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

描述(申请人提供)：大多数复发的头颈部鳞状细胞癌(HNSCC)患者都患有无法切除的疾病，目前的化疗方案对这些疾病只有10%-30%的短期缓解，中位生存期5-6个月，几乎没有长期治愈。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、间质压力升高、缺氧以及VEGF、PDGF和VEGFR2的过度表达都被发现与侵袭性疾病、不良预后和对常规治疗的抵抗有关。因此，具有广泛血管生成靶点的药物可能通过破坏肿瘤微血管而对HNSCC患者产生比传统化疗更好的临床疗效。AZD2171(NSC732208)是一种口服的小分子受体酪氨酸激酶抑制剂，对VEGFR1、2和3以及PDGFRb具有很强的活性。在这项研究中，我们建议对不能切除的复发性HNSCC患者进行AZD2171单一疗法的II期临床试验。我们的主要目标是评估AZD2171在这一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疗效指标联系起来。许多复发的HNSCC的独特可及性允许活检，并将使我们能够验证这些替代标记物与肿瘤的形态和生理变化。更好地了解AZD2171的生物学作用可能有助于该新药在头颈癌治疗中的进一步发展。我们提出了三个具体目标：目的1：确定AZD2171治疗复发性头颈癌的临床疗效和毒副作用。目的2：评价AZD2171的早期和晚期抗血管生成作用，寻找潜在的替代反应标记物。目的3：确定在AZD2171治疗过程中与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