Targeted Molecular Therapeutics for Melanoma: CCI-779 and Bevacizumab

描述(申请人提供)：转移性黑色素瘤几乎总是致命的，估计中位生存期为6-9个月，5年生存率不到5%。对晚期黑色素瘤患者的标准系统治疗只有10%-17%的患者产生了客观的临床反应。这些反应中的大多数是不可持续的，所使用的药物(大剂量IL-2、达卡巴津)与显著的毒性有关。毒性较小、可获得类似或改善的应答率的治疗方案将代表着晚期黑色素瘤治疗的重大进步。与传统化疗药物相比，有希望的癌症治疗方案包括那些更直接针对肿瘤的治疗方案，以及导致恶性行为的分子变化。就黑色素瘤而言，这些选择包括已知在黑色素瘤进展和转移中发挥关键作用的分子(例如血管内皮生长因子)和针对似乎在黑色素瘤发病机制中至关重要的细胞信号通路的分子(例如PI3K/Akt/mTOR途径)。这些药物单独或联合使用，可能具有免疫调节作用，可能会产生临床影响。这项研究将在分子靶向组合相关研究计划的多中心临床试验中，评估抗血管内皮生长因子抗体贝伐单抗与mTOR抑制剂CCI-779联合治疗晚期黑色素瘤患者的效果。这项试验的主要终点是临床肿瘤反应。此外，这项研究的一个组成部分是对肿瘤组织和外周血单个核细胞的分子和免疫终点进行评估。目的1：确定CCI-779和贝伐单抗联合治疗是否会导致转移性黑色素瘤的消退(III-IV期)；目标2：确定CCI-779和贝伐单抗对循环免疫细胞亚群的影响；目标3：确定CCI-779单独和CCI-779联合贝伐单抗对血液和肿瘤活检组织中mTOR和VEGF通路信号的影响；目标4：确定CCI-779单独或联合贝伐单抗是否会影响平行通路中的信号转导，特别是MAPK和eNOS通路。大约每70人中就有1人会在一生中被诊断为黑色素瘤，皮肤黑色素瘤的发病率正在上升。对晚期黑色素瘤患者的标准系统治疗只在10-17%的患者中产生了客观的临床反应，并与显著的毒副作用有关。以下建议是一项临床试验，旨在评估干扰血管形成和肿瘤生长的贝伐单抗和CCI-779治疗黑色素瘤的效果。

DESCRIPTION (provided by applicant): Metastatic melanoma is almost always fatal, with an estimated median survival of 6-9 months and a 5-year survival rate of less than 5%. Standard systemic therapy for patients with advanced melanoma induces objective clinical responses in only 10-17% of patients. Most of these responses are not sustained, and the agents utilized (high-dose IL-2, dacarbazine) are associated with significant toxicity. Treatment alternatives that elicit comparable or improved response rates with less toxicity would represent significant advance in the therapy of late stage melanoma. Promising cancer treatment options include those that more directly target the tumor and the molecular changes that underlie malignant behavior than do conventional chemotherapy agents. In the case of melanoma, these options include molecules known to play a key role in melanoma progression and metastasis (e.g. vascular endothelial growth factor) and molecules that target cell signaling pathways that appear to be critical in the pathogenesis of this disease (e.g. PI3K/Akt/mTOR pathway). These agents, individually and together, may have immune modulating effects that could have clinical impact. This study will evaluate the effects of the anti-VEGF antibody, bevacizumab, combined with the mTOR inhibitor, CCI-779, in patients with advanced melanoma, in a multicenter clinical trial in the Molecular Targeted Combinations Correlative Study Initiative. The primary endpoint of this trial is clinical tumor response. Also, integral to this study is the evaluation of tumor tissue and peripheral blood mononuclear cells for molecular and immunologic endpoints. The effects of bevacizumab combined with CCI-779 will be evaluated under the following specific aims: Aim 1: Determine whether combination therapy with CCI-779 and bevacizumab will induce regression of metastatic melanoma (Stage III-IV); Aim 2: Determine the effects of CCI-779 and bevacizumab on circulating immune cell subsets; Aim 3: Determine the effects of CCI-779 alone and of CCI- 779 plus bevacizumab on signaling in the mTOR and VEGF pathways, both in the blood and in tumor biopsies; Aim 4: Determine whether CCI-779 alone and in combination with bevacizumab will affect signaling in parallel pathways, specifically MAPK and eNOS pathways. Approximately 1 in 70 individuals will be diagnosed with melanoma during their lifetime, and the incidence of cutaneous melanoma is on the rise. Standard systemic therapy for patients with advanced melanoma induces objective clinical responses in only 10-17% of patients and is associated with significant toxicities. The following proposal is a clinical trial to evaluate the effects of bevacizumab and CCI-779, which interfere with vascularization and tumor growth, for the treatment of melanoma.