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). C max 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.
Highlights
This 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
Five 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
Ascorbic acid was eliminated by simple firstorder kinetics
Summary
Eligible patients were required to have measurable biopsyproven advanced and/or metastatic solid tumors that were progressing with no other available known beneficial treatments. Patients with current tobacco use, evidence of significant psychiatric disorder by history or examination that would prevent completion of the study or preclude informed consent, current aspirin (exceeding 325 mg/day) or acetaminophen (exceeding 2 g/day) use, or the presence of brain metastases that had not responded to therapy were not eligible for the study entry. The protocol was approved by the institutional review board of Cancer Treatment Centers of AmericaÒ at Midwestern Regional Medical Center, and written informed consent was obtained for each patient prior to performing study-related procedures. An independent Data Safety Monitoring Board was utilized to periodically review and evaluate patient safety, accumulate study data, study progress, and when appropriate make recommendations about continuing or modifying the study
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