PHASE II STUDY OF ARSENIC TRIOXIDE IN LEUKEMIA

描述(申请人的描述) 这项申请是为了支持三氧化二砷的二期临床试验。 作为一种抗白血病药物。这项研究利用了一种药物生产和 蒙特菲奥里医疗中心正在实施的管理方法 根据FDA Ind#54,209.中国的两篇报告建议主要临床 急性早幼粒细胞白血病三氧化二砷活性的研究一个 急性早幼粒细胞白血病难治性白血病患者每日输液可获得完全缓解 全反式维甲酸或化疗。须获得减刑 只要6周的治疗和许多缓解是持久的(继续 1年以上)。体外研究表明，这种制剂可以诱导 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。我们不仅在 APL细胞株的体外抗白血病活性，非APL细胞的体外抗白血病活性 台词。最近的更多报告也与这一观察结果一致 细胞毒性和诱导凋亡，这已经产生了相当大的 对这种非急性早幼粒细胞白血病形式的药物的研究的科学热情 白血病。这一假设构成了这项临床试验的基础。这 研究将使用相同的剂量、浓度和给药 上海工人在报告中描述的时间表，但患者全部 髓系白血病亚型与慢性髓系白血病的急变 将会得到治疗。中国人没有描述神经毒性 报告。然而，神经毒性在非治疗性疾病中有很好的文献记载。 报告说，这是军火库使用中的一个主要问题。本研究 包括密集的用药前、用药内和用药后的神经学 评估早期全身性或外周神经毒性的证据。 此外，对患者样本的实验室研究前、中和 治疗后将评估三氧化二砷对人类白血病的影响 成纤维细胞在体外对细胞生长的影响及其与临床疗效的关系 使用三氧化二砷进行治疗。

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.