Pancreatic cancer survival continues to be amongst the shortest of all cancers, and new therapies are urgently needed. The majority of patients with pancreatic cancer already have metastatic disease at clinical presentation 
, and many patients progress quickly even with standard treatment of gemcitabine alone or gemcitabine plus erlotinib 
Ascorbic acid (ascorbate, vitamin C) in cancer care has had a labyrinthine history 
. Several decades ago, observational and anecdotal clinical data obtained by Cameron and Pauling suggested an unexpected increase in survival in some patients who received 10 grams of ascorbic acid daily compared to retrospective controls 
. However, two double-blinded placebo-controlled trials showed no efficacy of the same ascorbic acid dose 
, and thus, ascorbate was dismissed from therapeutic consideration in 1985 
. A more recent review and analysis of patients receiving oral doses of ascorbic acid demonstrated no benefit in cancer patients 
Since then, renewed interest in ascorbic acid and cancer treatment arose serendipitously from clinical pharmacokinetics studies of ascorbic acid in healthy adults 
. In those studies, to determine true bioavailability, subjects received both oral and intravenous ascorbate. When ascorbic acid was given intravenously in doses above 0.5 grams, it was found that the usual tight control of ascorbic acid concentrations with oral doses was bypassed. Only intravenous administration resulted in very high ascorbic acid concentrations until renal excretion restored homeostasis. With these pharmacokinetics data as background, investigators revisited the earlier work on cancer and found that in the studies by Cameron and Pauling, patients received both intravenous as well as oral ascorbate, while patients from the later studies received only oral doses.
Detailed pharmacokinetics studies in humans and animals have confirmed that intravenous ascorbate in pharmacologic doses can produce peak plasma concentrations that are several hundred fold higher than those possible from maximal oral doses 
. In cell and animal experiments, such pharmacologic concentrations of ascorbate kill a number of cancer cell types, but not normal cells, and decrease tumor growth in mice 
. In humans, plasma ascorbate concentrations produced by intake of vitamin C rich foods (fruits and vegetables) are usually <0.1 mM, and by higher intake from supplements are <0.15 mM 
. In rodents, baseline plasma ascorbate concentrations are approximately 0.05 mM. When parenteral pharmacologic ascorbate doses are administered to animals or humans, peak plasma concentrations are as high as 30 mM 
. Across this broad range of concentrations, ascorbate in plasma readily diffuses into extracellular fluid 
. At extracellular fluid ascorbate concentrations above 3–4 mM, hydrogen peroxide concentrations above 5 µM are detectable in this fluid but not in blood 
. Such hydrogen peroxide concentrations do not otherwise occur with physiologic ascorbate concentrations. Hydrogen peroxide plus ascorbate in extracellular fluid results in formation of reactive oxygen species, which are selectively toxic to cancer cells but not normal tissues 
. Thus, pharmacologic ascorbate is a pro-drug for production of sustained concentrations of hydrogen peroxide in extracellular fluid but not blood 
There are limited human data on the use of pharmacologic ascorbate, despite surprisingly current wide use by practitioners of complementary and alternative medicine 
. One clinical safety study of pharmacologic ascorbate in patients with a variety of advanced cancers did not reveal untoward effects 
Pancreatic cancer is sensitive to pharmacologic ascorbate both in vitro and in animal models 
. Emerging evidence in both model systems indicates that ascorbate has synergistic effects with gemcitabine 
. When pharmacologic ascorbate was combined with gemcitabine, synergy was observed in all eight cell lines tested in vitro. In mouse models, ascorbate- gemcitabine combinations were more effective at inhibiting tumor growth compared to gemcitabine alone and also produced gemictabine dose-sparing effects.
Given what is known about the relative safety of pharmacologic ascorbate and its potential for efficacy, coupled to the pressing need for new treatments, we conducted a phase I trial of intravenous ascorbate added to gemcitabine and erlotinib in patients with stage IV metastatic pancreatic ductal adenocarcinoma with the specific primary aim of assessing safety and the secondary aim of assessing response to treatment. We investigated adverse events, measured peak plasma ascorbic acid concentrations after infusions, and conducted imaging pre- and post-treatment.