Cetuximab for Treatment of High-risk Pre-malignant Upper Aerodigestive Lesions

描述(申请人提供)：目前关于癌症相关途径的分子机制的知识涉及细胞信号、细胞周期调节和细胞死亡，正在产生针对这些途径的特定组成部分的治疗。表皮生长因子受体(EGF-R)是几种药物的靶标，包括小分子吉非替尼和埃洛替尼以及单抗西妥昔单抗。免疫组织化学(IHC)可用于分析通路成分的表达，提高了个体化预后和治疗的可能性。然而，在这种新的范例可以应用于实体肿瘤之前，必须证明侧写的效用和这一新兴类别药物的有效性。头颈部鳞状细胞癌(HNSCC)的高危患者为研究EGF-R作为化学预防的靶点提供了一个有趣且容易获得的模型。侵袭性HNSCC比其他实体肿瘤表达EGF-R的程度更高，病变可以进行活检，并且存在明确的癌前病变模式。癌前上呼吸道(UAD)病变恶性进展的风险特别高，包括：1)无法切除的弥漫性高级别异型增生，2)既往治疗过的HNSCC持续/复发的高级别异型增生，以及3)3p 9p LOH的异型增生病变。尽管使用药物治疗或完全手术切除，但没有确定的干预措施来改善这些患者的结果。这是一项针对高危、癌前UAD皮损患者的西妥昔单抗的前瞻性、多臂、随机、II期试验。患者将在第1周接受西妥昔单抗400 mg/m2的治疗，随后在第2-8周接受250 mg/m2的治疗或服用安慰剂。对照组患者在完成安慰剂治疗后可以进入治疗臂。治疗8周后，第2组和第3组将根据初始疾病的程度进行病变切除。主要结果是组织学反应，次要结果是对病变的直接可视化结合组织学分级的临床评估。探索性相关性将评估治疗前和治疗后活检组织中的EGF-R途径成分和分子变化。患者将接受HNSCC的随访。临床和分子变量将与主要结果相关。西妥昔单抗在该患者群体中的安全性也将得到评估。口腔和喉部癌前病变的进展风险特别高，包括：1)太大而不能通过手术切除的病变，2)既往有头颈癌病史的患者的病变，以及3)具有特定染色体异常的病变。尽管使用药物治疗或完全手术切除，但没有确定的干预措施来改善这些患者的结果。西妥昔单抗是一种阻断表皮生长因子受体途径的药物，已在口腔和喉癌患者中显示出效果。这是一项针对口腔和喉咙高风险癌前病变患者的西妥昔单抗的前瞻性试验，患者在接受这些癌前病变的常规治疗之前将接受西妥昔单抗或安慰剂。

DESCRIPTION (provided by applicant): Current knowledge about the molecular mechanisms of cancer-related pathways involved in cellular signaling, cell cycle regulation and cell death is yielding therapies directed at specific components of these pathways. The epidermal growth factor receptor (EGF-R) is a target of several drugs, including the small molecules gefitinib and erlotinib as well as the monoclonal antibody cetuximab. Immunohistochemistry (IHC) is available for profiling expression of pathway components, raising the possibility of individualized prognosis and therapy. Before such a new paradigm can be applied to solid tumor oncology, however, the utility of profiling and the effectiveness of this emerging class of drugs must be demonstrated. Patients at high risk for squamous cell cancer of the head and neck (HNSCC) offer both an intriguing and accessible model for studying the EGF-R as a target for chemoprevention. Invasive HNSCC expresses the EGF-R to a higher degree than any other solid tumor, the lesions are accessible for biopsy, and a defined model of pre-malignancy exists. Premalignant upper aerodigestive tract (UAD) lesions at particularly high risk for progression to malignancy include:1) unresectable, diffuse high grade dysplasia, 2) previously treated HNSCC with persistent/recurrent high grade dysplasia and 3) dysplastic lesions with 3p 9p LOH. Despite treatment with drugs or complete surgical excision, there are no identified interventions that improve outcome in these patients. This is a prospective, multi-arm, randomized, phase II trial of cetuximab for patients with high-risk, premalignant UAD lesions. Patients will receive cetuximab 400 mg/m2 week 1 followed by 250 mg/m2 weeks 2-8 or placebo. Control patients can move into a treatment arm after completion of placebo. Following the eight week treatment, groups 2 and 3 will undergo lesion resection based on extent of initial disease. The primary outcome is histologic response and secondary outcome is a clinical assessment of direct visualization of the lesion combined with histologic grade. Exploratory correlatives will evaluate EGF-R pathway components and molecular alterations in pre- and post-treatment biopsies. Patients will be followed for development of HNSCC. Clinical and molecular variables will be correlated with the primary outcome. Safety of cetuximab in this patient population will also be evaluated. Precancerous upper lesions of the mouth and throat that are at particularly high risk for progression to cancer include: 1) lesions that are too extensive to be removed by surgery, 2) lesions in patients with a prior head and neck cancer, and 3) lesions with specific chromosomal abnormalities. Despite treatment with drugs or complete surgical excision, there are no identified interventions that improve outcome in these patients. Cetuximab is a drug that blocks the epidermal growth factor receptor pathway, and has shown effect in patients with mouth and throat cancers. This is a prospective trial of Cetuximab, for patients with high-risk precancerous lesions of the mouth and throat, in which patients will receive Cetuximab or a placebo before undergoing conventional therapy for these precancerous lesions.