Following a search for anti-tumor antibiotics with stronger anti-tumor activity and less toxicity than existing chemotherapeutic agents, Fujisawa Pharmaceuticals discovered a novel compound produced by an actinomycete, Streptomyces sandaensis, isolated from soil in Japan. This compound has a unique hydroxylamine function, by which the hydroxy group constructs a hemiketal moiety in its chemical structure. Research into the structure-activity relationship was performed, and many derivatives of the compound were obtained. Preclinical data showed that FK973 had greater anti-tumor activity compared to mitomycin-C with almost no cross-resistance to mitomycin-C, adriamycin, and vincristine. Phase I studies of FK973 in patients with unresponsive malignant tumors such as synovial sarcoma and colon cancer were carried out in Japan and the United States from 1987 through 1989. Promising anti-cancer results, including partial responses in two of seventeen patients (one colon and one pancreatic) were obtained in these studies. However capillary leak syndrome, characterized by pericardial and pleural effusion, ascites, and subcutaneous edema was observed and the development was stopped. Upon further screening, the sponsor chose a structurally similar compound, FK317, for development. Nonclinical tests of FK317 conducted to date indicate that FK317 has potent antitumor activity without the risk of capillary leak syndrome. This is a phase I, open label, non-randomized dose-fading study to determine the dose-limiting toxicity and the maximum tolerated dose of FK317.
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