OSI-774 + DOCETAXEL + RADIATION IN LOCALLY ADVANCED HEAD/NECK CANCER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。已有机制研究证实转化生长因子-α及其酪氨酸激酶受体表皮生长因子受体(EGFR)在头颈部鳞状细胞癌中的过度表达在发病机制中所起的作用。作为对配体的响应，EGFR导致Stat蛋白(信号转导和转录激活子)的募集，这些蛋白在细胞的生长和增殖中发挥重要作用；这些事件在体外可以被反义Stat 3或EGFR拮抗。已有研究表明，头颈部原发肿瘤组织切片中的转化生长因子-α和表皮生长因子受体的表达与不良预后有关。有大量的临床前和临床数据支持将EGFR用作许多上皮性肿瘤，特别是头颈部鳞状细胞癌的治疗靶点。这些数据表明，阻断这一重要的细胞生存因子的功能可能会增强化疗和/或放射诱导的肿瘤消退的效果。有初步结果表明，OSI-774可能在多种表达EGFR的肿瘤中发挥活性。由于头颈部鳞状细胞癌大量过度表达EGFR，且易于活检，本病为研究EGFR抑制的临床和生物学效应提供了一个理想的肿瘤模型。基于上述临床前和临床理论基础，我们正在探索一种同步联合治疗方法，每日口服OSI-774和每周小剂量多西紫杉醇，同时放射治疗新诊断的区域性晚期头颈部鳞癌患者。本研究的目的是：1)确定EGFR抑制剂(OSI-774)、多西紫杉醇和放射治疗联合应用的最大耐受剂量和毒性；2)确定联合治疗方法和剂量对肿瘤组织和或周围黏膜生物相关因素的影响；3)确定OSI-774单独及与多西紫杉醇联合应用的药代动力学特征；4)确定联合用药的总体、完全缓解率；5)确定联合用药的总体、无病、无进展生存期。这是一项剂量递增，剂量发现阶段I研究。治疗将以门诊为基础进行，例外情况是患者将于第3天24小时住进GCRC，第1周、第2周第5天和第5周第3天进行药代动力学。OSI-774是一种连续两周每天服用的口服药物。然后，在每周服用多西紫杉醇的同时，再接受七周的放射治疗。在整个试验过程中，所有患者都将被要求进行三次肿瘤活组织检查。在前九周完成后，患者将接受计划中的颈部解剖。手术后，患者将在两年内恢复OSI-774。

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. Mechanistic studies have identified a pathogenetic role for over-expression of transforming growth factor-a (TGF-a) and its tyrosine kinase receptor epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the head and neck. In response to ligand, EGFR results in the recruitment of Stat proteins (signal transducer and activators of transcription), which play an important role in cell growth and proliferation; these events can be antagonized in vitro by antisense Stat 3 or EGFR. It has been demonstrated that TGF-a and EGFR expression in tissue sections obtained from primary head and neck tumors is associated with adverse outcomes. There is abundant preclinical and clinical data to support the use of EGFR as a therapeutic target in many epithelial tumors and squamous cell carcinoma of the head and neck in particular. These data indicate that blocking the function of this important cellular survival factor may enhance the effects of chemotherapy and/or radiation induced tumor regression. There are preliminary results that OSI-774 may be active in a wide variety of tumors which express EGFR. Since squamous cell carcinoma of the head and neck abundantly over-expresses the EGFR and can be readily biopsied, this disease provides an ideal tumor model in which to investigate both the clinical and biological effects of EGFR inhibition. On the basis of the above preclinical and clinical rationale we are exploring a concurrent combined modality treatment approach with daily oral dosing of OSI-774 and weekly low-dose docetaxel with concurrent radiation in patients with newly diagnosed regionally advanced squamous cell carcinoma of the head and neck. The goals of this study are to: 1) determine the maximum tolerated dose and toxicity of the combination of EGFR inhibitor (OSI-774), docetaxel and radiation; 2) determine the effect of treatment and dose of treatment on biologic correlates in tumor tissue and or surrounding mucosa; 3) determine the pharmacokinetic profile of OSI-774 alone and in combination with docetaxel; 4) determine the overall and complete response rate of this combination; 5) determine overall, disease free and progression free survival of this combination. This is a dose escalation, dose finding phase I study. Treatment will be administered on an outpatient basis with the exception that patients will be admitted to the GCRC for 24 hours on day -3 for week 1, day 5 of week 2 and day 3 of week 5 for pharmacokinetics. OSI-774 is an oral drug taken daily for two weeks. It is then given in combination with weekly docetaxel and radiation for an additional seven weeks. All patients will be required to have biopsies of their tumor three times throughout the trial. After the completion of the first nine weeks, patients will go to a planned neck dissection. Following surgery the patients will resume the OSI-774 for two years.