Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study

Preclinical and in vitro studies have determined that copper is an importan t cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an ef fective anticopper therapy for the initial treatment of Wilson's disease, a n autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lac k of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metast atic solid tumors, Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinic al trial in 18 patients with metastatic cancer who were enrolled at three d ose levels of oral TIW (90, 105, and 120 mg/day) administered in sis divide d doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a s urrogate marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% o f baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15-20% of baseline. The level III dose of TM (120 mg/day) was effective in reaching the target Cp without added toxicity. TM-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.