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数量和质量以检查点抑制的形式进行转移性去势抵抗性前列腺癌（mCRPC）的免疫治疗。在许多癌症中取得了良好的效果，包括肺癌、黑色素瘤、肾细胞癌和淋巴瘤等肿瘤特异性体细胞突变的频率以及新抗原。前列腺癌的形成强烈预测对检查点抑制剂（CPI）的客观反应。相对较低的突变负担，因此 mCRPC 的 CPI 在很大程度上无效也就不足为奇了，尽管在过去的几年中，偶尔观察到错配修复缺陷（dMMR）和在一小部分 mCRPC 患者中观察到 CDK12 (CDK12-/-) 双等位基因失活。这些基因损伤与点突变增加导致的突变负担增加有关在 dMMR 的情况下，在 CDK12-/- 的情况下，人员形成局灶性串联重复，因此， dMMR 或 CDK12-/- 肿瘤预计对 CPI 敏感。由于检测分析的灵敏度较差，dMMR 的频率被低估，这可能会导致此外，dMMR 或 CDK12-/- 的频率也未能检测到 MMR 基因的等位基因失活。已在退伍军人中研究了对检查点抑制或 dMMR 或 CDK12-/- 肿瘤的反应。退伍军人的主要人口统计差异凸显了退伍军人之间这种知识差距的相关性与美国总体人口相比，这原则上可能会影响 dMMR 和 CDK12-/- 的频率以及对检查点抑制的反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 的替代品，我们预测我们可以检测 dMMR 或至少 15% 的退伍军人中存在 CDK12-/- 此外，我们发现患有 dMMR 或 CDK12-/- 的退伍军人会出现 CDK12-/-。对检查点抑制表现出高反应率我们提出三个目标： 1. 通过 NGS 和 MSI 的灵敏分析工具确定 dMMR 和 CDK12-/- 的频率 MSI 生物分析，即 mSINGS（微卫星不稳定性）检测退伍军人。通过下一代测序），以及内置包括 CDK12 在内的靶向基因测序 OncoPlex 的组件，是 VA 内实施的 CLIA 认证的 NGS 平台之一前列腺癌精准肿瘤学计划 (POPCAP) 网络。 2. 进行抗 PD1 CPI 派姆单抗 (pembrolizumab) 的开放标签 2 期临床试验，以确定其疗效先前接受过 AR 信号传导的 dMMR 和 CDK12-/- mCRPC 退伍军人中使用派姆单抗 ≥ 主要终点是缓解率，定义为以下各项的综合：客观缓解率 iRECIST 1.1、12 周时的 PSA50、6 个月时的影像学无进展生存期。 3. 进行探索性分析，以确定 dMMR 中派姆单抗反应和耐药的生物标志物为此，我们将获取 CDK12-/- mCRPC 退伍军人的基线和进展时活检。转移以及连续血液样本以研究基因组、转录组、蛋白质组和免疫有助于响应的因素。这项研究将加深退伍军人和普通民众对 mCRPC 生物学的了解。识别对检查点抑制有反应的退伍军人，从而受益于潜在的生命延长此外，探索性/相关分析可以识别分子靶标，对其进行调节。可以增强检查点抑制的抗肿瘤作用。