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射治疗(MDT)的临床影响。 对新发的少转移前列腺癌(PCa)男性进行研究，并确定哪些男性可以治愈并受益 大多数来自MDT。我们的目标是通过进行第三阶段随机对照试验来实现这一目标 前瞻性成像和生物样品(如组织和血液)采集。这场审判很新颖，因为它是一场 对具有国际里程碑意义的MARM的下一个ARM(ARM)的随机北美分研究(n=200) ARM，多阶段，踩踏试验。使用全面的生物样品收集进行这项试验的能力 图像分析将通过我们独特的研究团队在壁外和壁内实现 中心，由预测和预测生物标记物特征识别、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遇 参与踩踏试验，而不是简单地确定MDT在有史以来第一个大型第三阶段的真正影响 在PCA中试验MDT，但使用这种与NCI合作的临床试验来开发第一个 使用常规和分子PET成像的放射组学预测MDT受益的生物标志物 作为对原发、转移和液体活检的测序。这一目标将通过三个具体的途径来实现 目标。目标1将侧重于进行第三阶段随机北美分研究，以确定 在标准的系统治疗和原发肿瘤治疗的基础上增加MDT可提高无失败存活率。五 包括NIH临床中心在内的中心将参与其中。这些患者都将被包括在国际 以总体生存为主要终点的踩踏试验。目标2将利用基线CT和骨骼 在所有患者身上收集的扫描，以及将被发送到NCI进行治疗前18F- DCFPyL PET/CT扫描(n=50)。将执行放射学分析和图像特征提取， 这些信息将被用来确定哪些男性从MDT中受益最大。我们假设有一个子集 的男性将从MDT中受益最大，并可通过成像生物标记物进行识别。目标3将利用 基线前列腺活检、转移性活检、根治性前列腺切除术标本和液体活检(循环 肿瘤细胞和无细胞DNA)，以诠释少转移性前列腺癌的分子图景。此数据将 然后被用来开发一种预测性生物标记物，以确定哪些男性从MDT中受益最大。国际 患者样本将被储存起来，以供以后验证。我们假设一个离散的分子轮廓将 确定哪些男性最有可能从MDT中治愈。这项工作的影响是非常大的，因为它 有可能治愈目前无法治愈的转移性前列腺癌患者。成功完成 这些目标将导致预测性生物标志物的产生，这些生物标志物可能直接影响男性患者的临床治疗 少转移性前列腺癌，并改变目前的治疗模式。