CLINICAL TRIAL: PHASE I AND PHARMACOKINETIC STUDY OF ENZASTAURIN (LY317615) IN C

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这是一项多中心的I期试验，目的是估计口服Ezastaurin(LY317615)连续28天对患有难治性原发中枢神经系统肿瘤的儿童和青少年的最大耐受剂量并描述剂量限制毒性。将在所有同意的患者中进行药代动力学、影像和生物学相关研究。在患有难治性原发中枢神经系统肿瘤的儿童和青少年中，氮沙他汀将具有抗肿瘤活性。 中枢神经系统肿瘤(CNS)是儿童最常见的实体恶性肿瘤，也是儿童第二常见的癌症。每年大约有2000例新诊断的儿童脑瘤。在过去的几十年里，使用包括手术、放疗和化疗在内的多种治疗方法，儿童中枢神经系统肿瘤的治疗有了一定的改善。然而，在儿童癌症中，中枢神经系统肿瘤造成的死亡人数最高。此外，与中枢神经系统肿瘤相关的发病率和目前可用的治疗策略可能在生理缺陷以及神经心理和神经内分泌后遗症方面影响深远。因此，需要新的药物和治疗策略来有效地治疗这些具有挑战性的恶性肿瘤。 新生血管对肿瘤的生长和转移具有重要意义，因此抑制血管生成途径的化疗药物是一类重要的新兴药物，值得在儿童恶性肿瘤患者中进行进一步的研究和表征。关于血管生成在儿童和成人中枢神经系统肿瘤中的作用的研究表明，在星形细胞肿瘤和胚胎肿瘤中都有显著的血管生成活性。在一些研究中，血管生成的程度与患者的生存呈负相关，特别是对于高级别肿瘤的患者。此外，对软脑膜转移患者脑脊液中血管内皮生长因子浓度的初步研究表明，脑脊液中的血管内皮生长因子水平反映了患者的临床进程，治疗反应明显减少，复发时增加。这表明血管生成的标记物可以作为治疗反应和结果的预测指标。

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. This is a multicenter, Phase I trial to estimate the maximum tolerated dose and describe dose limiting toxicities of enzastaurin (LY317615) administered orally for 28 consecutive days to children and adolescents with refractory primary CNS tumors. Pharmacokinetic, imaging and biology correlative studies will be performed in all consenting patients. Enzastaurin will have anti-tumor activity in children and adolescents with refractory primary CNS tumors. Central nervous system tumors (CNS) are the most common solid malignancy of childhood and the second most common pediatric cancer. There are approximately 2000 new childhood brain tumors diagnosed each year. There have been modest improvements in the treatment of childhood CNS tumors over the past several decades using multi-modality therapy including surgery, radiation and chemotherapy. Nevertheless, deaths caused by CNS tumors are the highest among pediatric cancers. In addition, the morbidity associated with CNS tumors and currently available therapeutic strategies may be profound with regard to physical deficits as well as neuro-psychological and neuroendocrine sequelae. Thus, new agents and treatment strategies are needed for the effective treatment of these challenging malignancies. Neovascularization is important for tumor growth and metastases and therefore chemotherapeutic agents that inhibit angiogenesis pathways are an important emerging class of agents that warrant further study and characterization in pediatric patients with malignancies. Studies of the role of angiogenesis in CNS tumors from both children and adults have shown that there is marked angiogenic activity in astrocytic as well as embryonal tumors. In some studies, the degree of angiogenesis inversely correlates with patient survival, particularly for patients with high-grade tumors. In addition, preliminary studies evaluating VEGF concentrations in the cerebrospinal fluid of patients with leptomeningeal metastasis reveal that CSF VEGF levels mirror the patient's clinical course with a marked reduction in response to therapy and an increase at relapse. This suggests that markers of angiogenesis may serve as predictors of response to therapy and outcome.