A phaseⅠ/Ⅱa clinical study of cetuximab combined with fruquintinib in the third-line treatment of RAS/BRAF wild-type colorectal cancer.
Authors: Li Yong , Qu Yan-chun , Liu Yufeng , Liu Yi-hong , Zhu Yan-juan , Ye Yongsong , Chen Xian , Qu Xin , Liu Li-rong , Li Wenzhu , Hou Fangfang , Zhang Haibo 
Published: January 2021

TPS151 Background: The standard third-line treatment of mCRC is regofenib, fruquintinib or TAS-102. However, the efficacy was not satisfied. Because VEGF and EGFR share the downstream signal pathway, targeting these two pathways may have synergistic efficacy. Preclinical studies have confirmed the effect of the combination of regorafenib and cetuximab. The subsequent phase Ⅰb study in advanced cancer showed the combination is effective. Fruquintinib is the same anti-VEGF drugs and was approved in China. Our department has treated one patient of advanced colorectal cancer, no standard regimen after third-line treatment. The efficacy is SD and PFS time exceeded 6 months. Therefore this study explores the safety and efficacy of fruquintinib combined with cetuximab. Methods: This is a single-center, non-random, prospective, open exploratory study. Eligible pts were diagnosed as advanced RAS/BRAF wild-type colorectal cancer and had received at least two prior regimens of standard therapies. The purpose of phase Ⅰ is to confirm the safety and the appropriate dose of fruquintinib combined with cetuximab. The phase Ⅱa investigate the safety and the efficacy of fruquintinib combined with cetuximab. Phase I: The dose of cetuximab is 500mg/m2 every two weeks which is clinically tolerable, so the dose need not be adjusted. fruquintinib is taken once daily for the first 21 days of each 28-day cycle and the dose adjustment is required due to the side effects. The standard dose of fruquintinib is 5mg/d, but the side effects are serious. The dose of 3mg/d is the minimum effective dose, therefore the initial dose of fruquintinib starts from 4mg, and three patients are enrolled. If DLT appeared in less than three patients, the dose elevated to 5mg/d. Three patients were enrolled in the 5mg/d dose group. If DLT appeared in less than three patients, the right dose of fruquintinib was 5mg/d. If DLT appeared in all three patients of the 5mg/d, fruquintinib was declined to 4mg/d combined with cetuximab to carry out a phase Ⅱa study. Fruquintinib initial dose is 4mg/d. If DLT was present in all three patients, the dose was reduced to 3mg/d. The standard dose of fruquintinib (3mg/d) was determined to be MDT, and the subsequent phase Ⅱa study was conducted by giving fruquintinib 3mg/d. The phase Ⅱa study is cetuximab 500mg/m2 biweekly combined with fruquintinib according to the confirmed dose in phase Ⅰ, taking it once daily for the first 21 days of each 28-day cycle. The number of cases is 20.Response assessment via CT/MRI is to be done q8 wks (RECIST 1.1). Continue until disease progression or unacceptable toxicity. The primary objective is to estimate safety, grade 3/4 adverse, and DLT. Secondary objectives include ORR, PFS, and OS. Final analysis to be done 6 mo after enrollment of the final pt. Clinical trial information: ChiCTR2000038227 . Research Sponsor: None