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A phase I trial of UCN-01 and prednisone in patients with refractory solid tumors and lymphomas

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Abstract

Purpose

UCN-01 potently inhibits protein kinase C, phosphatidylinositide-dependent kinase-1, and checkpoint kinase 1, which are involved in regulating cell cycle progression. We designed a phase I study to determine the maximum tolerated dose (MTD) of UCN-01 with prednisone in patients with advanced malignancies.

Methods

UCN-01 was administered as a continuous intravenous infusion over 72 h in cycle 1 and 36 h in subsequent cycles. Prednisone was given orally at 60 mg/m2 per day for five consecutive days within each 28-day cycle. Standard dose escalation was employed, and MTD was defined as the dose at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Plasma pharmacokinetics of UCN-01 were assessed.

Results

Fifteen patients received a total of 55 courses of treatment. The MTD and the recommended phase II dose of UCN-01 in this combination is 72 mg/m2 total dose over 72 h for cycle 1 followed by 36 mg/m2 per cycle over 36 h. All patients experienced hyperglycemia but responded to insulin treatment. Hypophosphatemia was a DLT in two patients. There were no cumulative toxicities. No objective responses were observed, but five patients had stable disease, including two patients with lymphoid malignancies who had prolonged disease stabilizations. UCN-01 has a long terminal half-life and low clearance; there was wide inter-patient variability in peak concentrations.

Conclusion

UCN-01 can be safely administered in combination with prednisone without unacceptable toxicity. The prolonged stable disease in two patients with lymphoid malignancies is a proof of principle for the evaluation of cyclin-dependent kinase inhibitors in oncology.

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Acknowledgments

This paper was written with support from the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National Cancer Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We would like to thank Gina Uhlenbrauck, SAIC-Frederick, Inc. for editorial assistance in the preparation of this manuscript.

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Author notes

  1. Barbara A. Conley

    Present address: Department of Medicine, Michigan State University, East Lansing, MI, USA

  2. Edward A. Sausville

    Present address: University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA

Authors and Affiliations

  1. Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD, 20892, USA

    Shivaani Kummar, Martin E. Gutierrez, William D. Figg, Barbara A. Conley, Anthony J. Murgo & James H. Doroshow

  2. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    Janet Dancey, Edward A. Sausville, Anthony J. Murgo & James H. Doroshow

  3. Science Applications International Corporation-Frederick, Inc, National Cancer Institute-Frederick, Frederick, MD, USA

    Erin R. Gardner & Giovanni Melillo

Authors
  1. Shivaani Kummar
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  2. Martin E. Gutierrez
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  3. Erin R. Gardner
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  4. William D. Figg
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Correspondence to Shivaani Kummar.

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Kummar, S., Gutierrez, M.E., Gardner, E.R. et al. A phase I trial of UCN-01 and prednisone in patients with refractory solid tumors and lymphomas. Cancer Chemother Pharmacol 65, 383–389 (2010). https://doi.org/10.1007/s00280-009-1154-y

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  • DOI: https://doi.org/10.1007/s00280-009-1154-y

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