IMAGENE 试验：多中心、概念验证、Ⅱ期研究，评估尼拉帕利联合 PD-1 抑制剂在同源重组修复基因突变的实体瘤患者中的疗效和安全性。

IMAGENE trial: multicenter, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy of niraparib with PD-1 inhibitor in solid cancer patients with homologous recombination repair genes mutation.

机构信息

Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Department of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.

出版信息

BMC Cancer. 2022 Dec 9;22(1):1292. doi: 10.1186/s12885-022-10398-6.

DOI:10.1186/s12885-022-10398-6

PMID:36494792

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9733213/

Abstract

BACKGROUND

Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis.

METHODS

Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood.

EXPECTED OUTCOME

Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs.

TRIAL REGISTRATION

The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

摘要

背景

先前的临床试验已经证明聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）在涉及同源重组修复（HRR）基因突变的癌症患者中的潜在疗效。此外，随着肿瘤突变负担的增加，HRR 基因突变的癌症可以通过免疫检查点抑制剂（ICIs）有效治疗。我们提出了一项多中心、单臂二期临床试验（IMAGENE 试验），用于评估尼拉帕利（PARPi）联合程序性细胞死亡-1 抑制剂联合治疗在 HRR 基因突变且对 ICI 治疗耐药的癌症患者中的疗效和安全性，该试验使用基于下一代测序的循环肿瘤 DNA（ctDNA）和肿瘤组织分析。

方法

该试验的关键入选标准包括任何癌症基因检测确定的 HRR 基因突变肿瘤；先前 ICI 治疗后进展；以及东部肿瘤协作组表现状态（ECOG PS）≤1。主要终点是所有患者的确认客观缓解率（ORR）。次要终点包括使用 Caris Assure（美国 CARIS）检测 ctDNA 中 HRR 基因突变患者的确认 ORR。IMAGENE 试验的目标样本量为 57 例。将同时进行生物标志物分析，使用 Caris Assure、蛋白质组分析和 T 细胞受体库分析，以揭示外周血中的肿瘤免疫监视。