OSI-774 IN PATIENTS WITH ORAL CAVITY OR OROPHARYNGEAL CANCER

OSI-774 用于口腔癌或口咽癌患者

• 批准号: 7378807
• 负责人: MAURA L GILLISON
• 金额: $ 0.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378807
• 关键词: OSI; 774; PATIENTS; ORAL; CAVITY

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。旨在靶向导致恶性肿瘤发病机制的特定信号通路的新型疗法对于提高癌症患者的生存率特别有希望。EGFR信号转导异常在头颈部鳞状细胞癌中普遍存在。EGFR在大多数头颈部鳞状细胞癌中过表达（80-100%），并可能与晚期T分期和淋巴结疾病的存在有关。EGFR过表达也被证明是生存的预测因子（1-3）。配体与表皮生长因子受体（EGFR）的结合导致信号转导级联和随后的细胞复制促进（4）。体外研究表明，EGFR的过度表达可能导致信号转导的组成性活性和细胞复制失调。EGFR信号传导在HNSCC中的重要性已在体外得到充分证明。抗EGFR寡核苷酸、单克隆抗体和EGFR特异性酪氨酸激酶抑制剂影响HNSCC增殖（4，5）。OSI-774是EGFR酪氨酸激酶的特异性抑制剂，在晚期难治性头颈癌患者中显示出单药活性。OSI-774已在体外与常规化疗和放疗显示出协同作用。这个两部分I期试验旨在评估在初次放疗和同步放化疗中加入OSI-774是否会在新诊断的HNSCC患者中产生可接受的毒性，并确定OSI-774每日推荐剂量与这些治疗方式联合用于随后的II期试验。 该临床试验是一项OSI-774联合放疗（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期剂量探索研究。本研究将分两个连续部分进行，即A部分和B部分。从机制上讲，临床试验是一项标准的I期剂量递增研究，在连续的队列。在A部分和B部分中，患者将在开始同步放化疗前的14天诱导“窗口”期间接受每日口服OSI-774单药治疗。A部分将是一项I期剂量探索研究，在II期（T2 N 0）或III期（T1- 2N 1）口咽（OP）和口腔（OC）鳞状细胞癌患者（A组）中每日口服OSI-774联合标准分次外射束放射治疗的最大耐受剂量（MTD）。在A部分确定OSI-774和标准分次外射束放射治疗的第一个剂量水平的安全性后，B部分将开始招募该剂量水平的患者。B部分是一项在III期（T3 N 0 -1）或IV期（T1- 4 N2 - 3 M0，T4 N 0 M0）OP和OC鳞状细胞癌患者（B组）中进行的每日口服OSI-774、每日低剂量顺铂化疗（6 mg/m2/天）和同步标准分割外射束放疗联合治疗的I期剂量探索研究。OSI-774的起始剂量将为50 mg/天，或基于先前单药II期试验的推荐每日口服剂量（150 mg/天）的33.3%。患者将继续每日口服OSI-774，直至出现不可接受的毒性或疾病进展，最长持续两年。 剂量递增将在3-6例患者的连续队列中进行。方案中描述了OSI-774、RT和顺铂的预期不良事件和适当剂量调整。最大耐受剂量将定义为OSI-774与放疗（A部分）或放化疗（B部分）联合治疗时，导致6例或更少患者中1例出现剂量限制性毒性（如方案中定义）的最高剂量水平。在确定MTD后，将在该剂量水平招募另外6例患者，以更好地定义毒性。我们预计在试验的A部分和B部分接受MTD OSI-774治疗的患者总数将为24例，所有剂量水平的患者总数为36例。