A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker
Kristen C. Kelley,
Kenneth F. Grossman,
Mary Brittain-Blankenship,
Kelli M. Thorne,
Wallace L. Akerley,
Moises C. Terrazas,
Ken M. Kosak,
Kenneth M. Boucher,
Saundra S. Buys,
Kimberly A. McGregor,
Theresa L. Werner,
Neeraj Agarwal,
John R. Weis,
Sunil Sharma,
John H. Ward,
Thomas P. Kennedy,
Douglas W. Sborov,
Paul J. Shami
Affiliations
Kristen C. Kelley
Department of Internal Medicine, University of Utah
Kenneth F. Grossman
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Mary Brittain-Blankenship
Department of Internal Medicine, University of Utah
Kelli M. Thorne
Huntsman Cancer Institute, University of Utah
Wallace L. Akerley
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Moises C. Terrazas
Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Ken M. Kosak
Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Kenneth M. Boucher
Department of Internal Medicine, University of Utah
Saundra S. Buys
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Kimberly A. McGregor
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Theresa L. Werner
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Neeraj Agarwal
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
John R. Weis
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Sunil Sharma
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
John H. Ward
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Thomas P. Kennedy
Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University
Douglas W. Sborov
Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Paul J. Shami
Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah
Abstract Background Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. Methods Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. Results Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28–124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. Conclusion Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. Trial registration NCT00742911 , first posted 28/08/2008.
