PHASE 1 CLINICAL TRIAL OF DAILY ORAL GLEEVE AND ONE HOUR WEEKLY PACLITAXEL IN

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。格列卫通过对Bcr-Abl、血小板衍生生长因子受体和C-Kit激活的酪氨酸激酶途径的有效活性，显示出对慢性髓性白血病（CML）和胃肠道间质肿瘤的活性。紫杉醇对微管具有广泛的抗肿瘤活性，通过其对微管组装的作用和微管抗解聚的稳定性，从而通过在细胞周期的中期和后期诱导持续的有丝分裂阻断来抑制细胞增殖。以往的临床前研究表明，当其他化疗药物与格列卫联合使用时，具有显著的协同效应，但紫杉醇尚未在此类比较中进行评估。通过将广谱药物紫杉醇与新药物格列卫联合使用，我们可以观察到叠加甚至协同作用，而不会显著增加独立抗肿瘤机制的继发毒性。描述格列卫和紫杉醇联合给药时的药代动力学特征。次要目的：记录格列卫和紫杉醇治疗患者的任何客观抗肿瘤反应。+记录C-Kit与肿瘤活检中血小板衍生生长因子受体（PDGF-R）表达的关系以及肿瘤对格列卫联合紫杉醇的反应。其他队列目标：+记录紫杉醇难治性乳腺癌患者肿瘤活检中C-Kit和PDGF-R表达与格列卫和紫杉醇肿瘤反应之间的关系。+记录紫杉烷难治性非小细胞肺癌患者肿瘤活检中C-Kit和PDGF-R表达与肿瘤对格列卫和紫杉醇的反应之间的关系。假设：确定联合使用这两种潜在的抗血管生成药物的安全性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gleevec has shown activity in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors via potent activity against Bcr-Abl, platelet-derived growth factor receptor, and the C-Kit activated tyrosine kinase pathway. Paclitaxel has broad antitumor activity on microtubules via its action on microtubular assembly and stabilization of the microtubules against depolymerization, thereby inhibiting cellular proliferation by inducing a sustained mitotic block at the metaphase-anaphase portion of the cell cycle. Previous preclinical studies have shown significant synergistic effects when other chemotherapy agents have been combined with Gleevec, however Paclitaxel has not been evaluated in such a comparison. By combining the broad acting agent Paclitaxel with the new agent Gleevec we may observe additive or even synergistic effects without significant increases in toxicities secondary to independent antineoplastic mechanisms SPECIFIC AIMS: Primary Aims: + Determine the dose-limiting toxicity and maximum tolerated dose of Gleevec and Paclitaxel when given in combination to patients with advanced tumors. + Characterize the pharmacokinetics of Gleevec and Paclitaxel when given in combination. Secondary Aims: + Document any objective antitumor response in patients treated with Gleevec and Paclitaxel. + Document the relationship between C-Kit and platelet derived growth factor receptor (PDGF-R) expression on tumor biopsies and tumor response to the combination of Gleevec and Paclitaxel. Additional Cohort Objectives: + Document any relationship between C-Kit and PDGF-R expression on tumor biopsies and tumor response to Gleevec and Paclitaxel in Taxane refractory breast cancer patients. + Document any relationship between C-Kit and PDGF-R expression on tumor biopsies and tumor response to Gleevec and Paclitaxel in Taxane refractory Non-Small Cell Lung Cancer patients. Hypothesis: To determine the safety of combining these two potential anti-angiogenic agents.