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

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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.

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Acknowledgments

The authors thank the John (Jack) Widness lab and the Sysmex Corporation, Kobe, Japan, for the use of XE-2100 and XT-2000 automated hematology analyzers. The authors also thank the Holden Comprehensive Cancer Center for its support for the clinical trial. TJvE gratefully acknowledges support from the Iowa Superfund Research Program (P42 ES013661) Training Core. The content is solely the responsibility of the authors and does not represent views of the National Institutes of Health. The University of Iowa ESR Facility provided invaluable support. This work was supported by the National Institutes of Health [grant numbers GM42056, GM073929, P42ES013661, P30 CA086862, CA137230, and CA148062], the Medical Research Service of the Department of Veterans Affairs, the Holden Comprehensive Cancer Center, and the Susan L. Bader Foundation of Hope. Dr. Mark Levine is supported by the Intramural Research Program NIDDK, NIH.

Conflict of interest

  The authors have declared no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Surgery, 1528 JCP—UIHC, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    J. L. Welsh & J. J. Cullen

  2. Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA, USA

    B. A. Wagner, T. J. van’t Erve, K. L. Bodeker, J. Du, G. R. Buettner & J. J. Cullen

  3. The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA

    P. S. Zehr, D. J. Berg, T. R. Halfdanarson, G. R. Buettner & J. J. Cullen

  4. Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USA

    D. J. Berg & T. R. Halfdanarson

  5. Penn State Hershey Cancer Institute, Hersey, PA, USA

    N. S. Yee

  6. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA

    L. J. Roberts II

  7. Integrative Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    J. Drisko

  8. Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    M. Levine

  9. The Veterans’ Affairs Medical Center, Iowa City, IA, USA

    J. J. Cullen

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  1. J. L. Welsh
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  2. B. A. Wagner
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  3. T. J. van’t Erve
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  4. P. S. Zehr
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  8. K. L. Bodeker
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  9. J. Du
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  10. L. J. Roberts II
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  11. J. Drisko
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  12. M. Levine
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  13. G. R. Buettner
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  14. J. J. Cullen
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Corresponding author

Correspondence to J. J. Cullen.

Electronic supplementary material

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280_2013_2070_MOESM1_ESM.tif

Supplemental Fig. 1. Patient weight changes while receiving ascorbate + gemcitabine therapy. The bar graph demonstrates the mean patient weight at baseline and at removal from the study. Error bars represent the variability in the distribution of patients’ weights. Supplementary material 1 (TIFF 93 kb)

Supplementary material 2 (DOC 29 kb)

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Welsh, J.L., Wagner, B.A., van’t Erve, T.J. et al. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol 71, 765–775 (2013). https://doi.org/10.1007/s00280-013-2070-8

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  • DOI: https://doi.org/10.1007/s00280-013-2070-8

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