Randomized Controlled Trial Novel Markers Predict Malignancy Elevated-Risk Women

随机对照试验新颖标记物可预测女性恶性肿瘤高风险

• 批准号: 8380120
• 负责人: BETH Y. KARLAN
• 金额: $ 14.76万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8380120
• 关键词: Address; Algorithms; BRCA1 gene; BRCA2 gene; CA-125 Antigen; California; Cities; Clinical; Clinical Investigator; Clinical Trials; Colon; Consult; Data; Diagnosis; Diagnostic; Disease; Early Diagnosis; Eligibility Determination; Enrollment; Epithelial ovarian cancer; Evaluation; Exhibits; Foundations; Future; Genetic Predisposition to Disease; Goals; High Risk Woman; Image; Industry; Institutes; Institution; Instruction; Lead; Lesion; Letters; Los Angeles; Lung; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Medical; Medical center; Modality; Modeling; Mutation; Operative Surgical Procedures; Ovarian; Ovary; Phase I Clinical Trials; Play; Postmenopause; Predictive Value; Prostate; Protocols documentation; Randomized Controlled Trials; Reporting; Risk; Risk Factors; Role; Safety; Screening Result; Screening for Ovarian Cancer; Screening procedure; Serinus; Serum Markers; Signal Transduction; Specificity; Staging; Testing; Time; Translations; WFDC2 gene; Woman; Work; aged; anticancer research; arm; base; cancer risk; clinical application; clinical research site; collaborative trial; cost; cost effectiveness; efficacy trial; experience; genetic pedigree; health related quality of life; improved; mortality; novel marker; prospective; two-arm study

We propose to conduct a randomized controlled trial (RCT) to compare safety, feasibility and positive predictive value (PPV) of two ovarian cancer screening strategies, one using CA125 and HE4 together as a first-line screen, the other introducing HE4 as a second-line screen. Women aged 35-80 will be eligible if they are at elevated risk based on a documented mutation in BRCA1 or BRCA2 or a pedigree suggestive of inherited susceptibility; 800 such women will be enrolled and screened semi-annually. Women aged 50-80 will be eligible if they have elevated risk based on a previously developed OvCaRisk model; 400 such women will be enrolled and screened annually. We will interpret serum markers using the previously developed parametric empirical Bayes (PEB) longitudinal algorithm (above a threshold corresponding to 90%, 95% or 99% specificity) to take advantage of rise in a marker as a signal of disease, a phenomenon that has been well documented. We will target a positive predictive value of 10% in both arms, corresponding to a ratio of 10 surgeries per cancer detected. In Aim 1 we will document protocol-indicated surgical procedures and malignancies detected in order to rule out a ratio of surgeries to malignancies greater than 20. In Aim 2 we will document compliance with first- and second-line screens and test the null hypothesis that compliance does not differ between the two arms. In Aim 3 we will document effects on health-related quality of life (HRQOL) and test the null hypotheses that 1) effects on HRQOL do not differ between the two arms and 2) effects on cancer worry do not differ between women who do and do not experience a false-positive first-line screen. Our goal is that the results of this RCT together with results of ongoing large efficacy trials will lead to clinical implementation of screening using novel markers within 5 years. We have partnered with Abbott Diagnostics and the Canary Foundation to accelerate translation. Four clinical centers (Swedish Medical Cancer, Cedars-Sinai, Stanford and City of Hope) will participate, and participation will be offered to all Ovarian SPORE institutions. Data will also support analyses ofthe cost- effectiveness of screening using each strategy, and estimation of the costs of conducting a full-scale efficacy trial should such a trial be required in the future. RELEVANCE (See instructions): This project will introduce HE4 as an early detection and diagnostic marker for the first time in a prospective clinical trial. We will denhonstrate and evaluate better strategies than are currently used for screening high- risk women. Clinical implementation may follow without the need for another large trial, by combining data from this study with reports from ongoing efficacy trials.

我们建议进行一项随机对照试验（RCT），以比较安全性，可行性和正面 两种卵巢癌筛查策略的预测价值（PPV），一种将CA125和HE4一起用作 一线屏幕，另一个将HE4作为二线屏幕引入。如果35-80岁的妇女将有资格 基于BRCA1或BRCA2中的已记录的突变或谱系，它们处于较高的风险 继承的敏感性； 800此类妇女将在半年度接受和筛查。 50-80岁的妇女 如果基于先前开发的卵泡模型具有升高的风险，则将符合条件； 400这样 妇女将每年入学和筛查。我们将使用先前的 发达的参数经验贝叶斯（PEB）纵向算法（高于阈值 90％，95％或99％的特异性）要利用标记作为疾病信号的崛起，一种现象 这已经有很好的记录。我们将以两个武器的积极预测值为10％， 对应于检测到的10个手术的比率。在AIM 1中，我们将记录协议指示的 检测到的手术程序和恶性肿瘤，以排除手术与恶性肿瘤的比率 大于20。在AIM 2中，我们将记录遵守一线和二线屏幕并测试NULL 假设两个臂之间的依从性没有差异。在AIM 3中，我们将记录对 与健康相关的生活质量（HRQOL）并测试无效假设，即1）对HRQOL的影响没有差异 在两个臂和2）对癌症忧虑的影响之间没有差异 体验假阳性的一线屏幕。我们的目标是该RCT的结果以及 正在进行的大型效力试验将导致使用5个以内的新标记进行筛查的临床实施 年。我们已经与雅培诊断和金丝雀基金会合作，以加速翻译。 四个临床中心（瑞典医学癌，雪松 - 西奈，斯坦福市和希望之城）将参加， 参与将提供给所有卵巢孢子机构。数据还将支持对成本的分析 - 使用每种策略进行筛查的有效性，并估算进行全尺度功效的成本 将来是否需要进行此类审判。 相关性（请参阅说明）： 该项目将首次引入HE4作为早期检测和诊断标记。 临床试验。我们将比目前用于筛查高的策略来确定和评估更好的策略 风险女性。临床实施可能会随访而无需进行其他大型试验，并结合数据 从这项研究中进行了正在进行的疗效试验的报告。