Phase II Clinical Trial of AZD2171 Monotherapy In Recurrent Head and Neck Cancer

描述（由申请人提供）：大多数复发的头颈部鳞状细胞癌（HNSCC）患者存在不可切除的疾病，目前的化疗方案仅导致10- 30%的短暂缓解，中位生存期为5 - 6个月，很少有长期治愈。因此，迫切需要新的药物来改善这些患者的结果。已经发现HNSCC中的肿瘤血管生成、升高的间质液压力、缺氧以及VEGF、PDGF和VEGFR 2的过表达都与侵袭性疾病、不良预后和对常规治疗的抗性相关。因此，具有广谱血管生成靶点的药物可能通过破坏肿瘤微血管系统而在HNSCC患者中诱导比常规化疗更好的临床反应。AZD 2171（NSC 732208）是一种口服小分子受体酪氨酸激酶抑制剂，对VEGFR 1、2和3以及PDGFRB具有强效活性。在这项研究中，我们提出了一项在不可切除的复发性HNSCC患者中进行AZD 2171单药治疗的II期临床试验。我们的主要目的是评估AZD 2171在该患者人群中的疗效和安全性。我们的次要目标是将临床反应与治疗效果指标相关联。许多复发性HNSCC的独特可及性允许活检，并将使我们能够用肿瘤的形态学和生理学变化来验证这些替代标志物。更好地了解AZD 2171的生物学效应可能有助于进一步开发这种新型药物治疗头颈癌。我们提出了三个具体目标：目的1：确定AZD 2171在复发性头颈癌中的临床反应和毒性特征。目标2：评价AZD 2171的早期和晚期抗血管生成作用，并确定潜在的反应替代标志物AIM 3：确定AZD 2171治疗期间与HNSCC肿瘤反应相关的差异表达基因

DESCRIPTION (provided by applicant): The majority of head and neck squamous cell carcinoma (HNSCC) patients who recur present with unresectable disease for which current chemotherapy regimens result in only brief response in 10-30%, median survival of 5 to 6 month and few long term cures. Novel agents are therefore desperately needed to improve the outcome of these patients. Tumor angiogenesis, elevated interstitial fluid pressure, hypoxia, as well as overexpression of VEGF, PDGF, and VEGFR2 in HNSCC have all been found to correlate with aggressive disease, poor prognosis, and resistance to conventional therapy. Therefore, drugs with a broad spectrum of angiogenesis targets may induce a better clinical response in HNSCC patients than conventional chemotherapy by destroying the tumor microvasculature. AZD2171 (NSC732208) is an orally available small molecule receptor tyrosine kinase inhibitor with potent activities against VEGFR1, 2, and 3 as well as PDGFRB. In this study, we propose a phase II clinical trial of AZD2171 monotherapy in patients with unresectable recurrent HNSCC. Our primary objective is to assess the efficacy and safety of AZD2171 in this patient population. Our secondary objective is to correlate clinical response with indicators of therapeutic efficacy. The unique accessibility of many recurrent HNSCC allows biopsy and will enable us to validate these surrogate markers with morphological and physiological changes in the tumor. A better understanding of the biological effect of AZD2171 may facilitate further development of this novel agent in the treatment o head and neck cancer. We propose three specific aims: AIM 1: Determine the clinical response and toxicity profile of AZD2171 in recurrent head and neck cancer. AIM 2: Evaluate the early and late antiangiogenic effects of AZD2171 and identify potential surrogate markers of response AIM 3: Identify differentially expressed genes that correlate with HNSCC tumor response during AZD2171 therapy