ERBB1 AND ERBB2 BLOCKADE IN ADVANCED BREAST CANCER

描述（由申请方提供）：HER 2信号传导抑制可增强紫杉醇的抗肿瘤作用，从而延长转移性乳腺癌（MBC）患者的生存期。EGFR阻断增强了HER 2抑制的抗肿瘤活性。EGFR在48%的MBC中表达，其表达类似于HER 2，与不良预后相关。HER 2过表达增加EGFR信号传导，并且在乳腺组织中过表达HER 2的转基因小鼠发展具有增加的EGFR信号传导的乳腺肿瘤。OSI-774是EGFR酪氨酸激酶和下游信号传导的口服喹唑啉抑制剂，也通过受体异源二聚化抑制HER 2信号传导。 假设：OSI-774阻断ErbB 1可增强曲妥珠单抗和紫杉醇的抗肿瘤活性，诱导MBC细胞凋亡、分化增加以及增殖和血管生成抑制。 具体目标：1.在一项I期研究中，描述连续口服OSI-774和曲妥珠单抗和紫杉醇每周方案的安全性，并为后续研究推荐剂量。2.确定EGFR信号传导在HER 2+和HER 2-疾病中的重要性，并在II期研究中评估该方案在HER 2 + EGFR+ MBC中的抗癌活性是否需要在III期研究中进行评价。3.探讨EGFR和HER 2联合阻断对适合连续肿瘤活检的MBC的生物学效应。 研究设计：这项由制药商发起、NCI-CTEP申办的I期研究将评价每周一次紫杉醇和曲妥珠单抗联合每日一次口服OSI-774的安全性、剂量限制性毒性和最大耐受剂量。然后将在两个单独的HER 2和EGFR表达MBC患者队列中进行非随机II期研究。在转移背景下未接受治疗的患者将使用单阶段累积设计进行治疗。紫杉烷和曲妥珠单抗难治性疾病患者将采用两阶段设计进行治疗，以确定EGFR阻断是否可以改变对治疗的耐药性。将在这些研究中接受治疗的30例患者中进行确证性生物学研究，这些患者的疾病可安全进行系列活检。仅在第一个疗程中按顺序引入药物，第1天开始曲妥珠单抗，第15天口服OSI-774，第29天每周一次紫杉醇。将在疗程1的第0、14和28天获得连续肿瘤活检，以评价HER 2阻断对EGFR表达和信号传导的影响，以及HER 2和EGFR联合阻断对肿瘤增殖、凋亡、分化（激素受体表达）和血管生成的影响。 相关性：如果这些结果是有利的，则计划在MBC患者中进行曲妥珠单抗和紫杉醇联合或不联合OSI-774的III期研究。

DESCRIPTION (provided by applicant): HER2 signaling inhibition increases the antitumor effects of paclitaxel increasing survival in patients with metastatic breast cancer (MBC). EGFR blockade enhances the antitumor activity of HER2 inhibition. EGFR is expressed in 48% of MBC, its expression like HER2, correlating with poor prognosis. HER2 overexpression increases EGFR signaling, and transgenic mice overexpressing HER2 in mammary tissue develop mammary tumors with increased EGFR signaling. OSI-774 is an oral quinazoline inhibitor of EGFR tyrosine kinase and downstream signaling that also inhibits HER2 signaling through receptor heterodimerization. HYPOTHESIS: ErbB 1 blockade by OSI-774 potentiates the antitumor activity of trastuzumab and paclitaxel induces increased apoptosis, differentiation, and inhibition of proliferation and angiogenesis in MBC. SPECIFIC AIMS: 1. To characterize, in a phase I study, the safety of continuous oral OSI-774 and a weekly regimen of trastuzumab and paclitaxel and to recommend a dose for subsequent studies. 2. To determine the importance of EGFR signaling in HER2+ and HER2- disease and to assess in phase II studies whether the anticancer activity of this regimen in HER2+ EGFR+ MBC warrants evaluation in phase III studies. 3. To explore the biologic effects of concomitant EGFR and HER2 blockade in MBC amenable to serial tumor biopsies. STUDY DESIGN: This investigator-initiated, NCI-CTEP sponsored, phase I study will evaluate the safety, dose-limiting toxicities, and maximum tolerated dose of weekly paclitaxel and trastuzumab with oral once daily OSI-774. A non-randomized phase II study will then be performed in two separate cohorts of patients with HER2 and EGFR expressing MBC. Patients untreated in the metastatic setting will be treated using a single stage accrual design. Patients with taxane and trastuzumab refractory disease will be treated utilizing a two-stage design to determine whether EGFR blockade can alter resistance to treatment. Corroborative biological studies will be pursued in 30 patients treated on these studies, who have disease safely amenable to serial biopsy. The agents will be introduced sequentially in the first course of treatment only, trastuzumab being commenced on day 1, oral OSI-774 on day 15, and weekly paclitaxel on day 29. Serial tumor biopsies will be obtained on days 0, 14 and 28 in course 1 to evaluate the effects of HER2 blockade on EGFR expression and signaling, and of combined HER2 and EGFR blockade on tumor proliferation, apoptosis, differentiation (hormone receptor expression) and angiogenesis. RELEVANCE: If these results are favorable, a phase III study of trastuzumab and paclitaxel with or without OSI-774 in patients with MBC is planned.