Quantifying and Personalizing the Clinical Benefit of Metastasis-Directed Therapy in Men with De Novo Oligometastatic Prostate Cancer

量化和个性化转移定向治疗对患有新发寡转移性前列腺癌的男性的临床益处

• 批准号: 10153007
• 负责人: Daniel Eidelberg Spratt
• 金额: $ 51.33万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10153007
• 关键词: Ablation; Address; African American; Aftercare; American; Androgen Receptor; Bioinformatics; Biological Markers; Biometry; Biopsy; Biopsy Specimen; Blood; Blood Cells; Cancer Etiology; Castration; Cessation of life; Clinical; Clinical Management; Clinical Trials; Collection; Country; Data; Diagnosis; Disease; Enrollment; Extramural Activities; FOLH1 gene; Failure; Genomics; Goals; Heterogeneity; Histologic; Image; Incidence; Individual; International; Intramural Research Program; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Profiling; Neoplasm Circulating Cells; Neoplasm Metastasis; Newly Diagnosed; North America; PET/CT scan; Patients; Pattern; Phase; Positron-Emission Tomography; Prognostic Marker; Prostatectomy; Quality of life; Radiation therapy; Radical Prostatectomy; Randomized; Randomized Controlled Trials; Receptor Signaling; Recording of previous events; Research; Resistance; Resources; Sampling; Site; Specimen; Systemic Therapy; Testing; Therapeutic Trials; Time; Tissues; Translations; United Kingdom; United States National Institutes of Health; Validation; Work; X-Ray Computed Tomography; arm; biomarker signature; bone imaging; burden of illness; cell free DNA; chemotherapy; clinical center; exome; experience; feature extraction; imaging biomarker; imaging modality; imaging program; improved; inhibitor/antagonist; liquid biopsy; men; molecular imaging; molecular marker; molecular subtypes; neoplastic cell; next generation; novel; patient biomarkers; personalized medicine; phase II trial; phase III trial; predicting response; predictive marker; primary endpoint; prospective; prostate biopsy; radiomics; randomized trial; response; response biomarker; standard of care; transcriptome; treatment response

Project Summary/Abstract The long-term goal of this project is to determine the clinical impact of metastasis-directed radiotherapy (MDT) in men with de novo oligometastatic prostate cancer (PCa), and identify which men may be cured and benefit most from MDT. We aim to achieve this goal through the conduct of a phase 3 randomized controlled trial with prospective imaging and biospecimen (e.g. tissue and blood) collection. This trial is novel in that it is a randomized North American sub-study (n=200) of the next arm (Arm M) of the international landmark multi- arm, multi-stage, STAMPEDE trial. The ability to conduct this trial with comprehensive biospecimen collection and imaging analysis will be achieved through our unique research team across extramural and intramural centers, comprised of experts in prognostic and predictive biomarker signature identification, bioinformatics, biostatistics, genomics, imaging, and clinical trial execution. We will leverage the opportunity for North America to participate in the STAMPEDE trial to not simply identify the true impact of MDT in the first ever large phase 3 trial testing MDT in PCa, but use this one of a kind clinical trial working with the NCI to develop the first predictive biomarkers of benefit of MDT using radiomics of conventional and molecular PET imaging, as well as sequencing of primary, metastatic, and liquid biopsies. This goal will be carried out through three specific aims. Aim 1 will focus on the conduct of the phase 3 randomized North American sub-study to determine if the addition of MDT to standard systemic therapy and treatment of the primary improves failure-free survival. Five centers will participate, including the NIH Clinical Center. These patients will all be included in the international STAMPEDE trial with the primary endpoint of overall survival. Aim 2 will leverage the baseline CT and bone scans collected on all patients, as well as a subset that will be sent to the NCI to have pre-treatment 18F- DCFPyL PET/CT scans performed (n=50). Radiomic analyses and image feature extraction will be performed, and this information will be used to identify which men benefit most from MDT. We hypothesize that a subset of men will benefit most from MDT and be identifiable through an imaging biomarker. Aim 3 will utilize the baseline prostate biopsy, metastatic biopsies, radical prostatectomy specimens, and liquid biopsies (circulating tumor cells and cell-free DNA), to annotate the molecular landscape of oligometastatic PCa. This data will then be used to develop a predictive biomarker to identify which men benefit most from MDT. International patient samples will be banked for later validation. We hypothesize that a discrete molecular profile will characterize which men are most likely to be cured from MDT. The impact of this work is extremely large, as it has the potential to cure a currently incurable subset of men with metastatic PCa. Successful completion of these aims would result in predictive biomarkers that could directly impact the clinical management of men with oligometastatic PCa, and transform current treatment paradigms.

项目摘要/摘要 该项目的长期目标是确定转移定向放疗（MDT）的临床影响 在从头寡聚前列腺癌（PCA）的男性中，确定哪些男性可以治愈并受益 大多数来自MDT。我们旨在通过进行3期随机对照试验实现这一目标 前瞻性成像和生物植物（例如组织和血液）收集。该试验是新颖的，因为它是 国际地标多的下一个臂（臂m）的随机北美子研究（n = 200） 手臂，多阶段，踩踏试验。通过全面的生物循环收集进行此试验的能力 并将通过我们在壁外和壁内的独特研究团队来实现成像分析 中心由预后和预测性生物标记识别的专家组成，生物信息学， 生物统计学，基因组学，成像和临床试验执行。我们将利用北美的机会 参加Stampede试验，不仅要在第一个大型阶段中确定MDT的真正影响 在PCA中测试MDT的试验，但使用此一种与NCI合作的临床试验来开发第一个试验 使用常规和分子PET成像的放射组学的MDT益处的预测生物标志物以及 作为原发性，转移和液体活检的测序。这个目标将通过三个特定的 目标。 AIM 1将侧重于第三阶段随机北美子研究的行为，以确定是否是否 在标准的全身疗法和主要治疗中添加MDT可改善无衰竭的生存率。五 中心将参加，包括NIH临床中心。这些患者将全部包括在国际 踩踏试验，其总体生存的主要终点。 AIM 2将利用基线CT和骨头 对所有患者收集的扫描以及将发送给NCI进行预处理的子集18F- 进行DCFPYL PET/CT扫描（n = 50）。将进行放射分析和图像特征提取， 这些信息将用于确定哪些男人从MDT中受益最大。我们假设一个子集 男性将从MDT中受益最大，并通过成像生物标志物可以识别。 AIM 3将利用 基线前列腺活检，转移活检，根治性前列腺切除术和液体活检（循环 肿瘤细胞和无细胞DNA），以注释寡聚pCA的分子景观。这些数据将 然后被用来开发预测性生物标志物，以确定哪些男性从MDT中受益最大。国际的 患者样本将用于以后的验证。我们假设离散的分子轮廓将 表征哪些男人最有可能从MDT治愈。这项工作的影响非常大，因为 有可能治愈当前无法治愈的转移性PCA男性子集。成功完成 这些目标将导致预测性生物标志物，这些标志物可能直接影响 寡聚PCA，并改变当前的治疗范例。