PHASE II STUDY OF ARSENIC TRIOXIDE IN LEUKEMIA

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DESCRIPTION (Applicant's Description) This application is to support a phase II clinical trial of arsenic trioxide as an anti-leukemic agent. This study utilizes a drug production and administration methodology being performed at Montefiore Medical Center under FDA IND #54,209. Two reports from China suggest major clinical activity for arsenic trioxide in acute promyelocytic leukemia (APL). A daily infusion led to complete remissions in patients with APL refractory to all-trans retinoic acid or chemotherapy. Achievement of remission required as long as 6 weeks of therapy and many remissions are durable (continuing beyond 1 year). In vitro studies indicate that this agent induces apoptosis, leads to degradation of PML/RAR-alpha, and may induce differentiation in APL leukemic cell lines. We have also not only shown in vitro anti-leukemic activity in APL cell lines, but also in non-APL cell lines. Additional recent reports concur with this observation of cytotoxicity and apoptosis induction and this has engendered considerable scientific enthusiasm for investigation of this agent in non-APL forms of leukemia. This hypothesis forms the basis for this clinical trial. This study will utilize the same dose and concentration and administration schedule described in the report by Shanghai workers, but patients with all subtypes of myeloid leukemia and blast crisis of chronic myeloid leukemia will be treated. Neurologic toxicity was not described by the Chinese reports. However, neurologic toxicity is well documented in non-therapeutic reports and is a major concern in the use of arsenicals. This study includes intensive pre-, intra-, and post-administration neurologic evaluations for evidence of early generalized or peripheral neurotoxicity. In addition, laboratory studies of patient samples pre-, intra-, and post-therapy will evaluate the effects of arsenic trioxide on human leukemic blasts and correlate in vitro effects on cell growth with clinical effects of therapy with arsenic trioxide.