EGFR antisense DNA added to cetuximab and radiotherapy for head and neck cancer

EGFR 反义 DNA 添加到西妥昔单抗和头颈癌放疗中

• 批准号: 7529236
• 负责人: ATHANASSIOS ARGIRIS
• 金额: $ 33.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529236
• 关键词: Age; Antisense DNA; Antisense Oligonucleotides; Biological Markers; Biopsy; CDKN1A gene; Cetuximab; Cisplatin; Clinical; Clinical Trials; Combined Modality Therapy; Common Terminology Criteria for Adverse Events; Comorbidity; Data; Dose; E-Cadherin; Elderly; End Point; Endoscopy; Epidermal Growth Factor Receptor; Erbitux; Evaluation; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Imagery; Immunohistochemistry; Incidence; Injection of therapeutic agent; MAPK14 gene; Malignant Neoplasms; Monoclonal Antibodies; Monoclonal Antibody C225; Outcome; Pathway interactions; Patients; Performance Status; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Progression-Free Survivals; Protein Microchips; Public Health; Radiation; Radiation therapy; Rate; Receptor Inhibition; Receptor Signaling; Recurrence; STAT3 gene; Safety; Sampling; Signaling Protein; Squamous cell carcinoma; Staging; Standards of Weights and Measures; Therapeutic; Tissue Microarray; Toxic effect; Treatment Protocols; Tumor Tissue; United States; United States Food and Drug Administration; Universities; Week; base; c-erbB-1 Proto-Oncogenes; cancer cell; chemotherapy; design; gene therapy; improved; novel; oncoprotein p21; outcome forecast; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; research clinical testing; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinoma of the head and neck (SCCHN) and has been associated with poor prognosis. We have developed intratumoral EGFR antisense oligonucleotide gene therapy (EGFR AS) as a safe and potentially efficacious treatment for SCCHN as shown in a previous phase I study conducted at the University of Pittsburgh. In the current proposal, we are incorporating EGFR AS in the treatment of potentially curable, locally advanced SCCHN. In recent years, standard therapeutic options for locally advanced SCCHN have improved with the addition of systemic agents to radiation. However, locoregional control and survival remain suboptimal. Moreover, cisplatin-based chemoradiotherapy is associated with a high incidence of serious toxicities. Cetuximab (Erbitux or C225) is a chimerized EGFR monoclonal antibody that has demonstrated survival benefit in a phase III trial in SCCHN and was approved by the FDA for the treatment of locally advanced SCCHN. Radiation plus cetuximab is currently considered standard therapy, especially for patients who are not good candidates for cisplatin chemotherapy. In the proposed phase II study, we plan to evaluate dual EGFR inhibition by adding intratumoral EGFR AS to standard cetuximab with concurrent cetuximab in 30 patients with previously untreated locally advanced SCCHN who either elderly (i.e. 70 years or older) or cisplatin-ineligible. We will evaluate the locoregional progression-free survival (primary endpoint), other efficacy parameters, and toxicities. EGFR AS will be administered weekly by direct intratumoral injection using direct visualization or endoscopy as clinically determined. In order to study the antitumor mechanism of dual EGFR inhibition we will evaluate tumor tissue biomarkers, including EGFR pathway-related signaling proteins, using reverse phase protein microarrays (RPPA) and immunohistochemistry in tumor samples taken before and after therapy. If combination therapy with EGFR AS, cetuximab, and radiation meets the prespecified efficacy criteria will be forwarded to further clinical testing. Our goal is to develop a novel, efficacious and safe combination therapy that will be particularly suitable for patients with SCCHN who cannot tolerate chemotherapy. PUBLIC HEALTH RELEVANCE: This project involves the use of gene therapy against the epidermal growth factor receptor (EGFR), an important molecule for the growth of head and neck cancer cells. We plan to inject an anti-EGFR gene into head and neck cancer tumors during treatment with standard radiation and cetuximab. Our goal is to develop a novel, efficacious and safe combination therapy for advanced head and neck cancer that will be particularly suitable for elderly or frail patients who cannot tolerate chemotherapy.

描述（由申请人提供）：表皮生长因子受体（EGFR）在头颈部鳞状细胞癌（SCCHN）中上调，并与不良预后相关。我们已经开发了肿瘤内EGFR反义寡核苷酸基因治疗（EGFR AS）作为SCCHN的安全和潜在有效的治疗方法，如在匹兹堡大学进行的先前I期研究所示。在目前的提案中，我们将EGFR AS纳入治疗可能治愈的局部晚期SCCHN。近年来，局部晚期SCCHN的标准治疗选择随着全身性药物的加入而得到改善。然而，局部区域控制和生存仍然是次优的。此外，基于顺铂的放化疗与严重毒性的高发生率相关。西妥昔单抗（爱必妥或C225）是一种嵌合的EGFR单克隆抗体，在SCCHN的III期试验中证明了生存获益，并被FDA批准用于治疗局部晚期SCCHN。放疗加西妥昔单抗目前被认为是标准治疗，特别是对于不适合顺铂化疗的患者。在拟定的II期研究中，我们计划在30例既往未接受过治疗的老年（即70岁或以上）或不适合顺铂治疗的局部晚期SCCHN患者中，通过在标准西妥昔单抗基础上加用瘤内EGFR AS，同时使用西妥昔单抗，评价双重EGFR抑制作用。我们将评估局部无进展生存期（主要终点）、其他疗效参数和毒性。EGFR AS将通过直接瘤内注射每周给药一次，使用直接可视化或内窥镜检查（根据临床确定）。为了研究双重EGFR抑制的抗肿瘤机制，我们将使用反相蛋白微阵列（RPPA）和免疫组织化学在治疗前后采集的肿瘤样本中评估肿瘤组织生物标志物，包括EGFR通路相关的信号传导蛋白。如果EGFR AS、西妥昔单抗和放疗的联合治疗符合预先规定的疗效标准，则将进行进一步的临床试验。我们的目标是开发一种新的，有效的和安全的联合治疗，将特别适合于SCCHN患者谁不能耐受化疗。公共卫生相关性：该项目涉及针对表皮生长因子受体（EGFR）的基因治疗，EGFR是头颈癌细胞生长的重要分子。我们计划在标准放疗和西妥昔单抗治疗期间，将抗EGFR基因注射到头颈癌肿瘤中。我们的目标是开发一种新的，有效的和安全的联合治疗晚期头颈癌，将特别适合老年人或体弱患者谁不能耐受化疗。