Colorectal cancer remains a major public health problem in the United States and other developed countries. In Australia colorectal cancer is the leading cancer by incidence, while in the United States 147,500 new cases are diagnosed annually and 57,100 people die from this condition each year. Approximately 50% of all colorectal cancer patients develop metastatic disease. While the number of therapeutic options for these patients has increased in recent times, curative treatment is not yet available and the natural history of metastatic colorectal cancer is short - with a median overall survival in the region of 6-12 months. The development of novel treatment modalities with superior anti-tumor activity may result in significant survival and quality of life benefits than the current chemotherapy-based paradigm. Capecitabine is an orally administered fluoropyrimidine carbamate which is rapidly absorbed, then metabolised to 5-flurouracil (5-FU) in three steps. The final conversion to 5-FU is by thymidine phosphorylase, which is much more active in colorectal tumor tissue compared to normal tissues. This preferential activation potentially reduces systemic toxicities and maximizes exposure of tumour cells to the cytotoxic metabolite. The humanized monoclonal antibody huA33 specifically detects a determinant expressed in greater than 95% of colorectal tumors, has immune cytotoxic activity, and can be radio-iodinated with retention of immunoreactivity. Our Phase I trials with iodine-131 labeled huA33 (131l-huA33) have demonstrated safety and prolonged tumor targeting in patients with advanced colorectal cancer. Radioimmunotherapy using single infusion 131l-huA33 is well tolerated at doses up to 40 mCi/m2 in patients with metastatic colorectal cancer, however preclinical animal tumor model studies indicate that the combination of 131l-huA33 with a fluoropyrimidine may have synergistic anti-tumor potential in the clinic. This Phase I trial will examine the safety, tolerability and provide preliminary tumor response data on the potentially active combination of capecitabine and 131l-huA33. Utilizing a cautious dose escalation protocol, this trial aims to define the maximum tolerated combination of capecitabine and 131l-huA33. ? ?
Fox, N; Solter, D (1988) Expression and regulation of the pituitary- and placenta-specific human glycoprotein hormone alpha-subunit gene is restricted to the pituitary in transgenic mice. Mol Cell Biol 8:5470-6 |