PH I STUDY OF EGFR AND HER2 BLOCKADE W/ OSI-774, TRASTUZUMAB AND PACLITAXEL

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目的：1.观察口服OSI-774联合曲妥珠单抗和紫杉醇治疗晚期癌症患者的安全性和量毒副反应。2.确定这些方案的最大耐受量和限量毒性。3.研究这些药物之间的药代动力学相互作用。4.观察持续口服OSI-774联合每周静脉注射曲妥珠单抗和紫杉醇对ErbB_1和Erb_2双重抑制的初步抗肿瘤活性。研究计划和方法：这是一项开放标签、剂量递增、非随机、单中心的OSI-774联合曲妥珠单抗和紫杉醇治疗晚期癌症患者的I期研究。组织学证实为HER2阳性(TO)转移性实体瘤的成年患者，有很高的EGFR表达可能性，但没有有效的标准治疗选择。预计将有多达40名符合条件的患者参加这一第一阶段试验，预计将有大约20名患者参加GCRC。OSI-774的剂量水平将从每天25毫克到150毫克不等。曲妥珠单抗的剂量为2毫克/公斤。紫杉醇的剂量水平将从每周60毫克/平方米到90毫克/平方米/周不等。紫杉醇将首先使用。曲妥珠单抗将在紫杉醇输注完成30分钟后跟进。OSI-774将始终最后管理。在开始给药后28天，一个疗程将被视为完成。在最初的疗程之后，可以根据患者的耐受性调整OSI-774的剂量。患者将被允许接受多个疗程。治疗将继续进行，直到出现进展性疾病、无法忍受的毒性或患者决定停止治疗。临床意义：OSI-774是一种口服活性的、有效的和选择性的EGFR酪氨酸激酶抑制剂。在体外的酶试验中，它抑制了人EGFR酪氨酸激酶，并减少了完整肿瘤细胞中的EGFR自磷酸化。

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. OBJECTIVES: 1. To determine the safety, and the quantitative and qualitative toxicities of combined erbB1 and erbB2 (EGFR and HER2) inhibition with OSI-774 administered continuously once daily by the oral route, in combination with intravenous Trastuzumab and paclitaxel administered on Days 1, 8, and 15 or Days 1, 8, 15, and 22 in patients with advanced cancer. 2. To determine the maximum tolerated doses and dose-limiting toxicities of these schedules. 3. To investigate relevant pharmacokinetic interactions between these agents. 4. To document the preliminary antitumor activity of dual erbB1 and erbB2 inhibition with continuous oral OSI-774 in combination with weekly intravenous Trastuzumab and Paclitaxel. RESEARCH PLAN AND METHODS: This is an open-label, dose-escalation, non-randomized, single center Phase I study of OSI-774 in combination with Trastuzumab and Paclitaxel in patients with advanced carcinoma. Adult patients with histologically confirmed HER2 positive (+ to +++) metastatic solid tumors that have a high likelihood of expressing EGFR with no effective standard treatment options will be enrolled. It is anticipated that up to 40 eligible patients will be enrolled in this Phase I trial, with enrollment of about 20 patients anticipated for the GCRC. OSI-774 dose levels will range from 25 mg/day to 150 mg/day. Trastuzumab will be dosed at 2 mg/kg. Paclitaxel dose levels will range from 60 mg/m2/week to 90 mg/m2/week. Paclitaxel will be administered first. Trastuzumab will follow 30 minutes after the completion of the paclitaxel infusion. OSI-774 will always be administered last. A course of treatment will be considered to be complete 28 days following the start of administration of treatment. Following the initial course, adjustments of OSI-774 dose are allowed based on patient tolerance. Patients will be allowed to receive multiple courses. The treatment will continue until development of progressive disease, intolerable toxicity, or the patient decides to discontinue therapy. CLINICAL RELEVANCE: OSI-774 is an orally active potent and selective inhibitor of the EGFR tyrosine kinase. In an in vitro enzyme assay, it inhibited the human EGFR tyrosine kinase and reduced the EGFR autophosphorylation in intact tumor cells.