[18F]FLT-PET as a Predictive Imaging Biomaker of Treatment Responses to Regorafenib
|Study Design:||Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
|Official Title:||3'-Deoxy-3'-18F-fluorothymidine Positron Emission Tomography ([18F] FLT-PET) for the Prediction of Response to Regorafenib in the Metastatic Colorectal Cancer Patients Who Progressed After All Standard Therapies|
- [18F]FLT-PET SUV_MAX [ Time Frame: upto 21 days, once before treatment and another at 21 days after regorafenib treatment ] [ Designated as safety issue: No ]Quantitative image analysis of [18F]FLT uptake includes Maximum Standardized Uptake Value (SUV_MAX) of all target lesions.
- Response evaluation by RECIST 1.1 [ Time Frame: upto 1 year, performed from before treatment and every 8 weeks during study treatment ] [ Designated as safety issue: No ]All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline and every 8 weeks.
|Study Start Date:||July 2014|
|Estimated Study Completion Date:||April 2017|
|Estimated Primary Completion Date:||April 2016 (Final data collection date for primary outcome measure)|
Experimental: Regorafenib and FLT-PET
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).
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).
Other Name: Stivarga
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02175095
|Contact: Yong Sang Hong, M.D., Ph.D.||+firstname.lastname@example.org|
|Contact: Tae Won Kim, M.D., Ph.D.||+email@example.com|
|Korea, Republic of|
|Asan Medical Center||Recruiting|
|Seoul, Songpa, Korea, Republic of, 138736|
|Contact: Yong Sang Hong, M.D., Ph.D. +82-2-3010-3227 firstname.lastname@example.org|
|Contact: Tae Won Kim, M.D., Ph.D. +82-2-3010-3910 email@example.com|
|Principal Investigator: Yong Sang Hong, M.D., Ph.D.|
|Sub-Investigator: Tae Won Kim, M.D., Ph.D.|
|Sub-Investigator: Jae-Lyun Lee, M.D., Ph.D.|
|Sub-Investigator: Kyu-pyo Kim, M.D., Ph.D.|
|Sub-Investigator: Jeong Eun Kim, M.D., Ph.D.|
|Sub-Investigator: Seong Joon Park, M.D.|
|Principal Investigator:||Yong Sang Hong, M.D., Ph.D.||Asan Medical Center|