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

Abstract

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 .

Keywords: Ascorbic acid; Metastatic colorectal cancer; Metastatic gastric cancer; Recommended phase 2 dose; chemotherapy.

Conflict of interest statement

The authors declare that they have no potential conflicts of interest to disclose.

Figures

Fig. 1

Study design. Ascorbic acid was administered in both study parts with 5-FU continuous infusion. Standard mFOLOX6 comprised a standard dose of 85 mg/m2 oxaliplatin on day 1 + leucovorin at 400 mg/m2 (2-h infusion during oxaliplatin administration) + 5FU at 400 mg/m2 (bolus immediately following irinotecan administration) and 2400 mg/m2 (46-h continuous infusion), every 2 weeks. Standard FOLFIRI consisted of a standard dose of irinotecan at 180 mg/m2 (90-min infusion) + leucovorin 400 mg/m2 (2-h infusion during irinotecan administration) + 5-FU at 400 mg/m2 (bolus immediately following irinotecan administration) and 2400 mg/m2 (46-h continuous infusion), every 2 weeks. In part 1, AA was administered once daily at 180 min (part 1) or at a fixed rate of 0.6, 0.8 and 1 g/min (part 2) for three consecutive days with continuous 5-FU infusion in a 14-day cycle

Fig. 2

Mean plasma concentration–time curve of ascorbic acid after 0.2~1.5 g/kg administration to cancer patients (n = 3) on Day 1 (a) and Day 3 (b). After i.v. administration, the plasma concentrations of ascorbic acid rose gradually and peaked at 3 h. The Cmax, and AUC values of ascorbic acid displayed dose-dependent increases. Ascorbic acid concentrations in the high-dose groups remained at 10–20 mmol/L for approximately 3 h and showed no accumulation in the body during 3 daily administrations. Curves varying in linetypes and colors correspond to different administration dosages of ascorbic acid

Fig. 3

Relative change from baseline in target lesion size (at the best tumor response). Shown is the percent change in the lowest sum of the target lesions from the baseline for patients who were on treatment for 3 cycles. Twenty-three patients had documented RAS and Braf genetic alterations