Raltitrexed, S-1 and fruquintinib (RSF) in the treatment of refractory metastatic colorectal cancer: study protocol for a multicenter, prospective, single-arm, phase II trial

BackgroundMetastatic colorectal cancer (mCRC) remains a significant clinical challenge, particularly for patients who have failed standard first- and second-line therapies. Despite advancements in targeted therapies, options for third-line treatments are limited, with current regimens such as regorafenib, fruquintinib, and TAS-102 demonstrating modest efficacy. The RS regimen, combining raltitrexed and S-1, has shown improved objective response rates (ORR) and progression-free survival (PFS) compared to standard therapies. Fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, has also demonstrated efficacy in heavily pretreated mCRC patients, including those resistant to prior anti-VEGF therapies. Combining these agents in the RSF regimen leverages complementary mechanisms of action to address resistance and improve outcomes.MethodsThis multicenter, prospective, single-arm, open-label Phase II clinical trial evaluates the efficacy and safety of the RSF regimen in mCRC patients who have failed first- and second-line therapies. Eligible patients will receive S-1 orally (14 days), raltitrexed intravenously (day 1), and fruquintinib orally (14 days) in a 21-day cycle. The primary endpoint is ORR, assessed using RECIST v1.1 criteria. Secondary endpoints include PFS, overall survival (OS), disease control rate (DCR), and quality of life (QoL). Safety will be monitored per NCI-CTCAE v4.0 criteria.DiscussionThe RSF regimen represents a novel approach to third-line treatment in mCRC, integrating chemotherapy and targeted therapy to enhance tumor response while managing toxicity. By leveraging complementary mechanisms of action, this study aims to optimize therapeutic outcomes in heavily pretreated patients. Further clinical research is essential to validate efficacy, safety, and potential biomarkers for patient selection.Trial registrationClinicalTrials.gov identifier: NCT06427005, registered on 19 June 2024.