Phase 2 Study of Anti Vegf Antibody in Melanoma

描述：(申请人提供)恶性黑色素瘤的发病率比任何其他癌症上升得更快，但患者的治疗选择 患有晚期疾病的患者仍然有限。抑制药物的发展 肿瘤血管化是治疗这些疾病的一种新方法 癌症。肿瘤分泌多种刺激新生细胞形成的因子 血管，这方面的两个重要分子是血管内皮细胞 血管内皮细胞生长因子(VEGF)和碱性成纤维细胞生长因子(BFGF)。鉴于此， 事实上，我们认为探索抗血管生成药物的组合是合乎逻辑的 一种试图实现更大的抗肿瘤活性的尝试。我们已收到NCI 批准进行重组抗人血管内皮生长因子的随机II期试验 (贝伐单抗)单独或联合小剂量干扰素-α(IFN-a) (目标1)。贝伐单抗抑制血管内皮生长因子与内皮细胞受体的结合 细胞，并在结肠癌、乳腺癌、肺癌和前列腺癌中表现出活性。 小剂量干扰素-α抑制碱性成纤维细胞生长因子的形成并已成功应用 治疗婴儿血管瘤。我们假设共同管理的 贝伐单抗和小剂量干扰素-a对新生血管的最大抑制作用 在患者肿瘤中形成，这将导致更好的反应 发病率和疾病进展时间的增加。转移性癌症患者 恶性黑色素瘤将接受贝伐单抗10 mg/kg静脉注射，每14天一次， 将随机接受任何额外的治疗或同时进行 干扰素-α每日皮下注射1MU/m2。在目标2中，我们将进行一系列相关的 旨在阐明其抗肿瘤作用机制的研究 这些药物的作用。病人的血液样本将在 给予贝伐单抗，并采购血清和外周血 单个核细胞。采用双抗体夹心法检测血清中血管内皮生长因子和碱性成纤维细胞生长因子的水平。在……里面 此外，我们将在开始治疗之前进行肿瘤活检，并 紧跟在第六剂贝伐单抗之后。将对肿瘤进行分析 血管密度(CD31和CD34)、血管生成因子水平以及 有凋亡细胞的存在。考虑到可获得的肿瘤存款的普遍性 在黑色素瘤患者中，我们认为我们将能够成功地对大多数患者进行活检 参与这项研究的患者的比例。这种方法是为数不多的 联合使用抗血管生成药物和积极计划的试验 用来采集肿瘤样本。从这次审判中获得的信息将帮助我们 了解抗血管生成药物的作用机制，帮助我们规划 未来对黑色素瘤和其他实体肿瘤的研究。

DESCRIPTION: (Provided by applicant) The incidence of malignant melanoma is rising faster than that of any other cancer, yet treatment options for patients with advanced disease remain limited. The development of agents that inhibit tumor vascularization represent a novel approach to the treatment of these cancers. Tumors secrete a number of factors that stimulate the formation of new vessels, and two important molecules in this regard are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Given this fact, we feel it is logical to explore combinations of anti-angiogenic drugs in an attempt to achieve greater anti-tumor activity. We have received NCI approval to conduct a randomized phase II trial of recombinant anti-human VEGF (Bevacizumab) alone or in combination with low-dose interferon-alpha (IFN-a) (Aim 1). Bevacizumab prevents the binding of VEGF to receptors on endothelial cells and has shown activity in colon, breast, lung, and prostate cancer. Low-dose IFN-a inhibits the elaboration of bFGF and has been successfully used to treat infantile hemangiomas. We hypothesize that co-administration of Bevacizumab and low-dose IFN-a will lead to maximal inhibition of new vessel formation in patient tumors and that this will result in improved response rates and increased time to disease progression. Patients with metastatic malignant melanoma will receive Bevacizumab at 10 mg/kg IV every 14 days and will be randomized to receive either no additional treatment or concurrent IFN-a at 1 MU/m2 SC daily. In Aim 2, we will conduct a series of correlative studies designed to elucidate the mechanisms that contribute to the anti-tumor actions of these drugs. Patient blood samples will be drawn just prior to the administration of Bevacizumab and procured for serum and peripheral blood mononuclear cells. Serum levels of VEGF and bFGF will be analyzed by ELISA. In addition, we will perform tumor biopsies prior to the initiation of therapy and immediately following the 6th dose of Bevacizumab. Tumors will be analyzed for vascularity (CD31 and CD34), levels of angiogenic factors, as well as the presence of apoptotic cells. Given the prevalence of accessible tumor deposits in melanoma patients, we feel we will be able to successfully biopsy a majority of patients enrolled in this study. This approach represents one of the few trials to employ combinations of anti-angiogenic drugs and an aggressive plan for tumor sampling. Information gained from this trial will help us to understand the mechanism of action of anti-angiogenic drugs and help us to plan future studies in melanoma and other solid tumors.