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

BACKGROUND: Preclinical 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). METHODS: In 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. RESULTS: Thirty-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. CONCLUSIONS: The favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT02969681 .

A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study).

PURPOSE: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

PD-1 antibody camrelizumab for Epstein-Barr virus-positive metastatic gastric cancer: a single-arm, open-label, phase 2 trial.

Gastric cancer (GC) patients with Epstein-Barr virus (EBV) positivity have demonstrated promising response with immunotherapy. We assessed the efficacy and safety of camrelizumab as salvage treatment in EBV-positive mGC. In this single-arm, phase 2 prospective clinical trial (NCT03755440), stage IV EBV-positive GC patients who failed/could not tolerate previous lines of chemotherapy were given intravenous camrelizumab 200 mg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response, and toxicity. Exploratory analysis included the associations between treatment response and tumor mutation burden (TMB), programmed cell death ligand-1 (PD-L1) expression. Six eligible patients were enrolled in the first stage of the study. No patient achieved an objective response; thus, the study did not proceed to the second stage. The DCR was 67% (4/6). The median PFS rate was 2.2 months (95% CI: 1.5-not reached [NR]) and median OS was 6.8 months (95% CI: 1.7-NR). All treatment-related adverse events were grade 1-2, with reactive cutaneous capillary endothelial proliferation (n=4 [67%]) being the most commonly observed event. The only patient with PD-L1 combined positive score >1 had disease progression. Two stable disease and one disease progression were observed in three patients with TMB >10 Mut/Mb. EBV positivity may not be a good predictor for response to camrelizumab in mGC. Newer biomarkers are needed to identify EBV-positive mGC respondents who might benefit from immunotherapy.