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

MEK162的2期试验

• 批准号: 9762575
• 负责人: Ping Chi
• 金额: $ 50万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762575
• 关键词: Phase2; trial; MEK162; imatinib; combined

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.

项目描述/摘要 胃肠道肿瘤（GIST）是一种罕见的癌症类型，影响约40,000例患者 在美国，每年发生5,000例病例。它来自胃肠道的“起搏器”细胞 并主要以在KIT或PDGFRA受体酪氨酸激酶中激活突变。尽管有 伊马替尼靶向突变套件/pDGFRA的最初临床成功，几乎所有高级要点患者都会发展 伊马替尼的抗性，最终死于疾病。更好地了解 要点的发病机理，并制定1）比一线更有效的新型治疗策略 伊马替尼治疗和2）可以延迟和/或预防伊马替尼的抗性。 ETV1，ETS家族转录因子和前列腺癌和黑色素瘤中良好的癌基因， 最近发现，在要点肿瘤发生中起着至关重要的作用。 ETV1高度表达，是 ETV1是ICC-GIST血统的主要调节器，是必需的 用于GIST肿瘤倡议和体内维持。 ETV1和突变套件形成一个正反馈电路 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 信号传导和稳定的ETV1反过来上调了套件的表达。因此，ETV1代表了一个新的药物靶标。 我们证明了MEK162和伊马替尼的组合可以两倍抑制ETV1蛋白，并导致 GIST细胞的凋亡增强并完全反应GIST肿瘤。这些临床前数据导致了 研究者启动了“ MEK162与伊马替尼相结合的IB/II期研究，未治疗的患者 高级要点”直接评估这种新型联合疗法的安全性和临床效率 高级要点。研究的一部分已经完成，并证明了安全性和 定义了GIST患者中建议的联合疗法的II期剂量。第二阶段研究是 目前累积并构成了该提案的基础。第二阶段研究的主要目标是评估 MEK162和伊马替尼组合的效率通过未经治疗的高级GIST中的恢复响应 患者。 II期试验包括评估无进展生存的次要终点，总体 生存和尊敬率。疾病有强制性的治疗前和治疗后活检和活检 进行纠正研究的进展，探讨了联合疗法在ETV1靶向抑制中的影响： A）抑制ETV1蛋白水平，以及2）抑制ETV1依赖性转录组。另外，我们 将检查组合抗性机制的遗传肿瘤异质性和遗传基础 从血浆肿瘤衍生的无细胞DNA和疾病进展中获得的临床样本的治疗。 我们认为，通过组合治疗策略将ETV1靶向ETV1代表了GIST的一种新方法 疗法。 II期临床试验（如果成功）有可能彻底改变 要点治疗并改变要点管理中临床实践的景观。