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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。目的：1.确定第1、8和15天或第1、8、15和22天连续每日一次口服给予OSI-774联合静脉给予曲妥珠单抗和紫杉醇联合抑制erbB 1和erbB 2（EGFR和HER 2）的安全性以及定量和定性毒性晚期癌症患者。2.确定这些方案的最大耐受剂量和剂量限制性毒性。3.研究这些药物之间的相关药代动力学相互作用。4.记录连续口服OSI-774联合每周静脉注射曲妥珠单抗和紫杉醇双重erbB 1和erbB 2抑制的初步抗肿瘤活性。 研究方法：这是一项开放标签、剂量递增、非随机化、单中心I期研究，研究OSI-774联合曲妥珠单抗和紫杉醇治疗晚期癌症患者。将入组经组织学证实的HER 2阳性（+至+）转移性实体瘤成人患者，这些患者表达EGFR的可能性很高，没有有效的标准治疗选择。预计将有多达40例合格患者入组本I期试验，预计GCRC将入组约20例患者。OSI-774剂量水平范围为25 mg/天至150 mg/天。曲妥珠单抗将以2 mg/kg给药。紫杉醇剂量水平范围为60 mg/m2/周至90 mg/m2/周。首先给予紫杉醇。紫杉醇输注完成后30分钟，将进行曲妥珠单抗给药。OSI-774将始终最后给药。在开始给药后28天，认为疗程完成。初始疗程后，允许根据患者耐受性调整OSI-774剂量。患者将被允许接受多个疗程。治疗将持续至疾病进展、不可耐受的毒性或患者决定停止治疗。 临床相关性：OSI-774是一种口服有效的EGFR酪氨酸激酶选择性抑制剂。在体外酶试验中，它抑制人EGFR酪氨酸激酶并减少完整肿瘤细胞中EGFR的自磷酸化。

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.