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

MEK162的2期试验

• 批准号: 9567835
• 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/9567835
• 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 胃肠道间质瘤 (GIST) 是一种罕见的癌症，影响约 40,000 名患者 美国每年有 5,000 例病例由胃肠道的“起搏器”细胞引起。 其主要特征是激活KIT或PDGFRA受体酪氨酸激酶的突变。 伊马替尼针对突变型 KIT/PDGFRA 的初步临床成功，几乎所有晚期 GIST 患者都出现了这种情况 更好地了解伊马替尼耐药并最终死于疾病至关重要。 GIST 的发病机制并开发新的治疗策略，这些策略 1）比一线疗法更有效 伊马替尼治疗和 2) 可以延迟和/或预防伊马替尼耐药。 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， 最近发现 ETV1 在 GIST 肿瘤发生中发挥关键作用。 ETV1 是 GIST 生长和生存所必需的，是 ICC-GIST 谱系的主要调节因子。 ETV1 和突变型 KIT 在体内形成正反馈回路，促进 GIST 肿瘤的发生和维持。 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 KIT 表达，因此，ETV1 代表了一种新的药物靶点。 我们证明 MEK162 和伊马替尼的组合可以持久抑制 ETV1 蛋白并导致 这些临床前数据导致了 GIST 细胞凋亡的增强和 GIST 肿瘤的完全反应。 研究人员启动了“MEK162 联合伊马替尼治疗未经治疗的患者的 Ib/II 期研究” 晚期 GIST”，直接评估这种新型联合疗法的安全性和临床疗效 晚期 GIST 的 Ib 期部分研究已经完成，并证明了其安全性和有效性。 确定了 GIST 患者联合治疗的推荐 II 期剂量。 目前正在积累并构成该提案的基础，第二阶段研究的主要目标是评估。 根据 RECIST 反应，MEK162 和伊马替尼联合治疗未经治疗的晚期 GIST 的疗效 II 期试验包括评估总体无进展生存期的次要终点。 生存率和尊重率有强制性的治疗前和治疗后活检以及疾病时的活检。 探索联合疗法对 ETV1 靶点抑制效果的进展相关研究： a) 抑制 ETV1 蛋白水平，以及 2) 抑制 ETV1 依赖性转录组。 将检查遗传肿瘤异质性和组合耐药机制的遗传基础 利用血浆肿瘤来源的游离 DNA 和疾病进展时获得的临床样本进行治疗。 我们相信，通过联合治疗策略靶向 ETV1 代表了 GIST 的一种新方法 II 期临床试验如果成功，有可能彻底改变一线疗法。 GIST 治疗并改变 GIST 管理临床实践的格局。