) Two clinical studies from China have recently reported induction of complete remission in patients with acute promyelocytic leukemia (APL) following continuous daily treatment with an inorganic arsenical (arsenic trioxide). Remission was apparently achieved by induction of both cytodifferentiation and apoptosis, therapy was completed with a very low order of toxicity, and molecularly-negative remissions have been surprisingly durable. Until now, no clinical formulation of arsenic trioxide existed in the West. Preliminary data from our group have shown that this agent has activity not only against APL, but selectively against a variety of non-myeloid leukemic cell lines. We have now obtained a limited supply of arsenic trioxide formulated for human use. This application seeks funding to begin a pilot clinical study of this arsenic trioxide as induction therapy for patients with advanced refractory APL in the United States. Following the input of FDA, and given both the novelty of the drug and the lack of animal toxicology, the study will be conducted in two stages, as follows: First, a pilot study will be conducted in 5 patients using the dose-schedule employed in China in order to evaluate short-term safety and pharmacokinetics; Second, assuming adequate safety in the pilot study, a phase II, daily dosing regimen will be studied to rapidly determine whether the striking antileukemic activity observed in China can be confirmed in the West. This combined clinical and laboratory program, developed in collaboration with FDA, will enable a critical evaluation of the use of arsenic trioxide as a therapy for APL. It comprises the first Western attempt to rapidly replicate the dramatic clinical results reported from China. This project may offer an alternative, substantially less toxic method of treatment for patients with APL, and its results should be useful for eventual NDA submission of this agent in the U.S.
