Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial
- 1.2k Downloads
Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma.
Nine subjects received twice-weekly intravenous ascorbate (15–125 g) employing Simon’s accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored.
Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months.
Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.
KeywordsPancreatic neoplasm Ascorbic acid Clinical trial Phase 1 Gemcitabine Drug toxicity
- 3.Winstead ER (2009) Pancreatic cancer report urges changes in clinical trials. NCI Cancer BulletinGoogle Scholar
- 4.Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol Off J Am Soc Clin Oncol 15(6):2403–2413Google Scholar
- 19.Kadiiska MB, Gladen BC, Baird DD, Graham LB, Parker CE, Ames BN et al (2005) Biomarkers of oxidative stress study III. Effects of the nonsteroidal anti-inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in CCl4 poisoning. Free Radic Biol Med 38(6):711–718PubMedCrossRefGoogle Scholar
- 24.Buettner GR, Wagner BA (2011) Rodgers VG. An approach to understand the role of reactive species in defining the cellular redox environment, Cell Biochem Biophys Quant Redox BiolGoogle Scholar