prejudice.
• Women of childbearing potential and men must agree to use adequate contraception since signing of the IC form until at least 8 weeks after the last study drug administration.

Exclusion Criteria

• Prior treatment of regorafenib.
• Liver-limited metastasis.
• Inability to perform [18F]FLT and [18F]FDG-PET imaging studies due to physical inability or claustrophobia.
• Concurrent or previous history of another primary cancer within 3 years prior to randomisation except for curatively treated cervical cancer in situ, non-melanomatous skin cancer, superficial bladder cancer (pTis and pT1) and curatively treated thyroid cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer without distant metastasis could be allowed with the agreement of the chief principal investigator.
• Uncontrolled CNS metastases.
• Prior radiation therapy would be permitted, but non-radiated evaluable lesions should be present at study entry.
• Uncontrolled hypertension (>150/90 mmHg) despite of optimal management; anti-hypertensive drugs for BP lowering before study entry would be permitted.
• Congestive heart failure ≥ New York Heart Association (NYHA) class 2.
• Unstable angina, new-onset angina within 3 months, or history of myocardial infarction within 6 months before the study entry.
• Arterial or venous thromboembolism within 6 months.
• Serious concurrent infections or non-malignant illness.
• Liver cirrhosis ≥ Child-Pugh class B.
• Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
• Peripheral neuropathy of grade ≥ 2.
• Major surgery or significant traumatic injury within 28 days prior to study treatment.
• Non-healing wound, ulcer, or bone fracture.
• Current evidence of significant gastrointestinal bleeding or (impending) obstruction.
• Any hemorrhage or bleeding event of grade ≥ 3 within 4 weeks prior to the start of study medication.
• Proteinuria ≥ 3+ in the routine urinalysis; in this case, the total protein in the 24-hour urine collection should be measured, and the accrual is permitted if total protein < 3.5 g/day.
• Pregnant of breast-feeding subjects. Women of child-bearing potential must have pregnancy test within 7 days and a negative result must be documented before start of study treatment.
• Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
• Use of strong CYP3A4 inducers or inhibitors which are known to decrease the metabolism of regorafenib (ketoconazole, rifampin, phenytoin, carbamazepine, phenobarbital).
• Known hypersensitivity to the study drug or any of its excipients.