PHASE II STUDY OF ARSENIC TRIOXIDE IN LEUKEMIA

申请人的描述（applicant's description） 此申请是为了支持三氧化二砷的II期临床试验 作为抗白血病药物。 这项研究利用药物生产和 在Montefiore医学中心进行的给药方法 FDA IND #54，209。 来自中国的两份报告表明， 三氧化二砷在急性早幼粒细胞白血病（APL）中的活性。 一 每日输注可使难治性APL患者完全缓解， 全反式维甲酸或化疗。 要求达到缓解 只要6周的治疗和许多缓解是持久的（持续的 1年以上）。 体外研究表明，该药物诱导 细胞凋亡，导致PML/RAR-α降解，并可能诱导 APL白血病细胞系的分化。 我们不仅展示了 在APL细胞系中的体外抗白血病活性，但也在非APL细胞中 线 最近的其他报告也同意这一看法， 细胞毒性和凋亡诱导，这已经产生了相当大的 科学界对研究这种非APL形式的药剂充满热情 白血病 这一假设构成了本临床试验的基础。 这 研究将使用相同的剂量和浓度， 上海工人的报告中描述的时间表，但所有患者 髓系白血病亚型与慢性髓系白血病急变 将得到治疗。 中国人未描述神经毒性 报道 然而，神经毒性在非治疗性 报告，是使用砷剂的一个主要问题。 本研究 包括给药前、给药中和给药后的强化神经病学检查 评估早期全身或周围神经毒性的证据。 此外，对患者样本的实验室研究， 治疗后将评估三氧化二砷对人类白血病的影响。 原始细胞和对细胞生长的相关体外效应与临床效应 三氧化二砷的治疗效果

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.