Phase2 trial of MEK162 & imatinib combined therapy in GIST, IND119794(09/20/2013)

项目说明/摘要 胃肠道间质瘤(GIST)是一种罕见的癌症类型，影响大约40,000名患者 在美国，每年的发病率为5000例。它起源于胃肠道的“起搏”细胞。 其主要特征是激活KIT或PDGFRA受体酪氨酸激酶的突变。尽管 靶向突变KIT/PDGFRA的伊马替尼的初步临床成功，几乎所有晚期GIST患者都发生了 对伊马替尼耐药，最终死于他们的疾病。更好地了解 GIST的发病机制和开发新的治疗策略：1)比一线更有效 伊马替尼治疗和2)可以延缓和/或防止对伊马替尼的耐药性。 ETV1是一种ETS家族转录因子，也是前列腺癌和黑色素瘤中公认的癌基因， 最近被发现在胃肠道间质瘤的发生中起关键作用。ETV1高度表达，是 GIST的生长和生存所需的。ETV1是ICC-GIST谱系的主调节器，是必需的 用于GIST肿瘤的体内启动和维持。ETV1和突变试剂盒形成正反馈电路 GIST肿瘤发生，其中ETV1蛋白通过KIT下游的活性MAP激酶信号稳定 信号转导和稳定的ETV1反过来上调KIT的表达。因此，ETV1代表了一个新的药物靶点。 我们证明了MEK162和伊马替尼的联合应用可以持续抑制ETV1蛋白并导致 促进GIST细胞的凋亡和GIST肿瘤的完全反应。这些临床前数据导致了 研究人员启动了MEK162与伊马替尼联合治疗未经治疗的慢性前列腺癌患者的Ib/II期研究 直接评估这一新的联合疗法的安全性和临床疗效 高级GIST。研究的第Ib阶段已经完成，并证明了安全和 确定了GIST患者联合治疗的推荐II期剂量。第二阶段的研究是 目前正在累积，并构成这项提议的基础。第二阶段研究的主要目标是评估 MEK162联合伊马替尼治疗初治晚期胃肠道间质瘤的疗效观察 病人。II期试验包括评估总体无进展存活率的次级终点 存活率和受尊敬程度。在疾病中心有强制性的治疗前和治疗后活组织检查和活组织检查 探讨联合治疗对ETV1靶向抑制作用的相关研究进展： A)抑制ETV1蛋白水平，以及2)抑制ETV1依赖的转录组。此外，我们 将研究肿瘤遗传异质性和遗传基础耐药机制相结合 治疗从血浆、肿瘤来源的无细胞DNA和疾病进展时获得的临床样本中获得。 我们认为，通过联合治疗策略靶向ETV1代表了GIST的一种新方法 治疗学。二期临床试验如果成功，有可能彻底改变一线治疗方法。 主旨治疗，改变GIST管理中的临床实践格局。

Project Description/Summary Gastrointestinal stromal tumor (GIST) is a rare type of cancer that affects approximately 40,000 patients with an annual incidence of 5,000 cases in the US. It arises from the “pacemaker” cells of the gastrointestinal tract and is mainly characterized by activating mutations in KIT or PDGFRA receptor tyrosine kinases. Despite the initial clinical success of imatinib that targets mutant KIT/PDGFRA, nearly all advanced GIST patients develop imatinib-resistance and eventually die of their disease. It is critical to gain a better understanding of the pathogenesis of GIST and to develop novel treatment strategies that are 1) more effective than first-line imatinib therapy and 2) can delay and/or prevent imatinib-resistance. ETV1, an ETS family transcription factor and a well-established oncogene in prostate cancer and melanoma, has recently been discovered to play a critical role in GIST oncogenesis. ETV1 is highly expressed and is required for growth and survival of GISTs. ETV1 is a master regulator of the ICC-GIST lineage and is required for GIST tumor initiation and maintenance in vivo. ETV1 and mutant KIT form a positive feedback circuit in GIST oncogenesis, where the ETV1 protein is stabilized by active MAP kinase signaling downstream of KIT signaling and stabilized ETV1 in turn upregulates KIT expression. Hence, ETV1 represents a novel drug target. We demonstrated that the combination of MEK162 and imatinib can durably inhibit ETV1 protein and lead to enhanced apoptosis in GIST cells and complete responses of GIST tumors. These preclinical data led to an investigator initiated “phase Ib/II study of MEK162 in combination with imatinib in patients with untreated advanced GIST” to directly evaluate the safety and clinical efficacy of this novel combination therapy in advanced GIST. The phase Ib portion of the study has been completed and has demonstrated the safety and defined the recommended phase II doses of the combination therapy in GIST patients. The phase II study is currently accruing and forms the basis of this proposal. The primary goal of the phase II study is to evaluate the efficacy of the combination of MEK162 and imatinib by RECIST responses in untreated advanced GIST patients. The phase II trial included secondary endpoints that evaluate the progression free survival, overall survival and respectability rate. There are mandatory pre- and post-treatment biopsies and biopsies at disease progression for correlative studies that explore the effect of the combination therapy in ETV1 target inhibition: a) inhibition of the ETV1 protein level, and 2) inhibition of the ETV1-dependent transcriptome. Additionally, we will examine the genetic tumor heterogeneity and genetic basis of resistance mechanisms to the combination therapy from the plasma tumor-derived cell-free DNA and clinical samples obtained at disease progression. We believe that targeting ETV1 by the combination treatment strategy represents a novel approach in GIST therapeutics. The phase II clinical trial, if successful, has the potential to revolutionize the first line therapy of GIST treatment and change the landscape of clinical practice in GIST management.