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（申请人提供）：hiv相关的卡波西肉瘤（KS）是一种多灶性血管增生疾病，主要累及皮肤，但也可累及内脏器官。干细胞因子（SCF）和血小板衍生生长因子（PDGF）与KS的发展有关，抑制这些生长因子激活的途径是KS的潜在治疗靶点。在一项初步研究中，10名男性艾滋病相关皮肤KS患者接受了PDGF和c-kit抑制剂甲酸伊马替尼（格列卫）治疗，尽管化疗和/或高活性抗逆转录病毒治疗（HAART）仍进展。在4周时，通过肿瘤测量，10名患者中有5名有部分反应，其余患者临床病情稳定。大多数患者因毒性需要减少剂量，腹泻是最常见的事件。活检显示，在伊马替尼治疗四周后，PDGF-R的抑制与组织学反应相关。我们的临床数据支持PDGF-R和c-kit的激活在KS肿瘤发生中至关重要的假设，抑制这些途径是潜在的治疗靶点。建议研究的具体目的如下：