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Published on: July 25, 2020
Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer
Bruce G Redman1, Peg Esper, Quintin Pan
1Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109-0948, USA. Redmanb@umich.edu
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.
Insights
Tetrathiomolybdate (TM) showed limited antitumor activity in advanced kidney cancer, offering stable disease for a median of 34.5 weeks. TM is well-tolerated and effectively depletes copper, suggesting potential combination therapy.
Area of Science:
- Oncology
- Pharmacology
- Neovascularization
Background:
- Tetrathiomolybdate (TM) is a copper-lowering agent with preclinical antiangiogenic properties.
- Advanced kidney cancer is characterized by significant angiogenesis, making antiangiogenic therapies a focus of research.
Purpose of the Study:
- To evaluate the antitumor activity of Tetrathiomolybdate (TM) in patients with advanced kidney cancer.
- To assess the safety and tolerability of TM in this patient population.
Main Methods:
- A Phase II clinical trial involving fifteen patients with advanced kidney cancer.
- TM administered orally to achieve copper depletion, monitored by serum ceruloplasmin (CP) levels.
- Tumor response assessed every 12 weeks; serum cytokine and vascular growth factor levels were assayed.
Main Results:
- All patients achieved copper depletion; thirteen were evaluable for response.
- No complete or partial responses were observed; four patients (31%) achieved stable disease for a median of 34.5 weeks.
- TM was well-tolerated, with manageable toxicity. Serum biomarkers did not correlate with clinical activity.
Conclusions:
- Tetrathiomolybdate (TM) is well-tolerated and effectively depletes copper in patients with advanced kidney cancer.
- Clinical activity was limited to stable disease, suggesting TM may be more effective in combination therapies.
- Further research is warranted to explore TM's role in combination with other antiangiogenic agents for kidney cancer treatment.
