A Phase 2 study of a Checkpoint Inhibitor in Men with Progressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

一项检查点抑制剂治疗以错配修复缺陷或双等位基因 CDK12 失活为特征的进行性转移性去势抵抗性前列腺癌男性的 2 期研究

• 批准号: 10417047
• 负责人: MATTHEW B RETTIG
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417047
• 关键词: Affect; Alleles; American; Biological Assay; Biology; Biopsy; Blood specimen; CLIA certified; Cancer Etiology; Cancer Patient; Cessation of life; Characteristics; Colon Carcinoma; Cyclin-Dependent Kinases; Data; Detection; Diagnosis; Exhibits; Frequencies; Gene Fusion; Gene Mutation; Genes; Genetic; Genome Stability; Genomics; Head and Neck Cancer; Health; Hodgkin Disease; Human; Immune checkpoint inhibitor; Immunologic Factors; Immunotherapy; Knowledge; Large Intestine Carcinoma; Learning; Lesion; Life; Lymphoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of prostate; Microsatellite Instability; Mismatch Repair; Mismatch Repair Deficiency; Molecular; Molecular Target; Monoclonal Antibodies; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Open Reading Frames; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Point Mutation; Population; Primary Neoplasm; Primary carcinoma of the liver cells; Progression-Free Survivals; Prospective Studies; Prospective cohort; Prostate Cancer therapy; Proteins; Proteomics; Quality of life; Renal Cell Carcinoma; Reporting; Resistance; SECTM1 gene; Signal Transduction; Site; Somatic Mutation; Transitional Cell Carcinoma; Veterans; alternative treatment; analytical tool; antitumor effect; base; cancer diagnosis; castration resistant prostate cancer; checkpoint inhibition; checkpoint therapy; clinical efficacy; detection assay; detection sensitivity; effective therapy; epigenetic silencing; exome; immune checkpoint; immune checkpoint blockade; immunogenic; improved; inhibitor; insertion/deletion mutation; male; melanoma; men; military veteran; neoantigens; next generation sequencing; novel strategies; objective response rate; oncology program; open label; pembrolizumab; phase 2 study; precision oncology; predicting response; primary endpoint; prospective; radiological imaging; response; response biomarker; sequencing platform; success; tool; transcriptomics; tumor; Affect; Alleles; American; Biological Assay; Biology; Biopsy; Blood specimen; CLIA certified; Cancer Etiology; Cancer Patient; Cessation of life; Characteristics; Colon Carcinoma; Cyclin-Dependent Kinases; Data; Detection; Diagnosis; Exhibits; Frequencies; Gene Fusion; Gene Mutation; Genes; Genetic; Genome Stability; Genomics; Head and Neck Cancer; Health; Hodgkin Disease; Human; Immune checkpoint inhibitor; Immunologic Factors; Immunotherapy; Knowledge; Large Intestine Carcinoma; Learning; Lesion; Life; Lymphoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of prostate; Microsatellite Instability; Mismatch Repair; Mismatch Repair Deficiency; Molecular; Molecular Target; Monoclonal Antibodies; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Open Reading Frames; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Point Mutation; Population; Primary Neoplasm; Primary carcinoma of the liver cells; Progression-Free Survivals; Prospective Studies; Prospective cohort; Prostate Cancer therapy; Proteins; Proteomics; Quality of life; Renal Cell Carcinoma; Reporting; Resistance; SECTM1 gene; Signal Transduction; Site; Somatic Mutation; Transitional Cell Carcinoma; Veterans; alternative treatment; analytical tool; antitumor effect; base; cancer diagnosis; castration resistant prostate cancer; checkpoint inhibition; checkpoint therapy; clinical efficacy; detection assay; detection sensitivity; effective therapy; epigenetic silencing; exome; immune checkpoint; immune checkpoint blockade; immunogenic; improved; inhibitor; insertion/deletion mutation; male; melanoma; men; military veteran; neoantigens; next generation sequencing; novel strategies; objective response rate; oncology program; open label; pembrolizumab; phase 2 study; precision oncology; predicting response; primary endpoint; prospective; radiological imaging; response; response biomarker; sequencing platform; success; tool; transcriptomics; tumor

Alternative treatment approaches are urgently needed to improve quantity and quality of life of patients with metastatic castration resistant prostate cancer (mCRPC). Immunotherapy in the form of checkpoint inhibition has yielded auspicious results in many cancers, including lung cancer, melanoma, renal cell carcinoma, and lymphoma amongst several others. The frequency of tumor-specific somatic mutations and hence neoantigen formation strongly predicts for objective response to checkpoint inhibitors (CPIs). Prostate cancer is typified by a relatively low mutational burden, so it is not surprising CPIs for mCRPC are largely ineffective, although occasional responses have been observed. Over the last few years, mismatch repair deficiency (dMMR) and biallelic inactivation of CDK12 (CDK12-/-) have been observed in a small subset of mCRPC patients. Importantly, these genetic lesions have been associated with increased mutational burden due to increased point mutations in the case of dMMR and heightened formation of focal tandem duplications in the case of CDK12-/-. Accordingly, dMMR or CDK12-/- tumors are expected to be sensitive to CPIs. The frequency of dMMR has been underestimated due to poor sensitivity of detection assays, which can fail to detect allelic inactivation of MMR genes. Moreover, neither the frequency of dMMR or CDK12-/- nor the response to checkpoint inhibition or dMMR or CDK12-/- tumors has been studied amongst Veterans. The relevance of this knowledge gap amongst Veterans is highlighted by key demographic differences in Veterans compared to the US population at large, which could in principle affect the frequencies of dMMR and CDK12-/- as well as response to checkpoint inhibition. Using a sensitive next generation sequencing platform and bioanalytic tool to detect microsatellite instability, a surrogate for dMMR, we predict that we can detect dMMR or CDK12-/- in at least 15% of Veterans. Furthermore, we hypothesize that Veterans with dMMR or CDK12-/- will exhibit a high response rate to checkpoint inhibition. We propose three aims: 1. Identify the frequency of dMMR and CDK12-/- as determined by NGS and a sensitive analytic tool for MSI detection amongst Veterans with mCRPC. The MSI bioanalysis, known as mSINGS (microsatellite instability by next generation sequencing), as well as targeted gene sequencing inclusive of CDK12 are built-in components of OncoPlex, one of the CLIA-certified NGS platforms being implemented within the VA Precision Oncology Program Cancer of the Prostate (POPCAP) network. 2. Perform an open label phase 2 clinical trial of pembrolizumab, an anti-PD1 CPI, to determine the efficacy of pembrolizumab amongst dMMR and CDK12-/- mCRPC Veterans who have received prior AR signaling ≥ inhibitors. The primary endpoint will be response rate, defined as a composite of: objective response rate by iRECIST 1.1, PSA50 at 12 weeks, radiographic progression free survival at 6 months. 3. Perform exploratory analyses to identify biomarkers of response and resistance to pembrolizumab in dMMR and CDK12-/- mCRPC Veterans. For this purpose, we will acquire baseline and at-progression biopsies of metastases as well as serial blood samples to investigate genomic, transcriptomic, proteomic, and immune factors that contribute to response. This study will result in enhanced understanding of the biology of mCRPCs amongst Veterans and the identification of Veterans who respond to checkpoint inhibition, thereby benefiting from potentially life extending therapy. In addition, exploratory/correlative analyses could identify molecular targets, the modulation of which could potentiate the anti-tumor effects of checkpoint inhibition..

迫切需要采用替代治疗方法来改善患者的生活质量和生活质量 与转移性cast割前列腺癌（MCRPC）。以检查点抑制形式的免疫疗法 在许多癌症中产生了吉祥的效果，包括肺癌，黑色素瘤，肾细胞癌和 其他几个淋巴瘤。肿瘤特异性的体细胞突变的频率和新抗原 形成强烈预测对检查点抑制剂（CPI）的客观响应。前列腺癌是 相对较低的突变烧伤，因此MCRPC的CPI在很大程度上不可能效果 已经观察到偶尔的反应。在过去的几年中，不匹配维修缺陷（DMMR）和 在一小部分MCRPC患者中，已经观察到CDK12（CDK12 - / - ）的双重失活。重要的是， 由于点突变增加，这些遗传病变与突变负担增加有关 如果是DMMR并在CDK12 - / - 的情况下增加了焦点串联重复的形成。因此， DMMR或CDK12 - / - 肿瘤对CPI敏感。 由于检测测定的敏感性较差，DMMR的频率已被低估了，这可以 未能检测到MMR基因的灭绝式灭活。此外，dmmr或cdk12的频率也不 对检查点抑制作用或DMMR或CDK12 - / - 肿瘤的反应已在退伍军人中研究。这 退伍军人的关键人口差异强调了这种知识差距的相关性 与美国总体相比，这原则上可能影响DMMR和CDK12 - / - 的频率 以及对检查点抑制的响应。使用敏感的下一代测序平台和 检测微卫星不稳定性的生物分析工具，DMMR的替代物，我们预测我们可以检测到DMMR或 至少15％的退伍军人中的CDK12 - / - 。此外，我们假设具有DMMR或CDK12的退伍军人将 对检查点抑制的响应率很高。我们提出了三个目标： 1。确定由NGS确定的DMMR和CDK12 - / - 的频率以及MSI敏感的分析工具 用MCRPC的退伍军人发现。 MSI生物分析，称为MSING（微卫星不稳定性） 通过下一代测序）以及包括CDK12的靶向基因测序是内置的 Oncoplex的组件，即在VA中实现的CLIA认证的NGS平台之一 前列腺癌（Popcap）网络的精确肿瘤学计划。 2。执行pembrolizumab抗PD1 CPI的开放标签2期临床试验，以确定 DMMR和CDK12 - / - MCRPC退伍军人的pembrolizumab ≥ 抑制剂。主要终点将是响应率，定义为以下综合：客观响应率 IRECIST 1.1，PSA50在12周时，6个月时的放射学进展无生存。 3。执行探索性分析，以识别DMMR中对Pembrolizumab的反应和抗性的生物标志物 和CDK12 - / - MCRPC退伍军人。为此，我们将获得基线和建立活检 转移和连续血样品研究基因组，转录组，蛋白质组学和免疫 有助于响应的因素。 这项研究将增强对退伍军人和退伍军人的MCRPC生物学的了解 识别对检查点抑制的退伍军人，从而受益于潜在的生活 治疗。此外，探索性/相关分析可以识别分子靶标，其调节 可能会抑制检查点的抗肿瘤效应。