Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal cancer or gastric cancer

BMC Cancer

Jia-Jia Hu¹  Su Li²  Bing-Tian Bi²  Zhi-Da Lv³  Feng-Hua Wang³  Shuang-Zhen Chen³  De-Shen Wang³  Rui-Hua Xu³  Zi-Xian Wang³  Feng Wang³  Ming-Ming He³  Zhi-Qiang Wang³  Yu-Hong Li³  Chao Ren³  Si-Mei Shi³  Ying Jin³ 

[1] 0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, People’s Republic of China;0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, People’s Republic of China;0000 0004 1803 6191, grid.488530.2, Department of Clinical Trial Center, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China;0000 0004 1803 6191, grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, People’s Republic of China;0000 0004 1803 6191, grid.488530.2, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China;

关键词: Ascorbic acid;    Metastatic colorectal cancer;    Metastatic gastric cancer;    Recommended phase 2 dose;    chemotherapy;   

DOI  :  10.1186/s12885-019-5696-z

来源: publisher

【 摘 要 】

BackgroundPreclinical studies suggest synergistic effectiveness of ascorbic acid (AA, vitamin C) and cytotoxic agents in gastrointestinal malignancies. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AA combined with mFOLFOX6 or FOLFIRI regimens in patients with metastatic colorectal cancer (mCRC) or gastric cancer (mGC).MethodsIn the dose-escalation phase, patients received AA (0.2–1.5 g/kg, 3-h infusion, once daily, days 1–3) with mFOLFOX6 or FOLFIRI in a 14-day cycle until the MTD was reached. In the speed-expansion phase, AA was administered at the MTD or at 1.5 g/kg if the MTD was not reached at a fixed rate of 0.6, 0.8 or 1 g/min. Pharmacokinetics and preliminary efficacy were also assessed.ResultsThirty-six patients were enrolled. The MTD was not reached. The RP2D was established as AA at 1.5 g/kg/day, days 1–3, with mFOLFOX6 or FOLFIRI. No dose-limiting toxicity (DLT) was detected during dose escalation. The most common treatment-emergent adverse events (TRAEs) were sensory neuropathy (50%), nausea (38.9%), vomiting (36.1%) and neutropenia (27.8%). Grade 3–4 TRAEs were neutropenia (13.9%), sensory neuropathy (2.8%), vomiting (2.8%), diarrhea (2.8%) and leukopenia (2.8%). AA exposure was dose-proportional. The objective response rate was 58.3%, and the disease control rate was 95.8%. No difference in efficacy was found between mCRC patients with wild-type RAS/BRAF and mutant RAS or BRAF.ConclusionsThe favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC.Trial registrationClinicalTrial.gov Identifier: NCT02969681.

【 授权许可】

CC BY