OSI-774 + DOCETAXEL + RADIATION IN LOCALLY ADVANCED HEAD/NECK 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。机制研究已经确定了转化生长因子-a （TGF-a）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的发病作用。EGFR对配体的响应导致Stat蛋白（信号换能器和转录激活因子）的募集，Stat蛋白在细胞生长和增殖中起重要作用；这些事件可以通过反义Stat 3或EGFR在体外拮抗。已有研究表明，原发性头颈部肿瘤组织切片中TGF-a和EGFR的表达与不良预后相关。有大量的临床前和临床数据支持将EGFR作为许多上皮性肿瘤尤其是头颈部鳞状细胞癌的治疗靶点。这些数据表明，阻断这一重要细胞存活因子的功能可能会增强化疗和/或放疗诱导的肿瘤消退的效果。初步结果表明，OSI-774可能在多种表达EGFR的肿瘤中具有活性。由于头颈部鳞状细胞癌大量过度表达EGFR，并且易于活检，因此该疾病为研究EGFR抑制的临床和生物学效应提供了理想的肿瘤模型。基于上述临床前和临床基础，我们正在探索一种每日口服osi774和每周低剂量多西他赛同时放射治疗新诊断的局部晚期头颈部鳞状细胞癌患者的联合治疗方法。本研究的目的是：1)确定EGFR抑制剂（OSI-774）、多西他赛和放疗联合使用的最大耐受剂量和毒性；2)确定治疗和治疗剂量对肿瘤组织和/或周围粘膜生物相关物的影响；3)测定OSI-774单独及联合多西他赛的药动学特征；4)确定该组合的总有效率和完全有效率；5)确定该联合治疗的总生存率、无病生存率和无进展生存率。这是剂量递增，剂量发现的第一阶段研究。治疗将在门诊进行，但患者将在第1周的第3天、第2周的第5天和第5周的第3天在GCRC住院24小时进行药代动力学检查。OSI-774是一种口服药物，每天服用两周。然后与每周多西紫杉醇和放疗联合使用，再持续7周。在整个试验过程中，所有患者都需要进行三次肿瘤活检。在前九周完成后，患者将按计划进行颈部解剖。手术后，患者将在两年内恢复使用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.