Phase I Radiosensitization Study of GW572016 in Recurrent Breast Cancer

描述(申请人提供)：表皮生长因子受体家族成员，EGFR和HER2，与乳腺癌的放射抵抗有关，这些受体的抑制剂在临床前模型和早期临床试验中显示出有效的放射增敏作用。由于EGFR和HER2都参与乳腺癌的发病机制，针对这两种受体的抑制剂可能比只针对一种受体的抑制剂具有更广泛的适用性。事实上，临床前数据表明，双重EGFR/HER2抑制剂GW572016对EGFR和HER2过表达的乳腺癌细胞株都具有抗增殖和放射增敏作用。本研究的主要目的是评估GW572016联合放射治疗局部复发或难治性乳腺癌的毒性和生物活性。我们假设，GW572016在放疗的同时给予的耐受性良好，并将使局部复发的乳腺癌变得放射增敏。此外，我们假设，尽管受体磷酸化受到抑制，但关键的下游信号只在一小部分肿瘤中被抑制，并且下游信号的抑制将与放射增敏相关。这是一项增加GW57201-G剂量与标准放射治疗相结合的I期研究。将获得一系列的肿瘤活检，以确定Ras-MAPK和PI3K-AKT的抑制以及受体的磷酸化。主要目标将是评估联合用药的毒性，并确定GW572016在放射治疗环境中对受体和下游信号的影响；次要终点将是评估反应，并获得反应与下游信号抑制之间相关性的初步迹象。相关性：尽管采用现代辅助治疗，早期乳腺癌仍有5%-20%的患者会出现局部复发，其中大多数患者不能有效地接受常规治疗，5年生存率仅为35%-50%。此外，不受控制的局部复发可能是高度病态的，导致疼痛、出血和感染。这项建议试验了一种新的联合疗法来治疗这一常见且具有挑战性的临床问题。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor family members, EGFR and HER2, are implicated in breast cancer radioresistance, and inhibitors of these receptors demonstrate effective radiosensitization in preclinical models and early stage clinical trials. Since both EGFR and HER2 are involved in breast cancer pathogenesis, inhibitors that target both of these receptors may have wider applicability than those that target just one receptor. Indeed, preclinical data indicates that the dual EGFR/HER2 inhibitor, GW572016, has antiproliferative and radiosensitizing effects on both EGFR and HER2 over-expressing breast cancer cell lines. The broad objective of this study is to evaluate the toxicity and biologic activity of GW572016 in combination with radiotherapy for locoregionally recurrent or refractory breast cancer. We hypothesize that GW572016 will be well-tolerated when given concurrently with radiotherapy, and will radiosensitize locally recurrent breast cancer. Further we hypothesize that, despite inhibition of receptor phosphorylation, critical downstream signals will be inhibited in only a subset of tumors, and that inhibition of downstream signaling will correlate with radiosensitization. This is a phase I study of escalating doses of GW57201-G in combination with standard radiotherapy. Serial tumor biopsies will be obtained to determine inhibition of Ras-MAPK and PI3K-AKT as well as receptor phosphorylation. The primary objectives will be to evaluate toxicity of the combination and determine the effect of GW572016 on receptor and downstream signaling in the setting of radiation therapy; secondary endpoints will be to evaluate response and gain preliminary indication of correlation between response and inhibition of downstream signaling. Relevance: Despite modern adjuvant therapy, 5-20% of patients with early stage breast cancer will develop locoregional recurrence, and the majority of those will not be effectively treated with conventional therapy, with 5 year survival rates only 35-50%. Furthermore uncontrolled locoregional recurrence can be highly morbid causing pain, bleeding, and infection. This proposal pilots a novel combination therapy to treat this common and challenging clinical problem.