Targeted Molecular Therapeutics for Melanoma: CCI-779 and Bevacizumab

描述（由申请人提供）：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年生存率低于5%。晚期黑色素瘤患者的标准全身治疗仅在10-17%的患者中诱导客观临床反应。大多数这些反应不是持续的，并且所使用的药剂（高剂量IL-2、达卡巴嗪）与显著毒性相关。引起相当或改善的反应率且毒性较小的治疗替代方案将代表晚期黑色素瘤治疗的重大进展。有前途的癌症治疗方案包括那些更直接靶向肿瘤和分子变化的恶性行为比传统的化疗药物。在黑色素瘤的情况下，这些选择包括已知在黑色素瘤进展和转移中起关键作用的分子（例如血管内皮生长因子）和靶向在该疾病的发病机制中似乎至关重要的细胞信号传导途径的分子（例如PI 3 K/Akt/mTOR途径）。这些药物，单独或一起，可能具有免疫调节作用，可能具有临床影响。本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VEGF抗体贝伐单抗联合mTOR抑制剂CCI-779治疗晚期黑色素瘤患者的效果。本试验的主要终点是临床肿瘤缓解。此外，本研究的组成部分是评价肿瘤组织和外周血单核细胞的分子和免疫学终点。贝伐单抗联合CCI-779的效果将在以下特定目标下进行评价：目标1：确定CCI-779和贝伐单抗的联合治疗是否会诱导转移性黑色素瘤消退（III-IV期）;目的2：确定CCI-779和贝伐单抗对循环免疫细胞亚群的影响;目的3：确定CCI-779单独和CCI- 779加贝伐单抗对血液和肿瘤活检中mTOR和VEGF途径中信号传导的影响;目的4：确定CCI-779单独和与贝伐单抗组合是否将影响平行途径中的信号传导，特别是MAPK和eNOS途径。大约每70个人中就有1人在其一生中被诊断患有黑色素瘤，并且皮肤黑色素瘤的发病率正在上升。晚期黑色素瘤患者的标准全身治疗仅在10-17%的患者中诱导客观临床应答，并与显著毒性相关。以下建议是一项临床试验，以评估贝伐单抗和CCI-779（干扰血管形成和肿瘤生长）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.