Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial

• Published in: Cancer chemotherapy and pharmacology Vol. 71; no. 3; pp. 765 - 775
• Main Authors: Welsh, J. L., Wagner, B. A., van’t Erve, T. J., Zehr, P. S., Berg, D. J., Halfdanarson, T. R., Yee, N. S., Bodeker, K. L., Du, J., Roberts, L. J., Drisko, J., Levine, M., Buettner, G. R., Cullen, J. J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-03-2013; Springer; Springer Nature B.V
• Subjects: Adenocarcinoma - drug therapy; Aged; Antimetabolites, Antineoplastic - administration & dosage; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antioxidants - administration & dosage; Ascorbic Acid - administration & dosage; Ascorbic Acid - blood; Biological and medical sciences; Cancer Research; Chromatography, High Pressure Liquid; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Disease-Free Survival; Drug Administration Schedule; Female; Gastroenterology. Liver. Pancreas. Abdomen; Glutathione - blood; Humans; Infusions, Intravenous; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Original Article; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Patient Compliance; Patient Safety; Pharmacology. Drug treatments; Pharmacology/Toxicology; Sentinel Lymph Node Biopsy; Tumors; Clinical trial; Ascorbic acid; Phase 1; Pancreatic neoplasm; Gemcitabine; Drug toxicity; Antineoplastic agent; Human; Drug; Toxicity; Vitamin; Malignant tumor; Metastasis; Antimetabolic; Pancreas cancer; Phase I trial; Pyrimidine derivatives; Digestive diseases; Advanced stage; Fluorine Organic compounds; Pharmacokinetics; Pyrimidine nucleoside; Cancer; Pancreatic disease
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2070-8

Background
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.
Design
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.
Results
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.
Conclusions
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.