Anti-angiogenic Tetrathiomolybdate +XRT in NSCLC-Phase 1

NSCLC 中的抗血管生成四硫代钼酸盐 XRT - 第 1 期

• 批准号: 6796756
• 负责人: MOHAMED K KHAN
• 金额: $ 30.4万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-05 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6796756
• 关键词: angiogenesis; angiogenesis inhibitors; antineoplastics; biomarker; clinical research; clinical trial phase I; combination cancer therapy; computed axial tomography; copper; drug screening /evaluation; fibroblast growth factor; human subject; human therapy evaluation; interleukin 6; interleukin 8; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; neoplasm /cancer relapse /recurrence; nonsmall cell lung cancer; nuclear medicine; patient oriented research; reduction; thoracic radiography; toxicology; transforming growth factors; vascular endothelial growth factors

DESCRIPTION (provided by applicant): This is a phase I trial that will seek to determine the acute toxicity that occurs when the anti-angiogenic copper reduction agent Tetrathiomolybdate (TM), is combined with standard radiotherapy treatment in patients with stages II, IlIA, or IllB non-small cell lung cancer (NSCLC). TM is a copper reduction agent shown to be anti-angiogenic in humans, and to affect multiple proteins involved in angiogenesis via the copper depletion mechanism. Preclinical experiments demonstrate that TM can be successfully combined with radiotherapy to improve the treatment of local tumors in mice, and that the effect is additive and non-toxic. This trial will test whether a multi-target anti-angiogenic agent can be combined with radiotherapy in the treatment of cancer. The specific aims of this proposal are: 1) to determine the acute toxicity that occurs when anti-angiogenic copper reduction therapy with tetrathiomolybdate (TM) is combined with standard radiotherapy in stage II-IIIB NSCLC. 2) To determine whether non-invasive markers of the effect of TM on angiogenesis can be found in these irradiated patients. The measurement of biological markers (VEGF, bFGF, TGF-?, IL-6, IL-8), and imaging studies with 99mTc-MIBI scanning will be used for this. Both have previously been shown to be important in angiogenesis. 3) To assess the late toxicity that occurs when TM is combined with standard radiotherapy in stage II-IIIB NSCLC. 4) To record the tumor response, recurrence, and survival data. Patients will begin on an induction regimen of TM that will rapidly deplete their copper down to ranges where angiogenesis is inhibited. The patients will be placed into one of four possible pre-assigned ranges of copper depletion and then standard radiotherapy will then be delivered. They will then continue at their assigned range of copper reduction for a total of one year using maintenance dosages of TM. The dose of TM will be determined by empiric (ceruloplasmin, Cp) measurements of each individual's copper chelation state. Serum collection and measurements of pro-angiogenic factors (shown to be affected by TM or radiotherapy), and 99mTc-MIBI scanning (shown to correlate with angiogenesis in tumors) will be done to non-invasively assess angiogenesis at different time points. Chest CT and Chest x-ray will be taken to record tumor response, and to compare with 99mTc-MIBI scans.

描述（由申请人提供）：这是一项 I 期试验，旨在确定当抗血管生成铜还原剂四硫代钼酸盐 (TM) 与标准放射治疗联合治疗 II、IIA 期患者时发生的急性毒性。或 IllB 非小细胞肺癌 (NSCLC)。 TM 是一种铜还原剂，在人体中具有抗血管生成作用，并通过铜消耗机制影响多种参与血管生成的蛋白质。临床前实验表明，TM可以成功地与放疗结合，改善小鼠局部肿瘤的治疗效果，且效果具有累加性和无毒性。该试验将测试多靶点抗血管生成剂是否可以与放射疗法联合治疗癌症。该提案的具体目的是：1) 确定在 II-IIIB 期 NSCLC 中使用四硫代钼酸盐 (TM) 进行抗血管生成铜还原治疗与标准放疗联合时发生的急性毒性。 2) 确定是否可以在这些受辐射的患者中发现TM对血管生成影响的非侵入性标志物。为此，将使用生物标志物（VEGF、bFGF、TGF-β、IL-6、IL-8）的测量以及99mTc-MIBI扫描的成像研究。两者先前已被证明在血管生成中很重要。 3) 评估II-IIIB期NSCLC TM联合标准放疗时发生的晚期毒性。 4) 记录肿瘤反应、复发和生存数据。患者将开始接受 TM 诱导方案，该方案将迅速将铜消耗至抑制血管生成的范围。患者将被置于四个可能的预先指定的铜消耗范围之一，然后将进行标准放射治疗。然后，他们将使用 TM 的维持剂量，继续在指定的铜还原范围内进行为期一年的铜还原。 TM 的剂量将通过对每个个体的铜螯合状态的经验（铜蓝蛋白，Cp）测量来确定。将进行血清采集和促血管生成因子测量（显示受 TM 或放射治疗的影响）以及 99mTc-MIBI 扫描（显示与肿瘤血管生成相关），以非侵入性评估不同时间点的血管生成。将进行胸部CT和胸部X光检查以记录肿瘤反应，并与99mTc-MIBI扫描进行比较。