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: 7493928
• 负责人: HENRY B KOON
• 金额: $ 21.74万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493928
• 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）：HIV相关卡波西肉瘤（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）参与KS的发生发展，抑制这些生长因子激活的通路是KS的潜在治疗靶点。在一项初步研究中，10名患有艾滋病相关皮肤KS的男性患者接受了PDGF和c-kit抑制剂甲磺酸伊马替尼（格列卫）治疗，尽管接受了化疗和/或高效抗逆转录病毒治疗（HAART），但病情仍在进展。在四周时，10名患者中有5名通过肿瘤测量获得部分缓解，其余患者的疾病临床稳定。大多数患者因毒性需要降低剂量，腹泻是最常见的事件。活检显示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这一假设，激活的PDGF-R和c-kit是至关重要的KS肿瘤的发生和抑制这些途径是潜在的治疗目标。拟议研究的具体目标是： 1.评价甲磺酸伊马替尼治疗卡波西肉瘤的临床疗效和耐受性。 2.通过免疫组化评估确定PDGF受体抑制是否可预测卡波西肉瘤对伊马替尼治疗的反应。 3.确定突变PDGF或c-kit受体是否与卡波西肉瘤对伊马替尼治疗的原发性和继发性耐药相关。 这种翻译研究的治疗抑制PDGF/c-kit在KS将提供深入了解KS的病因，并可能有重大影响KS的治疗方法。