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

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来源获得了主要资金，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。机制研究已经确定了在头颈部鳞状细胞癌中过度表达转化生长因子-α（TGF-α）及其酪氨酸激酶受体表皮生长因子受体（EGFR）的致病作用。在对配体的应答中，EGFR导致Stat蛋白（信号转导子和转录激活子）的募集，其在细胞生长和增殖中起重要作用;这些事件可以在体外被反义Stat 3或EGFR拮抗。已经证明，从原发性头颈部肿瘤获得的组织切片中的TGF-α和EGFR表达与不良结果相关。有丰富的临床前和临床数据支持EGFR作为许多上皮肿瘤，特别是头颈部鳞状细胞癌的治疗靶点。这些数据表明，阻断这种重要的细胞存活因子的功能可以增强化疗和/或放射诱导的肿瘤消退的效果。初步结果表明，OSI-774可能在表达EGFR的多种肿瘤中具有活性。由于头颈部鳞状细胞癌大量过表达EGFR，并且可以容易地进行活检，因此这种疾病提供了一种理想的肿瘤模型，用于研究EGFR抑制的临床和生物学效应。基于上述临床前和临床原理，我们正在探索每日口服OSI-774和每周低剂量多西他赛同时放射治疗新诊断的头颈部区域晚期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）、多西他赛和放射的组合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/或周围粘膜中的生物学相关物的影响; 3）确定OSI-774单独和与多西他赛组合的药代动力学特征; 4）确定该组合的总体和完全响应率; 5）确定该组合的总体、无疾病和无进展生存期。这是一项剂量递增、剂量探索I期研究。治疗将在门诊进行，但患者将在第1周第-3天、第2周第5天和第5周第3天入住GCRC 24小时进行药代动力学研究。OSI-774是一种口服药物，每天服用两周。然后与每周一次的多西他赛和放疗联合给药，再持续7周。在整个试验期间，所有患者都需要进行三次肿瘤活检。在前九周完成后，患者将进行计划的颈部清扫。手术后，患者将恢复OSI-774两年。

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.