OSI-774 IN PATIENTS WITH ORAL CAVITY OR OROPHARYNGEAL CANCER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。针对恶性肿瘤发病机制的特定信号通路设计的新疗法对提高癌症患者的生存率具有特殊的希望。EGFR信号转导异常在头颈部鳞状细胞癌中很常见。EGFR过表达已在大多数（80-100%）头颈部鳞状细胞癌中被证实，并且可能与晚期T期和淋巴结疾病的存在有关。EGFR过表达也被证明是生存的一个预测因子（1-3）。配体与表皮生长因子受体（EGFR）结合导致信号转导级联，随后促进细胞复制(4)。体外研究表明，EGFR的过表达可能导致信号转导的组成活性和细胞复制的失调。EGFR信号在HNSCC中的重要性已经在体外得到了很好的证明。反义寡核苷酸、EGFR单克隆抗体和EGFR特异性酪氨酸激酶抑制剂可影响HNSCC增殖（4,5）。OSI-774是一种特异性EGFR酪氨酸激酶抑制剂，在晚期难治性头颈癌患者中已显示出单药活性。OSI-774已证明与常规化疗和放疗在体外具有协同作用。这项分为两部分的I期试验旨在评估在初次放疗和同步化疗中添加osii -774是否会对新诊断的HNSCC患者产生可接受的毒性，并确定后续II期试验中每日osii -774与这些治疗方式联合的推荐剂量。该临床试验是OSI-774联合放射治疗（RT）和顺铂治疗新诊断的口腔（OC）和口咽（OP）局部晚期鳞状细胞癌（SCC）患者的I期剂量发现研究。该研究将分A部分和b部分进行。从机制上讲，该临床试验是一个标准的连续队列的I期剂量递增研究。在A部分和B部分，患者将在同步放化疗开始前的14天诱导“窗口”内每天接受单药口服OSI-774。A部分将是一项针对II期（T2N0）或III期（T1-2N1）口咽（OP）和口腔（OC）鳞状细胞癌（A组）患者每日口服osi774联合标准分次外束放射治疗的最大耐受剂量（MTD）的I期剂量研究。在A部分确定了第一剂量水平的OSI-774和标准分馏外束放射治疗的安全性后，B部分将开始在该剂量水平下招募患者。B部分将是一项I期剂量发现研究，对III期（T3N0-1）或IV期（T1-4N2-3M0, T4N0M0） OP和OC鳞状细胞癌（B组）患者进行每日口服OSI-774、低剂量每日顺铂化疗（6mg /m2/天）和同步标准分次外束放疗的联合治疗。osii -774的起始剂量为50mg /天，或根据以往单药II期试验推荐的每日口服剂量（150mg /天）的33.3%。患者将继续每日口服OSI-774，直到出现不可接受的毒性或疾病进展，最多持续两年。剂量增加将发生在3-6例患者的连续队列中。方案中描述了OSI-774的预期不良事件和适当的剂量调整，以及RT和顺铂。最大耐受剂量将被定义为OSI-774与放射治疗（A部分）或放化疗（B部分）联合使用的最高剂量水平，使6名患者中有1名或更少的患者经历剂量限制性毒性（如方案中定义）。确定MTD后，将在该剂量水平下再招募6名患者，以更好地确定毒性。我们预计在试验的A部分和B部分的MTD中接受OSI-774治疗的患者总数将为24人，所有剂量水平的患者总数将为36人。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Novel therapeutics designed to target specific signaling pathways that contribute to the pathogenesis of malignancy have particular promise for improving survival for patients with cancer. Abnormalities of EGFR signal transduction are common in squamous cell carcinoma of the head and neck. Over expression of EGFR has been demonstrated in the majority (80-100%) of head and neck squamous cell carcinomas, and may be related to advanced T stage and presence of nodal disease. EGFR overexpression has also been shown to be a predictor of survival(1-3). Ligand binding to the epidermal growth factor receptor (EGFR) results in a cascade of signal transduction and subsequent promotion of cell replication(4). In vitro studies have shown that over expression of EGFR may lead to constitutive activity of signal transduction and dysregulated cell replication. The importance of EGFR signaling in HNSCC has been well demonstrated in vitro. Antisence oligonucleotides, monoclonal antibodies to EGFR and EGFR-specific tyrosine kinase inhibitors effect HNSCC proliferation (4,5). OSI-774 is a specific inhibitor of EGFR tyrosine kinase that has shown activity as a single agent in patients with advanced, drug-refractory head and neck cancer. OSI-774 has demonstrated synergy in vitro with conventional chemotherapy and radiation. This two-part phase I trial is designed to evaluate whether the addition of OSI-774 to primary radiation therapy and to concurrent chemo-radiotherapy will produce acceptable toxicities in patients with newly diagnosed HNSCC and to determine the recommended dose of daily OSI-774 in combination with these treatment modalities for subsequent phase II trials. The clinical trial is a phase I dose-finding study of OSI-774 in combination with radiation therapy (RT) and cisplatin in patients with newly diagnosed, locally advanced squamous cell cancers (SCC) of the oral cavity (OC) and oropharynx (OP). The study will be conducted in two sequential parts, Part A and B. Mechanistically, the clinical trial is a standard phase I dose escalation study in successive cohorts. In both Parts A and B, patients will receive single agent daily oral OSI-774 during a fourteen day induction "window" prior to start of concurrent chemoradiation. Part A will be a phase I dose finding study to maximum tolerated dose (MTD) of daily oral OSI-774 in combination with standard fractionation external beam radiation therapy in patients with stage II (T2N0) or stage III (T1-2N1) squamous cell carcinoma of the oropharynx (OP) and oral cavity (OC) (Group A). After the safety of the first dose level of OSI-774 and standard fractionation external beam radiation therapy has been determined in Part A, Part B will begin to enroll patients at that dose level. Part B will be a phase I dose finding study of the combination of daily oral OSI-774, low dose daily cisplatin chemotherapy (6 mg/m2/day) and concurrent standard fractionation external beam radiation therapy in patients with stage III (T3N0-1) or IV (T1-4N2-3M0, T4N0M0) squamous cell carcinoma of the OP and OC (Group B). Starting dose of OSI-774 will be 50 mg/day, or 33.3% of the recommended daily oral dose (150 mg/day) based on previous single agent Phase II trials. Patients will continue daily oral OSI-774 until unacceptable toxicity or disease progression for a maximum of two years. Dose escalations will occur in successive cohorts of 3-6 patients. Expected adverse events and appropriate dose modifications for OSI-774, and RT and cisplatin are described in the protocol. The maximally tolerated dose will be defined as the highest dose level of OSI-774 in combination with radiation therapy (Part A) or chemoradiation (Part B) that causes 1 of 6 or less patients to experience a dose limiting toxicity (as defined in the protocol). After the MTD has been defined, 6 additional patients will be enrolled at that dose level to better define toxicities. We expect the total number of patients treated with OSI-774 at the MTD in Parts A and B of the trial will be 24 and a total of 36 patients in all dose levels.