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。列出的机构是 中心，不一定是研究者的机构。 这是一项多中心、I期试验，旨在估计恩扎鲁肽（LY 317615）连续28天口服给药难治性原发性CNS肿瘤儿童和青少年的最大耐受剂量并描述剂量限制性毒性。将在所有知情同意的患者中进行药代动力学、影像学和生物学相关研究。恩扎洛宁将在患有难治性原发性CNS肿瘤的儿童和青少年中具有抗肿瘤活性。 中枢神经系统肿瘤（CNS）是儿童期最常见的实体恶性肿瘤，也是第二常见的儿科癌症。每年大约有2000例新的儿童脑肿瘤被诊断出来。在过去的几十年里，儿童CNS肿瘤的治疗有了适度的改善，采用了包括手术、放疗和化疗在内的多模式治疗。然而，CNS肿瘤引起的死亡在儿科癌症中最高。此外，与CNS肿瘤和目前可用的治疗策略相关的发病率可能在身体缺陷以及神经心理和神经内分泌后遗症方面是深刻的。因此，需要新的药物和治疗策略来有效治疗这些具有挑战性的恶性肿瘤。 新血管形成对于肿瘤生长和转移是重要的，因此抑制血管生成途径的化疗剂是一类重要的新兴药物，值得在患有恶性肿瘤的儿科患者中进行进一步研究和表征。对儿童和成人CNS肿瘤中血管生成作用的研究表明，星形细胞肿瘤和胚胎性肿瘤中存在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率呈负相关，特别是对于高级别肿瘤患者。此外，评估软脑膜转移患者脑脊液中VEGF浓度的初步研究表明，CSF VEGF水平反映了患者的临床病程，对治疗的反应显著降低，复发时增加。这表明血管生成的标志物可以作为对治疗和结果的反应的预测因子。

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.