Evaluation of the Efficacy of Trametinib + Navitoclax in recurrent ovarian carcinoma

项目3：项目总结 上皮性卵巢癌由几种亚型组成，根据组织学和分子组成进行区分。 根据特定的组织学有不同程度的铂敏感性。高级别浆液性癌 最常见且对铂类药物和聚腺苷二磷酸核糖聚合酶(PARP)抑制剂敏感。 然而，随着随后的治疗，复发的HGSC变得越来越像铂类和PARP 抗抑制剂。此外，其他组织学亚型，如低级别浆液性和粘液性卵巢 癌症，有时RAS突变，通常在最初诊断和新的治疗方法中表现出铂耐药 对于这些癌症是RAS突变或RAS野生型的患者，需要采取相应的策略。整体而言 本方案的目的是探讨以RAS-ERK为靶点的联合治疗的临床疗效。 丝氨酸苏氨酸激酶MEK途径和两个抗凋亡蛋白BCL2和BCLXL。基于证据 Ras-ERK通路在很大比例的卵巢癌中被激活，并有证据表明 联合抑制MEK-bcl-2/XL对(1)化疗耐药高级别浆液性卵巢癌模型的临床前研究 癌症(HGSC)，(2)临床前研究显示MEK和bcl2/xl联合抑制RAS突变的疗效 肿瘤，以及(3)显示曲美替尼联合治疗的安全性和耐受性的第一阶段临床试验 (MEK抑制剂)和Navitoclax(BCL-2/XL抑制剂)，我们假设MEK和BCL-2/XL结合 抑制对难治性/复发性卵巢癌有作用。为了检验这一假设，我们将进行一项 曲美替尼联合奈维替克治疗复发的II期临床试验 对铂耐药和难治性HGSOC和低级别浆液性癌，以及卵巢癌 RAS和Raf途径基因的改变。一项正在进行的积极研究，达纳-法伯/哈佛癌症中心 (DF/HCC)协议13-505(由U01CA062490、NCT02079740支持的CTEP 9525)是第一阶段研究， 已经测试了口服MEK抑制剂曲美替尼与口服bcl2xl抑制剂Navitoclax的组合。这 试验自2014年3月以来一直开放，测试了不同的剂量计划，并建立了 推荐的第二阶段剂量(RP2D)。CTEP 9525中的RP2D将用于我们的第二阶段研究，建议 在这项研究中，题为“曲美替尼和奈维替克联合治疗复发性卵巢疾病的第二阶段研究” 癌症。“我们将研究与疗效相关的遗传和蛋白质组标记。此外，我们还将 在临床前研究中，研究提高这种联合治疗效果的治疗方法。 这些研究承诺提供对确定新的治疗策略至关重要的信息。 耐药卵巢癌，如果有效，可能会延长复发卵巢患者的生命 癌症。

Project 3: Project Summary Epithelial ovarian cancer is comprised of several subtypes differentiated by histology and molecular composition, with varying levels of platinum sensitivity based on specific histology. High grade serous carcinoma (HGSC) is the most common and is sensitive to platinum drugs and poly (ADP ribose) polymerase (PARP) inhibitors. However, with subsequent exposure to treatment, recurrent HGSC becomes increasingly platinum and PARP inhibitor resistant. Additionally, other histologic subtypes such as low grade serous and mucinous ovarian cancers, sometimes RAS mutated, often display platinum resistance at initial diagnosis, and new treatment strategies are needed for these patients whose cancers are either RAS mutated or RAS wild-type. The overall objective of this proposal is to investigate the clinical efficacy of a combination therapy targeting the Ras-ERK pathway serine threonine kinase MEK and two anti-apoptotic proteins, BCL2 and BCLXL. Based on evidence that the RAS-ERK pathway is activated in a large percentage of ovarian cancers and evidence of efficacy of combined MEK- BCL-2/XL inhibition in (1) preclinical PDX models of chemoresistant high grade serous ovarian cancer (HGSC), (2) preclinical studies showing efficacy of combined MEK and BCL-2/XL inhibition in Ras mutant tumors, and (3) a Phase 1 clinical trial showing safety and tolerability of combined treatment with trametinib (MEK inhibitor) and navitoclax (BCL-2/XL inhibitor), we hypothesize that combination MEK and BCL-2/XL inhibition will have activity in refractory/relapsed ovarian cancer. To test this hypothesis, we will carry out a phase II clinical trial to test the efficacy of combined treatment with trametinib and navitoclax in recurrent platinum-resistant and refractory HGSOC and low grade serous cancer in addition to ovarian cancers harboring alterations in Ras and Raf pathway genes. An active and ongoing study, Dana-Farber/Harvard Cancer Center (DF/HCC) Protocol 13-505 (CTEP 9525 supported by U01CA062490, NCT02079740) is a phase 1 study that has tested the combination of the oral MEK inhibitor trametinib with the oral BCL-2 XL inhibitor navitoclax. This trial has been open to accrual since March 2014, has tested different dose schedules, and has established a recommended phase 2 dose (RP2D). This RP2D from CTEP 9525 will be used in our Phase II study, proposed in this project, and is entitled “A Phase 2 study of combination trametinib and navitoclax in recurrent ovarian cancer.” We will investigate genetic and proteomic markers that correlate with efficacy. In addition, we will investigate therapeutic approaches to enhance the efficacy of this combination in pre-clinical studies. These studies promise to provide information critical to the identification of a new therapeutic strategy to treat resistant ovarian cancers, which if effective, could potentially extend the lives of patients with recurrent ovarian cancer.