COMBINATION ANTIANGIOGENIC THERAPY FOR ADVANCED MELANOMA

晚期黑色素瘤的联合抗血管生成疗法

• 批准号: 6748537
• 负责人: VIKAS P SUKHATME
• 金额: $ 31.46万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748537
• 关键词: angiogenesis inhibitors; blood chemistry; clinical research; clinical trial phase II; combination chemotherapy; dosage; drug screening /evaluation; human subject; human therapy evaluation; melanoma; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; paclitaxel; patient oriented research

DESCRIPTION (provided by applicant): Melanoma progression is angiogenesis dependent. Pre-clinical studies have suggested that several chemotherapeutic agents possess antiangiogenic effects at below cytotoxic concentrations. In preliminary studies we have confirmed the antiangiogenic effects of the chemotherapeutic agent paclitaxel at concentrations 100 to 1000-fold lower than cytotoxic concentrations. In addition, we have found that paclitaxel's antiangiogenic effects are enhanced by co-treatment with COX-2 inhibitors. Also, in preliminary studies, we have demonstrated that low dose, continuous infusion paclitaxel combined with the COX-2 inhibitor celecoxib can be safely administered in five patients with advanced cancer, and that antiangiogenic activity can be demonstrated in patients' blood while on treatment. Moreover, the biologic effects seen in the blood of two patients seems to correlate with clinical benefit. Translation of these findings into a clinical trial for patients with advanced melanoma forms the basis of this proposal as follows: Specific Aim 1: To evaluate the safety/tolerability and demonstrate the clinical efficacy of combination antiangiogenic therapy as a novel strategy to treat patients with advanced melanoma. Specific Aim 2: To evaluate the patients' blood angiogenic profile and measure plasma drug levels before and during therapy. Specific Aim 3: To develop predictive rules relating baseline and changes in the angiogenic profile, and serum levels of paclitaxel and celecoxib to clinical outcome. Encouraging results from this clinical trial of two already FDA approved drugs could be immediately translated to other tumor types. Additionally, the resulting analyses may find novel biomarkers that could be useful as monitoring tools in future antiangiogenesis clinical trials.

描述（由申请人提供）：黑色素瘤进展取决于血管生成。临床前研究表明，在低于细胞毒性浓度下，几种化学治疗剂具有抗血管生成作用。在初步研究中，我们证实了化学治疗剂紫杉醇的抗血管生成作用，其浓度比细胞毒性浓度低100至1000倍。此外，我们发现紫杉醇的抗血管生成作用通过与COX-2抑制剂共同治疗增强。同样，在初步研究中，我们已经证明，低剂量，连续输注紫杉醇与COX-2抑制剂Celecoxib结合在五名晚期癌症患者中可以安全地给药，并且可以在患者的血液中证明抗血管生成活性。此外，在两名患者的血液中看到的生物学作用似乎与临床益处相关。这些发现将晚期黑色素瘤患者的临床试验转换为本提案的基础：特定目的1：评估安全/耐受性，并证明抗血管生成疗法的临床疗效是治疗晚期黑色素瘤患者的新型策略。特定目的2：评估患者的血管生成特征并在治疗之前和期间测量血浆药物水平。特定目的3：制定有关基线和血管生成特征变化的预测规则，紫杉醇和塞来昔布的血清水平与临床结果。这项已经通过FDA批准的药物的这项临床试验的令人鼓舞的结果可以立即转化为其他肿瘤类型。此外，由此产生的分析可能会发现新型的生物标志物，这些标志物可以用作未来的抗血管生成临床试验中的监测工具。

项目成果

A phase 2 pilot trial of low-dose, continuous infusion, or "metronomic" paclitaxel and oral celecoxib in patients with metastatic melanoma.

• DOI: 10.1002/cncr.24902
• 发表时间: 2010-04-01
• 期刊: CANCER
• 影响因子: 6.2
• 作者: Bhatt, Rupal S.;Merchan, Jaime;Parker, Robert;Wu, Hua-Kang;Zhang, Liang;Seery, Virginia;Heymach, John V.;Atkins, Michael B.;McDermott, David;Sukhatme, Vikas P.
• 通讯作者: Sukhatme, Vikas P.