ERBB1 AND ERBB2 BLOCKADE IN ADVANCED BREAST CANCER

描述(由申请人提供)：HER2信号抑制增加了紫杉醇的抗肿瘤作用，提高了转移性乳腺癌(MBC)患者的生存率。EGFR阻断可增强HER2抑制的抗肿瘤活性。EGFR在48%的MBC中表达，其表达类似于HER2，与预后不良相关。HER2过表达增加了EGFR信号，在乳腺组织中过表达HER2的转基因小鼠发生乳腺肿瘤时EGFR信号增加。OSI-774是一种口服喹唑啉抑制剂，可以抑制EGFR酪氨酸激酶及其下游信号，也可以通过受体异构化来抑制HER2信号。 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，紫杉醇可增加MBC的凋亡、分化、抑制增殖和血管生成。 具体目标：1.在I期研究中，确定连续口服OSI-774以及每周服用曲妥珠单抗和紫杉醇方案的安全性，并为后续研究推荐剂量。2.确定EGFR信号在HER2+和HER2-病中的重要性，并在II期研究中评估该方案在HER2+EGFR+MBC中的抗癌活性是否值得在III期研究中进行评估。3.探讨EGFR和HER2联合阻断对连续肿瘤活检MBC的生物学作用。 研究设计：这项由研究者发起、NCI-CTEP赞助的第一阶段研究将评估每周服用一次OSI-774的紫杉醇和曲妥珠单抗的安全性、剂量限制毒性和最大耐受量。一项非随机化的II期研究将在两个单独的HER2和EGFR表达MBC的患者队列中进行。未在转移性环境中治疗的患者将采用单期权责发生设计进行治疗。紫杉烷和曲妥珠单抗难治性疾病的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。在这些研究中接受治疗的30名患者将进行确凿的生物学研究，这些患者的疾病可以安全地接受连续活检。这些药物将只在第一个疗程中按顺序推出，曲妥珠单抗在第1天开始，口服OSI-774在第15天开始，每周紫杉醇在第29天开始。观察HER2阻断对EGFR表达和信号转导的影响，以及联合阻断HER2和EGFR对肿瘤细胞增殖、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，曲妥珠单抗和紫杉醇在MBC患者中使用或不使用OSI-774的III期研究正在计划中。

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.