Phase II Trial on Imatinib in Kaposi's Sacroma

伊马替尼治疗卡波西骶骨的 II 期试验

• 批准号: 6887573
• 负责人: HENRY B KOON
• 金额: $ 26.4万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-18 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887573
• 关键词: AIDS related neoplasm /cancer; AIDS therapy; Kaposi' s sarcoma; antiAIDS agent; biopsy; carcinogenesis; clinical research; clinical trial phase II; growth factor receptors; human subject; human therapy evaluation; immunocytochemistry; microorganism disease chemotherapy; patient oriented research; pharmacokinetics; platelet derived growth factor; polymerase chain reaction; protooncogene; stem cell factor; western blottings

DESCRIPTION (provided by applicant): HIV-related Kaposi's sarcoma (KS) is a disease of multi-focal vascular proliferation, which predominantly involves the skin but can also involve the visceral organs. Stem cell factor (SCF) and platelet derived growth factor (PDGF) have been implicated in the development of KS and inhibition of the pathways activated by these growth factors is potential therapeutic targets in KS. In a pilot study, ten male patients with AIDS-related cutaneous KS, which progressed despite chemotherapy and/or highly active antiretroviral therapy (HAART), received the PDGF and c-kit inhibitor, imatinib mesylate (Gleevec). At four weeks, five of ten patients had a partial response by tumor measurement and the remainder had clinically stable disease. The majority of patients required dose reductions for toxicity with diarrhea being the most frequent event. Biopsies showed inhibition of PDGF-R after four weeks of imatinib therapy correlated with histologic response. Our clinical data support the hypothesis that activation of the PDGF-R and c-kit are critical in KS tumorigenesis and inhibition of these pathways are potential therapeutic targets. The specific aims of the proposed study are: 1. Evaluate the clinical efficacy and tolerability of imatinib mesylate treatment of Kaposi's sarcoma. 2. Determine if inhibition of PDGF receptor as assessed by immunohistochemistry predicts response to imatinib therapy in Kaposi's sarcoma. 3. Determine if mutations PDGF or c-kit receptors correlate with primary and secondary resistance to imatinib therapy in Kaposi's sarcoma. This translational study of therapeutic inhibition of PDGF/c-kit in KS would provide insights into etiology of KS and could have a major impact on KS treatment approaches.

描述（由申请人提供）：与HIV相关的Kaposi的肉瘤（KS）是一种多焦点血管增殖的疾病，主要涉及皮肤，但也可能涉及内脏器官。干细胞因子（SCF）和血小板衍生的生长因子（PDGF）与KS的发展有关，这些生长因子激活的途径是KS中的潜在治疗靶标。在一项试点研究中，尽管化疗和/或高度活跃的抗逆转录病毒疗法（HAART），十名患有与AIDS相关的皮肤KS的男性患者接受了PDGF和C-KIT抑制剂伊马替尼 - 伊马替尼（Gleevec）。在四个星期时，十名患者中有五名通过肿瘤测量有部分反应，其余患者患有临床稳定的疾病。大多数患者需要降低毒性的剂量，而腹泻是最常见的事件。在伊马替尼治疗四个星期后，活检显示与组织学反应有关的抑制作用。我们的临床数据支持以下假设：PDGF-R和C-KIT的激活在KS肿瘤发生中至关重要，并且对这些途径的抑制是潜在的治疗靶标。拟议研究的具体目的是： 1。评估伊马替尼麦甲酸盐治疗卡波西肉瘤的临床功效和耐受性。 2。确定通过免疫组织化学评估的PDGF受体的抑制是否可以预测Kaposi肉瘤中对伊马替尼治疗的反应。 3。确定突变PDGF或C-KIT受体是否与Kaposi肉瘤中对伊马替尼治疗的一级和继发性相关。 这项对KS中PDGF/C-KIT治疗性抑制的翻译研究将提供对KS病因的见解，并可能对KS治疗方法产生重大影响。