PHASE I STUDY OF TETRATHYMOLYBDATE IN METASTATIC CANCER

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DESCRIPTION (Applicant's Description) Patients with metastatic solid tumors often have very limited treatment options due to the cumulative toxicity of cytoreductive chemotherapy and drug resistance. A new approach to the maintenance or reduction in size of metastatic tumors consists of the inhibition of new blood vessel growth into the tumor bed, a process known as angiogenesis. As copper has been shown to be a requirement for angiogenesis in animal models, we seek to determine whether a decrease in copper causes shrinkage or slows down the growth of solid tumors. The most potent inhibitor of copper known is tetrathiomolybdate (TM) which has been developed at the University of Michigan for the treatment of patients with Wilson's disease who suffer from extremely high levels of copper in the tissues. Whereas TM has been safely administered to humans with Wilson's disease, its toxicity profile in patients with metastatic cancer is not known. Here we propose a phase I study of TM in patients with metastatic solid tumors who have exhausted other treatment options. Twelve to eighteen patients will be enrolled in a graduated dose regimen of 90-120 mg/day. The major side-effect of mild copper deficiency is mild anemia (Hct greater than 70 percent of baseline). This study will determine the optimal decoppering dose of TM in patients with metastatic disease and the pharmacodynamics of TM in patients with normal synthetic liver function. In patients with accessible lesions, the neovascularization index of the lesions sampled before and after therapy will be measured as an intermediate microscopic end-point of efficacy. Any effects on the size or rate of growth of tumors will also be noted. These results, if promising, will help guide the design of phase II wills of TM for different types of cancer and of prevention and adjuvant.