Original Article

Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 3, pp 765-775

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

  • J. L. WelshAffiliated withDepartment of Surgery, 1528 JCP—UIHC, The University of Iowa Carver College of Medicine
  • , B. A. WagnerAffiliated withDepartment of Radiation Oncology, The University of Iowa Carver College of Medicine
  • , T. J. van’t ErveAffiliated withDepartment of Radiation Oncology, The University of Iowa Carver College of Medicine
  • , P. S. ZehrAffiliated withThe Holden Comprehensive Cancer Center, The University of Iowa
  • , D. J. BergAffiliated withThe Holden Comprehensive Cancer Center, The University of IowaDepartment of Internal Medicine, The University of Iowa Carver College of Medicine
  • , T. R. HalfdanarsonAffiliated withThe Holden Comprehensive Cancer Center, The University of IowaDepartment of Internal Medicine, The University of Iowa Carver College of Medicine
  • , N. S. YeeAffiliated withPenn State Hershey Cancer Institute
  • , K. L. BodekerAffiliated withDepartment of Radiation Oncology, The University of Iowa Carver College of Medicine
  • , J. DuAffiliated withDepartment of Radiation Oncology, The University of Iowa Carver College of Medicine
    • , L. J. RobertsIIAffiliated withVanderbilt-Ingram Cancer Center, Vanderbilt University
    • , J. DriskoAffiliated withIntegrative Medicine, University of Kansas Medical Center
    • , M. LevineAffiliated withMolecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
    • , G. R. BuettnerAffiliated withDepartment of Radiation Oncology, The University of Iowa Carver College of MedicineThe Holden Comprehensive Cancer Center, The University of Iowa
    • , J. J. CullenAffiliated withDepartment of Surgery, 1528 JCP—UIHC, The University of Iowa Carver College of MedicineDepartment of Radiation Oncology, The University of Iowa Carver College of MedicineThe Holden Comprehensive Cancer Center, The University of IowaThe Veterans’ Affairs Medical Center Email author 

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Abstract

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.

Keywords

Pancreatic neoplasm Ascorbic acid Clinical trial Phase 1 Gemcitabine Drug toxicity