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A randomized, open-label, multicenter, phase III study of high-dose vitamin C plus FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line treatment in patients with unresectable metastatic colorectal cancer
Background
Previous studies showed that intravenously high dose vitamin C probably have anti-cancer effect. Preclinical study found that high dose vitamin C selectively killed human colorectal cancer cells harboring KRAS or BRAF mutations. Our phase I dose-escalation and expansion study has shown that high dose (up to 1.5g/kg) intravenous vitamin C with FOLFOX or FOLFIRI is well tolerated in patients with colorectal or gastric cancer.
Methods
This is a randomized, open-label, phase III study, enrolled patients with unresectable metastatic colorectal cancer (mCRC), normal G6PD status and no prior treatment. Patients with mCRC were randomized 1:1 into one of two groups. Patients in the control group were treated with FOLFOX with or without bevacizumab every 2 weeks. Patients in the experimental group were treated with vitamin C intravenously (1.5g/kg/day, d1-3) plus FOLFOX with or without bevacizumab every 2 weeks. Randomization was stratified by the location of primary site (left- or right-sided) and treatment with bevacizumab (with or without). The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate, assessment of treatment-related adverse events (TRAEs), and PFS and OS in RAS or BRAF mutant patients.
Results
Between July 2017 and December 2019, 442 patients were randomized 1:1 into the control group (chemotherapy only) and the experimental group (chemotherapy plus high-dose vitamin C) respectively. After a median follow-up of 24.5 months (95% confidence interval [CI], 23.4 to 27.2 months), chemotherapy plus high dose vitamin C was not superior to chemotherapy only group in terms of PFS (8.6 vs 8.3 months; hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.70-1.05, P = 0.1). An overall response, as evaluated with Response Evaluation Criteria in Solid Tumors version 1.1, was observed in 44.3% of the patients in the experimental group and 42.1% in the control group. In the prespecified subgroup analysis, patients with RAS mutation (HR = 0.67, 95%CI, 0.50-0.91) showed significantly improved PFS in the experimental group than in the control group. Patients with RAS mutation showed longer PFS in the experimental group than in the control group (9.2 vs 7.8 months, P = 0.01). TRAEs of grade 3 or higher occurred in 33.5% of the patients in the experimental group, as compared with 30.3% in the control group.
Conclusions
High-dose vitamin C plus FOLFOX with or without bevacizumab failed to show superior PFS than FOLFOX with or without bevacizumab in patients with mCRC as first-line treatment, but showed some benefit in patients with RAS mutation.
Clinical trial identification
NCT02969681.
Legal entity responsible for the study
The authors.
Funding
The Sun Yat-sen University Clinical Research 5010 Program (2018014); National Natural Science Foundation of China (81930065, 82173128); Science and Technology Program of Guangdong (2019B020227002); Science and Technology Program of Guangzhou (201904020046).
Disclosures
All authors have declared no conflicts of interest.
