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

项目描述/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例患者， 在美国每年有五千例它起源于胃肠道的“起搏”细胞 并且主要特征在于激活KIT或PDGFRA受体酪氨酸激酶中的突变。尽管 靶向突变型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 伊马替尼耐药性，并最终死于他们的疾病。更好地了解 GIST的发病机制，并开发新的治疗策略，1）比一线治疗更有效 伊马替尼治疗和2）可以延迟和/或预防伊马替尼耐药性。 ETV 1是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， 最近发现在GIST肿瘤发生中起关键作用。ETV 1是高表达的， 为GIST的成长和生存所必需。ETV 1是ICC-GIST谱系的主调节因子， 用于体内GIST肿瘤的引发和维持。ETV 1和突变型KIT形成正反馈回路， GIST肿瘤发生，其中ETV 1蛋白通过KIT下游的活性MAP激酶信号传导稳定 信号转导和稳定的ETV 1反过来上调KIT表达。因此，ETV 1代表了一种新的药物靶点。 我们证明了MEK 162和伊马替尼的组合可以持久地抑制ETV 1蛋白，并导致 增强GIST细胞的凋亡和GIST肿瘤的完全应答。这些临床前数据导致了 研究者发起的“MEK 162与伊马替尼联合治疗未经治疗的 先进的GIST”，以直接评估这种新的联合治疗在 先进的GIST该研究的Ib期部分已经完成，并证明了安全性和 定义了GIST患者联合治疗的II期推荐剂量。II期研究是 目前正在积累，并形成了这一建议的基础。II期研究的主要目标是评估 MEK 162和伊马替尼联合治疗未经治疗的晚期GIST的疗效（根据RECIST反应） 患者II期试验包括次要终点，评价无进展生存期，总体 存活率和体面率。有强制性的治疗前和治疗后活检， 探索联合治疗对ETV 1靶点抑制作用的相关研究进展： a）抑制ETV 1蛋白水平，和2）抑制ETV 1依赖性转录组。另外我们 将研究遗传肿瘤异质性和耐药机制的遗传基础， 利用血浆肿瘤来源的无细胞DNA和疾病进展时获得的临床样本进行治疗。 我们认为，通过联合治疗策略靶向ETV 1代表了GIST的新方法 治疗学II期临床试验，如果成功，有可能彻底改变一线治疗， GIST治疗和改变GIST管理的临床实践的景观。

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.