CLINICAL TRIAL: H-23957 ADVL0812 A PHASE I STUDY OF MLN8237, AN ORAL SELECTIVE S

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 丝氨酸/苏氨酸蛋白激酶的Aurora家族在有丝分裂过程中染色体分离和胞质分裂的调节中起着关键作用。Aurora A和B在所有活跃分裂的细胞中表达，而Aurora C的表达主要限于分裂的生殖细胞。Aurora A激酶基因在许多肿瘤中扩增或过表达，包括结肠癌、乳腺癌、胰腺癌和膀胱癌。Aurora A过表达与非整倍体和中心体扩增相关，Aurora A激酶的过表达导致正常细胞的转化，支持Aurora A是癌基因的假设。有报道表明，在培养的细胞中，使用核糖核酸干扰（RNAi）减少Aurora A会降低Aurora A蛋白含量，并导致有丝分裂纺锤体缺陷、有丝分裂延迟和细胞凋亡。MLN 8237是一种选择性Aurora A激酶小分子抑制剂，正在开发用于治疗晚期恶性肿瘤。考虑到有丝分裂在几乎所有恶性肿瘤进展中的核心作用，这种抑制剂预计在广泛的人类肿瘤中具有潜在的应用。如方案背景章节所述，MLN 8237已证明对广泛的体外和体内临床前模型具有活性。 MLN 8237是一种小分子、ATP竞争性可逆Aurora A激酶抑制剂，正在开发用于治疗晚期恶性肿瘤。考虑到有丝分裂在几乎所有恶性肿瘤的进展中的核心作用，预期这种抑制剂在广泛的人类肿瘤中具有潜在的应用。MLN 8237已证明对多种体外和体内临床前肿瘤模型具有活性。该药物还预期对增殖的正常组织（如骨髓和GI上皮）具有毒性，因为在Aurora A表达和活性的有丝分裂中的任何细胞都应对Aurora A激酶抑制剂的作用敏感。 主要目标1。估计MLN 8237在难治性实体瘤儿童中的最大耐受剂量（MTD）和推荐II期剂量，每日一次口服给药，持续7天，每21天一次。2.定义并描述按照该方案给药的MLN 8237的毒性。3.描述MLN 8237在难治性癌症儿童中的药代动力学特征。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Aurora family of serine/threonine protein kinases plays a critical role in the regulation of chromosomal segregation and cytokinesis during mitotic progression. Aurora A and B are expressed in all actively dividing cells, while Aurora C expression is largely restricted to dividing germ cells. The Aurora A kinase gene is amplified or overexpressed in many tumors, including colon, breast, pancreatic, and bladder cancers. Aurora A overexpression is associated with aneuploidy and centrosome amplification, and overexpression of Aurora A kinase results in the transformation of normal cells, supporting the hypothesis that Aurora A is an oncogene. Reports have demonstrated that in cultured cells, reduction of Aurora A using ribonucleic acid interference (RNAi) reduces Aurora A protein content and results in mitotic spindle defects, mitotic delay, and apoptosis. MLN8237 is a selective small molecule inhibitor of Aurora A kinase being developed for treatment of advanced malignancies. This inhibitor is expected to have potential application across a broad range of human tumors, given the central role of mitosis in the progression of virtually all malignancies. MLN8237 has demonstrated activity against a broad range of both in vitro and in vivo preclinical models, as described in the Background section of the protocol. MLN8237 is a small molecule, ATP-competitive, reversible inhibitor of Aurora A kinase that is being developed for the treatment of advanced malignancies. Such an inhibitor would be expected to have potential application across a broad range of human tumors, given the central role of mitosis in the progression of virtually all malignancies. MLN8237 has demonstrated activity against a broad range of both in vitro and in vivo preclinical tumor models. This drug is also expected to be toxic to proliferating normal tissues, such as bone marrow and GI epithelium, since any cell that is in mitosis where Aurora A is expressed and active should be susceptible to the effects of an Aurora A kinase inhibitor. Primary Aims-1. To estimate the maximum tolerated dose (MTD) and recommended Phase II dose of MLN8237 administered orally once daily for 7 days every 21 days to children with refractory solid tumors. 2. To define and describe the toxicities of MLN8237 administered on this schedule. 3. To characterize the pharmacokinetics of MLN8237 in children with refractory cancer.