Phase II Trial of Tetrathiomolybdate in Patients with Advanced Kidney Cancer

Phase II Trial of Tetrathiomolybdate in Patients with Advanced Kidney Cancer1

Division of Hematology and Oncology [B. G. R., P. E., Q. P., S. D. M.], Departments of Internal Medicine [G. J. B.], Radiology [H. K. H., T. C.], Human Genetics [G. J. B.], and University of Michigan Comprehensive Cancer Center [B. G. R., R. L. D., S. D. M.], University of Michigan, Ann Arbor, Michigan 48109-0948

Abstract

Purpose: Tetrathiomolybdate (TM), a copper-lowering agent, has been shown in preclinical murine tumor models to be antiangiogenic. We evaluated the antitumor activity of TM in patients with advanced kidney cancer in a Phase II trial.

Experimental Design: Fifteen patients with advanced kidney cancer were eligible to participate in this trial. TM was initiated p.o. at 40 mg three times a day with meals and 60 mg at bedtime to deplete copper. A target serum ceruloplasmin (CP) level of 5–15 mg/dl was defined as copper depletion. Doses of TM were reduced for grade 3–4 toxicity and to maintain a CP level in the target range. Once copper depletion was attained, patients underwent baseline tumor measurements and then again every 12 weeks for response assessment. Patients not exhibiting progressive disease at 12 weeks after copper depletion continued on treatment. Serum levels of Interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assayed pretreatment and at various time points on treatment. Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was performed on selected patients in an attempt to assess changes in tumor vascularity.

Results: All of the patients rapidly became copper depleted. Thirteen patients were evaluable for response. No patient had a complete response or PR. Four patients (31%) had stable disease for at least 6 months during copper depletion (median, 34.5 weeks). TM was well tolerated, with dose reductions most commonly occurring for grade 3–4 granulocytopenia of short duration not associated with febrile episodes. Serum levels of IL-6, IL-8, VEGF, and bFGF did not correlate with clinical activity. Serial DCE-MRI was performed only in four patients, and a decrease in vascularity seemed to correlate with necrosis of a tumor mass associated with tumor growth.

Conclusions: TM is well tolerated and consistently depletes copper as measured by the serum CP level. Clinical activity was limited to stable disease for a median of 34.5 weeks in this Phase II trial in patients with advanced kidney cancer. Serum levels of proangiogenic factors IL-6, IL-8, VEGF, and bFGF may correlate with copper depletion but not with disease stability in this small cohort. TM may have a role in the treatment of kidney cancer in combination with other antiangiogenic therapies.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported by NIH Grant MO1-RR00042 (to the General Clinical Research Center), NIH Grant RO1-CA-77612 (to S. D. M.), and United States Army Breast Cancer Research Program Postdoctoral Fellowship (to Q. P.). S. D. M. and G. J. B. are consultants and have a financial interest in Attenuon, Limited Liability Corporation, which has licensed tetrathiomolybdate as an anticancer compound from the University of Michigan.
↵2 To whom requests for reprints should be addressed, at 7216 Cancer Center Geriatric Center, 1500 East Medical Center Drive, Ann Arbor MI 48109-0948. Phone: (734) 936-8906; Fax: (734) 615-2719; E-mail: Redmanb{at}umich.edu
↵3 The abbreviations used are: IL, interleukin; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; TGF-α, transforming growth factor α; TM, tetrathiomolybdate; CP; ceruloplasmin; MR, magnetic resonance; DCE, dynamic contrast enhanced; DCE-MRI, DCE-MR imaging; CR, complete response; PR, partial response; VHL, von Hippel-Lindau; AUC, area under the curve; IAUC, initial area under the enhancement curve.
↵4 Proleukin: Update of Product License Application, 1996 (on file, Food and Drug Administration).
↵5 Unpublished observations.
- Accepted December 30, 1902.
- Received October 10, 1902.
- Revision received December 30, 1902.