ERBB1 AND ERBB2 BLOCKADE IN ADVANCED BREAST CANCER

晚期乳腺癌中的 ERBB1 和 ERBB2 阻断

• 批准号: 6584548
• 负责人: JOHANN S DE BONO
• 金额: $ 27.85万
• 依托单位: CANCER THERAPY AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-23 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584548
• 关键词: angiogenesis inhibitors; apoptosis; biopsy; breast neoplasms; cell differentiation; cell proliferation; clinical research; clinical trial phase I; combination chemotherapy; drug administration rate /duration; drug screening /evaluation; epidermal growth factor; growth factor receptors; human subject; human therapy evaluation; immunocytochemistry; metastasis; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; paclitaxel; patient oriented research; protooncogene; quinazolines; receptor expression

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.

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，增加了转移性乳腺癌患者（MBC）的生存率。 EGFR阻滞增强了HER2抑制作用的抗肿瘤活性。 EGFR在48％的MBC中表达，其表达像HER2，与预后不良相关。 HER2的过表达增加了EGFR信号传导，并且在乳腺组织中过表达HER2的转基因小鼠会随着EGFR信号的增加而形成乳腺肿瘤。 OSI-774是EGFR酪氨酸激酶和下游信号传导的口服喹啉唑啉抑制剂，它也通过受体异二聚体抑制HER2信号传导。 假设：OSI-774的ERBB 1阻断增强了曲妥珠单抗和紫杉醇的抗肿瘤活性，可诱导MBC中凋亡，分化和抑制增殖和血管生成的增加。 具体目的：1。在I期研究中表征连续的口服OSI-774的安全性以及Trastuzumab和Paclitaxel的每周疗程，并建议对后续研究的剂量进行剂量。 2。确定EGFR信号在HER2+和HER2-疾病中的重要性，并在II阶段评估该方案在HER2+ EGFR+ MBC中的抗癌活性是否需要在III期研究中评估。 3。探索伴随EGFR和HER2封锁在MBC中的生物学效应，适合连续肿瘤活检。 研究设计：该研究者发起的NCI-CTEP赞助，I期研究将评估安全性，限制剂量毒性，以及每周一次OSI-774口服的每周紫杉醇和曲妥珠单抗的最大耐受剂量。然后，将在两名单独的HER2和EGFR表达MBC的患者中进行非随机II期研究。在转移环境中未经治疗的患者将使用单阶段的应计设计进行治疗。患有紫杉烷和曲妥珠单抗难治性疾病的患者将使用两阶段设计来治疗EGFR阻滞是否可以改变对治疗的抵抗力。在30名接受这些研究治疗的患者中，将进行佐证的生物学研究，这些患者患有疾病，可安全地进行连续活检。药剂将仅在第一个治疗过程中依次引入，曲妥珠单抗在第1天开始，在第15天口服OSI-774，以及第29天的每周紫杉醇。将在第0、14和28天获得串行肿瘤活检，以评估Her2封锁对EGFR表达和信号的效果，并将其组合给EGFR的效果。凋亡，分化（激素受体表达）和血管生成。 相关性：如果这些结果是有利的，则计划在MBC患者中对有或没有OSI-774的曲妥珠单抗和紫杉醇的III期研究。