Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer

Abstract

PurposeThis phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy.MethodsFive cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m2 in the first cohort. For subsequent cohorts, dose was increased by 20 g/m2 until a maximum tolerated dose was found.ResultsAscorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m2, respectively). Cmax and AUC values increased proportionately with dose between 0 and 70 g/m2, but appeared to reach maximal values at 70 g/m2 (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m2 maintained levels at or above 10–20 mM for 5–6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response.ConclusionsAscorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient’s blood and was well tolerated. The recommended dose for future studies is 70–80 g/m2.

Proposed Insights in the Pharmaco-Dynamic Theory of Ascorbate Pro-Oxidant Activity

“…Meanwhile, a large amount (mM) of ascorbate would be interacting with RBC. Basically, our data demonstrates the existence of a multitude of OS damage in RBC following incubation with AA at pharmacologic doses and that these effects occur in a dose dependant manner within the pharmacologic interval defined by Stephenson et al (2013) (Fig. 3).…”

Ascorbic Acid in Cancer: A Renewed Hope?

“…This aspect could be one of the reasons for failure of previous clinical trials to show benefit in administering AA to cancer patients [38,39]. However, intravenous (IV) administration of AA can bypass this saturation and can achieve plasma concentrations up to 50 mM, which have been well tolerated without side effects [36,40,41]. Recently concluded phase 1 clinical trials conducted on small groups of pancreatic cancer patients show that there is no toxicity observed in cancer patients treated with high dose IV AA (target concentration around 20 mM) [42,43] …”

Effects of X-ray irradiation in combination with ascorbic acid on tumor control

“…The marked inhibition of cell growth observed in the cells treated with X-ray irradiation combined with AsA treatment appeared to be attributed to the combined effect of X-ray irradiation and the added suppressive effect of AsA on cancer cells. Therefore, X-ray irradiation combined with AsA treatment may be effective against solid tumors (24).…”