Conditions: Colorectal Cancer
Keywords: regorafenib fluorothymidine positron emission tomography metastatic colorectal cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 68
Healthy volunteers: no

Brief summary:
Regorafenib is approved in the treatment for metastatic colorectal cancer patients who have been progressed after standard therapies, however, there has not been a predictive biomarker. The investigators designed this study to investigate whether \[18F\]FLT-PET might paly a role as a predictive imaging biomarker of treatment responses to regorafenib.

Detailed description:
Recent advances have been made in the treatments for the patients with metastatic colorectal cancer (mCRC) owing to the introductions of targeted agents, which included bevacizumab, cetuximab, panitumumab, and aflibercept. And in addition, regorafenib, a newer tyrosine kinase inhibitor (TKI), has been approved in the treatment for the mCRC patients.

Regorafenib (BAY 73-4506) is an orally available multikinase inhibitor with activity against multiple targets, including tumor angiogenesis (VEGFR-1, -2, -3 and TIE-2), oncogenesis (KIT, RET, RAF-1, BRAF, and BRAFV600E), and tumor microenvironment (PDGF and FGFR). Regorafenib has shown antitumor activities in multiple solid tumors, and demonstrated significant efficacy outcomes in patients with advanced gastrointestinal stromal tumors and colorectal cancers.

The CORRECT study, which compared regorafenib vs placebo in mCRC patients who have been treated with all standard treatment, showed survival improvements with statistical significances; median OS 6.4 vs 5.0 months, HR 0.77, p=0.0052; median PFS 1.9 vs 1.7 months, HR 0.49, p\<0.000001. Above these results, regorafenib monotherapy has been recently approved for the treatment of mCRC patients who have been refractory to all of standard therapies.

However, there are still only a few biomarkers which have been established as predictive of treatment responses in the fields of treatments for mCRC patients; KRAS or BRAF mutations for the lack of responses to anti-EGFR agents, cetuximab or panitumumab. There still has not been any biomarker which would be predictive of treatment responses to bevacizumab, aflibercept or regorafenib. The difficulties in search for biomarkers for these agents might come from the facts as following; either bevacizumab or aflibercept does not act directly against tumor itself and should be combined with cytotoxic agents to show efficacy; regorafenib is a multikinase inhibitor which has too many potential targets.

Above these reasons, imaging modalities can be fascinating and alternative candidates for predictive biomarkers of treatment responses. Conventional anatomic imaging studies such as computed tomography (CT) scans can hardly predict the treatment responses earlier, and the RECIST using CT scans, which is widely used for measurement of treatment responses, might have several limitations for measurement of efficacy from targeted agents such as cystic necrosis without tumor shrinkage. In the CORRECT study, overall response rate by RECIST was only 1%, although the rates for disease stabilization was up to 40%, which might be a good example for the limitations of the RECIST using conventional anatomical imaging studies for the response evaluation of regorafenib.

Among imaging studies, PET scans are useful tools for the noninvasive measurement of functional changes after treatment with targeted agents, and \[18F\]FLT-PET is potentially useful tool for earlier prediction of treatment responses because it can detect earlier changes of cellular proliferation using \[18F\]FLT (fluorothymidine), a radiotraceable substitute for thymidine which is essential for DNA synthesis. Several studies have been reported that \[18F\]FLT-PET may allow an early assessment of the response to chemotherapy including targeted agents. There also has been a report that \[18F\]FLT-PET could predict treatment responses of BRAF inhibitors in the colorectal cancer xenograft model; regorafenib also has an inhibitory effect on BRAF.

Therefore, the investigators have planned this study with hypothesis that \[18F\]FLT-PET could be useful for identifying a subgroup of mCRC patients with clinical responsiveness to regorafenib.

Arms:
arm 1: After checking the eligibility for the study entry, patients will be scheduled to perform \[18F\]FLT-PET scans before and on 21st day from the administration of regorafenib. Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal. Standard anatomical response evaluation will be performed every 8 weeks (without regard to the cycles or schedules of chemotherapy). Additional \[18F\]FDG-PET will be performed before treatment and at 8 weeks (just once at the point of first response evaluation).

Interventions: intervention 1: Regorafenib intervention 2: [18F]FLT-PET intervention 3: [18F]FDG-PET
Intervention descriptions: intervention 1: Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal. intervention 2: \[18F\]FLT-PET scans before and on 21st day from the administration of regorafenib. intervention 3: \[18F\]FDG-PET will be performed before treatment and at 21 days after treatment.

Protocol document: