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

曲美替尼纳维托克治疗复发性卵巢癌的疗效评价

• 批准号: 10684234
• 负责人: URSULA Anne MATULONIS
• 金额: $ 38.34万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684234
• 关键词: Aftercare; Apoptotic; BCL1 Oncogene; BCL2 gene; BCL2L1 gene; BCL2L11 gene; BIM Bcl-2-binding protein; Biopsy; Cancer Center; Cancer Therapy Evaluation Program; Carcinoma; Cells; Chemoresistance; Clinical; Clinical Trials; Combined Modality Therapy; DNA Damage; DNA Sequence Alteration; Data; Development; Diagnosis; Dose; Drug Combinations; Epithelial ovarian cancer; Exposure to; Fibroblasts; Genes; Genetic; Genomics; Grant; Histologic; Histology; Human; Immune; Knowledge; MAP3K1 gene; MEK inhibition; MEKs; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Metabolic; Modeling; Molecular; Mucinous; Mutate; Mutation Analysis; Oral; Organoids; Ovarian Carcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Polymerase; Pre-Clinical Model; Progression-Free Survivals; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Protocols documentation; Public Health; Ras/Raf; Recommendation; Recurrence; Refractory; Relapse; Research; Resistance; Safety; Sampling; Schedule; Serine; Serous; Signal Pathway; Testing; Therapeutic; Toxic effect; Tumor Cell Line; cancer subtypes; cancer type; chemotherapy; clinical efficacy; efficacy evaluation; efficacy testing; enzyme activity; imaging approach; in situ imaging; inhibitor; mutant; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; participant enrollment; patient derived xenograft model; phase 1 study; phase 2 study; pre-clinical; preclinical study; refractory cancer; response; targeted treatment; therapy resistant; treatment duration; treatment response; tumor; tumor microenvironment

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.

项目3：项目总结 上皮性卵巢癌由组织学和分子组成分化的几种亚型组成， 基于特定的组织学具有不同水平的铂敏感性。高级别浆液性癌（HGSC）是 最常见的是对铂类药物和聚（ADP核糖）聚合酶（PARP）抑制剂敏感。 然而，随着随后的治疗暴露，复发性HGSC变得越来越铂和PARP 抑制剂抗性。此外，其他组织学亚型，例如低度浆液性和粘液性卵巢癌 癌症，有时是RAS突变的，通常在最初诊断时显示铂耐药，新的治疗方法 对于这些癌症是RAS突变型或RAS野生型的患者，需要有治疗策略。整体 本提案的目的是研究靶向Ras-ERK的联合治疗的临床疗效 途径丝氨酸苏氨酸激酶MEK和两种抗凋亡蛋白BCL 2和BCL XL。基于证据 RAS-ERK通路在很大比例的卵巢癌中被激活， 在（1）化学抗性高级别浆液性卵巢癌的临床前PDX模型中的组合MEK-BCL-2/XL抑制 （2）临床前研究，显示MEK和BCL-2/XL联合抑制在Ras突变体中的功效 肿瘤，以及（3）显示与曲美替尼联合治疗的安全性和耐受性的1期临床试验 (MEK抑制剂）和navitoclax（BCL-2/XL抑制剂），我们假设组合MEK和BCL-2/XL 抑制将在难治性/复发性卵巢癌中具有活性。为了验证这个假设，我们将进行一个 II期临床试验，以测试曲美替尼和navitoclax联合治疗复发性 铂耐药和难治性HGSOC和低级别浆液性癌，以及卵巢癌， Ras和Raf通路基因的改变。一项正在进行的研究，Dana-Farber/哈佛癌症中心 (DF/HCC）方案13-505（CTEP 9525，由U 01 CA 062490、NCT 02079740支持）是一项I期研究， 已经测试了口服MEK抑制剂曲美替尼与口服BCL-2 XL抑制剂navitoclax的组合。这 自2014年3月以来，该试验已开放供招募，测试了不同的剂量方案，并建立了 推荐的II期剂量（RP 2D）。CTEP 9525的RP 2D将用于我们的II期研究， 在这个项目中，题为“曲美替尼和navitoclax联合治疗复发性卵巢癌的2期研究”， 癌症”我们将研究与疗效相关的遗传和蛋白质组学标记。此外，我们会 在临床前研究中研究治疗方法，以提高该组合的疗效。 这些研究有望为确定新的治疗策略提供关键信息， 耐药卵巢癌，如果有效，可能会延长复发性卵巢癌患者的生命， 癌