Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer.
OBJECTIVE
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.


METHODS
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.
Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109-0948, USA. Redmanb@umich.edu
Bruce G
BG
Redman
Peg
P
Esper
Quintin
Q
Pan
Rodney L
RL
Dunn
Hero K
HK
Hussain
Thomas
T
Chenevert
George J
GJ
Brewer
Sofia D
SD
Merajver
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood*; D002570:Ceruloplasmin / Q000032:analysis; D003300:Copper / Q000097:blood / Q000172:deficiency; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008982:Molybdenum / Q000009:adverse effects / Q000627:therapeutic use*; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D015850:Interleukin-6; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin