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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

基本信息

批准号：
10917011
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

项目摘要

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..

迫切需要替代治疗方法来改善患者的生活质量和数量转移性去势抵抗性前列腺癌（mCRPC）。检查点抑制形式的免疫疗法已经在许多癌症中取得了可喜的成果，包括肺癌，黑色素瘤，肾细胞癌，淋巴瘤等。肿瘤特异性体细胞突变的频率和由此产生的新抗原形成强烈预测对检查点抑制剂（CPI）的客观反应。前列腺癌的症状有哪些相对较低的突变负荷，因此mCRPC的CPI在很大程度上无效并不奇怪，尽管观察到偶尔的反应。在过去的几年里，错配修复缺陷（dMMR）和在一小部分mCRPC患者中观察到CDK 12（CDK 12-/-）的双等位基因失活。重要的是，这些遗传损伤与由于点突变增加而导致的突变负担增加有关在dMMR的情况下，以及在CDK 12-/-的情况下，局灶性串联重复的形成增加。因此，委员会认为，预期dMMR或CDK 12-/-肿瘤对CPI敏感。 dMMR的频率被低估，这是由于检测分析的灵敏度差，未能检测到MMR基因的等位基因失活。此外，无论是dMMR或CDK 12-/-的频率，已经在退伍军人中研究了对检查点抑制或dMMR或CDK 12-/-肿瘤的反应。的退伍军人中的关键人口统计学差异突出了退伍军人之间这种知识差距的相关性与美国人群相比，这在原则上可能会影响dMMR和CDK 12-/-的频率。以及对检查点抑制的反应。使用灵敏的下一代测序平台，生物分析工具来检测微卫星不稳定性，dMMR的替代品，我们预测我们可以检测dMMR或 CDK 12-/-在至少15%的退伍军人中。此外，我们假设患有dMMR或CDK 12-/-的退伍军人将表现出对检查点抑制的高应答率。我们提出三个目标： 1.通过NGS和敏感的MSI分析工具确定dMMR和CDK 12-/-的频率 mCRPC退伍军人中的检测。MSI生物分析，称为mSINGS（微卫星不稳定性通过下一代测序），以及包括CDK 12在内的靶向基因测序是内置的 Oncocomp的组件，这是在VA内实施的CLIA认证的NGS平台之一前列腺癌精准肿瘤计划（POPCAP）网络。 2.进行Pembrolizumab（一种抗PD 1 CPI）的开放标签2期临床试验，以确定既往接受过AR信号转导的dMMR和CDK 12-/- mCRPC退伍军人中的派姆单抗 ≥ 抑制剂的主要终点为缓解率，定义为以下各项的复合终点： iRECIST 1.1，12周时的PSA 50，6个月时的放射学无进展生存期。 3.进行探索性分析，以确定dMMR患者对帕博利珠单抗的应答和耐药的生物标志物和CDK 12-/- mCRPC退伍军人。为此，我们将采集以下患者的基线和进展时活检标本：转移以及系列血液样本，以研究基因组学，转录组学，蛋白质组学和免疫有助于反应的因素。这项研究将加深对退伍军人中mCRPC生物学的理解，识别对检查点抑制有反应的退伍军人，从而受益于潜在的寿命延长疗法此外，探索性/相关性分析可以识别分子靶点，其调节可以增强检查点抑制的抗肿瘤作用。