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

描述（由申请人提供）：大多数头颈部鳞状细胞癌（HNSCC）患者复发时存在不可切除的疾病，目前的化疗方案仅导致10-30%的短暂反应，中位生存期为5至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预后。在HNSCC中，肿瘤血管生成、间质液压力升高、缺氧以及VEGF、PDGF和VEGFR2的过表达都被发现与疾病的侵袭性、预后不良和对常规治疗的抵抗相关。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，在HNSCC患者中诱导比传统化疗更好的临床反应。AZD2171 （NSC732208）是一种口服小分子受体酪氨酸激酶抑制剂，对VEGFR1、2和3以及PDGFRB具有有效活性。在这项研究中，我们提出了一项AZD2171单药治疗不可切除复发性HNSCC患者的II期临床试验。我们的主要目标是评估AZD2171在该患者群体中的有效性和安全性。我们的次要目标是将临床反应与治疗效果指标联系起来。许多复发性HNSCC的独特可及性允许活检，并将使我们能够通过肿瘤的形态和生理变化来验证这些替代标志物。更好地了解AZD2171的生物学效应可能有助于进一步开发这种治疗头颈癌的新药物。我们提出了三个具体目标：目的1：确定AZD2171在复发性头颈癌中的临床反应和毒性特征。目的2：评估AZD2171的早期和晚期抗血管生成作用，并确定反应的潜在替代标志物。目的3：确定AZD2171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