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

描述（由申请人提供）：目前关于参与细胞信号传导、细胞周期调节和细胞死亡的癌症相关通路的分子机制的知识正在产生针对这些通路的特定组分的治疗。表皮生长因子受体（EGF-R）是几种药物的靶点，包括小分子吉非替尼和厄洛替尼以及单克隆抗体西妥昔单抗。免疫组织化学（IHC）可用于分析通路组分的表达，提高个体化预后和治疗的可能性。然而，在将这种新的范例应用于实体瘤肿瘤学之前，必须证明这种新兴药物的谱分析和有效性的实用性。头颈部鳞状细胞癌（HNSCC）高危患者为研究EGF-R作为化学预防靶点提供了一个有趣且易于获得的模型。侵袭性HNSCC表达EGF-R的程度高于任何其他实体瘤，病变可进行活检，并且存在确定的癌前病变模型。恶性进展风险特别高的癌前上呼吸消化道（UAD）病变包括：1）不可切除的弥漫性高度异型增生，2）既往治疗过的HNSCC伴持续性/复发性高度异型增生和3）伴3 p 9 p洛缺失的异型增生病变。尽管使用药物或完全手术切除治疗，但没有确定的干预措施可以改善这些患者的结局。这是一项关于西妥昔单抗治疗高危UAD癌前病变患者的前瞻性、多组、随机、II期临床试验。患者将在第1周接受西妥昔单抗400 mg/m2，随后在第2-8周接受250 mg/m2或安慰剂。对照组患者在完成安慰剂治疗后可转入治疗组。在8周治疗后，第2组和第3组将根据初始疾病的程度进行病变切除。主要结局是组织学缓解，次要结局是病变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中EGF-R通路组分和分子改变。将随访患者是否发生HNSCC。临床和分子变量将与主要结局相关。还将评估西妥昔单抗在该患者人群中的安全性。具有特别高的癌症进展风险的口腔和咽喉的癌前上部病变包括：1）太广泛而不能通过手术切除的病变，2）先前患有头颈癌的患者中的病变，以及3）具有特定染色体异常的病变。尽管使用药物或完全手术切除治疗，但没有确定的干预措施可以改善这些患者的结局。西妥昔单抗是一种阻断表皮生长因子受体途径的药物，在口腔癌和喉癌患者中显示出效果。这是一项西妥昔单抗的前瞻性试验，用于口腔和咽喉高危癌前病变患者，患者将在接受这些癌前病变的常规治疗前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.