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

描述（由申请人提供）：目前关于细胞信号传导、细胞周期调节和细胞死亡中涉及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特定成分的治疗方法。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）可用于分析途径组分的表达，提高个体化预后和治疗的可能性。然而，在这种新模式可以应用于实体肿瘤肿瘤之前，必须证明分析的效用和这类新兴药物的有效性。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可接近的模型。浸润性HNSCC表达EGF-R的程度高于任何其他实体肿瘤，病变可进行活检，存在明确的恶性前病变模型。恶性前上气消化道（UAD）病变进展为恶性的风险特别高，包括：1)不可切除的弥漫性高级别不典型增生，2)既往治疗过的伴有持续/复发性高级别不典型增生的HNSCC， 3)伴有3p9p LOH的不典型增生病变。尽管用药物治疗或完全手术切除，目前还没有确定的干预措施可以改善这些患者的预后。这是一项前瞻性、多组、随机、西妥昔单抗用于高风险、癌前病变患者的II期试验。患者将在第1周接受西妥昔单抗400mg /m2，然后在第2-8周接受250mg /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。8周治疗后，2组和3组根据初始病变程度进行病灶切除。主要结果是组织学反应，次要结果是直接观察病变并结合组织学分级的临床评估。探索性相关研究将评估治疗前和治疗后活检中EGF-R通路成分和分子变化。将对患者进行随访，以了解HNSCC的发展情况。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进行评估。口腔和喉咙上部癌前病变发展为癌症的风险特别高，包括：1)病变范围太广，无法通过手术切除；2)既往患有头颈癌的患者的病变；3)具有特定染色体异常的病变。尽管用药物治疗或完全手术切除，目前还没有确定的干预措施可以改善这些患者的预后。西妥昔单抗是一种阻断表皮生长因子受体途径的药物，已在口腔癌和咽喉癌患者中显示出效果。这是一项针对口腔和咽喉高危癌前病变患者的西妥昔单抗前瞻性试验，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.