PH I: ORAL GLEEVEC & ONE HR WEEKLY PACLITAXEL INFUSION- METASTATICS SOLID TUMORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Gleevec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具有强大的活性，在慢性粒细胞白血病(CML)和胃肠道间质瘤中显示出活性。紫杉醇在微管上具有广泛的抗肿瘤活性，它通过作用于微管的组装和稳定微管的解聚，从而通过在细胞周期的中后期诱导持续的有丝分裂阻滞来抑制细胞的增殖。以前的临床前研究表明，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，但紫杉醇尚未在这样的比较中进行评估。通过将广泛的作用药物紫杉醇与新药格列卫联合使用，我们可以观察到相加甚至协同作用，而不会显著增加独立抗肿瘤机制的毒性。 具体目标： 主要目标： 确定格列卫和紫杉醇联合应用于晚期肿瘤患者时的剂量限制毒性和最大耐受量。 格列卫和紫杉醇合用时的药代动力学特征。 次要目标： 记录使用格列卫和紫杉醇治疗的患者是否有任何客观的抗肿瘤反应。 记录肿瘤活检组织中C-Kit和血小板衍生生长因子受体(PDGF-R)的表达与联合应用格列卫和紫杉醇后肿瘤反应的关系。 其他队列目标： 记录紫杉类难治性乳腺癌患者肿瘤活检组织中C-Kit和PDGF-R的表达与格列卫和紫杉醇的肿瘤疗效之间的任何关系。 在紫杉类难治性非小细胞肺癌患者中，记录肿瘤活检组织中C-Kit和PDGF-R的表达与格列卫和紫杉醇的肿瘤反应之间的任何关系。 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.