PO.CTP01.02 · 进行中的临床试验

Pidnarulex在晚期实体瘤患者中的药效学初步研究

Pilot study of pidnarulex pharmacodynamics in patients with advanced solid tumors

编号 CT293 展板 27 时间 4/21 02:00–05:00 区域 Section 51 主讲 Jibran Ahmed, MD

分会场 Phase I and Phase II Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Jibran Ahmed¹, Brian Ko², Sarah J. Shin¹, Murielle Hogu¹, Lawrence Rubinstein³, Himabindu Gali⁴, Deborah F. Wilsker⁴, Ralph E. Parchment⁴, Laura Kuhlmann¹, Steven Gore², James H. Doroshow¹, Alice P. Chen¹

¹Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD,²Cancer Therapy Evaluation Program Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD,³Biometric Research Program, National Cancer Institute, National Institutes of Health, Bethesda, MD,⁴Clinical Pharmacodynamics Biomarker Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD

摘要 Abstract

中文摘要

背景：Pidnarulex（CX-5461）是一种首创的G-四链体稳定剂，可诱导复制依赖性DNA损伤，抑制RNA聚合酶I和拓扑异构酶II（Top2）。Pidnarulex在此前的一项I期研究（NCT02719977）中已展现出安全性和初步疗效，32例患者中有4例出现部分缓解，11例出现疾病稳定，其中4例缓解持续≥6个月。美国国家癌症研究所（NCI）在同源重组（HR）功能正常（OVCAR3）和HR缺陷（HRD）（A2780、IGROV1）细胞系中开展的临床前体外研究显示，pidnarulex（体外1 µM或3 µM）在治疗后24小时显著增加了RPA32、pSer33-RPA32、53BP1和Rad51核内焦点的百分比，表明DNA损伤应答被激活。在两种浓度下，所有3种细胞系中均观察到G4稳定化（BG4抗体）。本项初步研究（NCT06606990）旨在确定pidnarulex是否诱导Rad51应答，该应答定义为治疗后肿瘤活检中具有≥5个Rad51阳性核内焦点的细胞百分比。方法：本项单中心初步研究旨在招募40例成年患者（年龄≥18岁），平均分配至2个队列：伴或不伴HRD相关改变（有害的BRCA1/2；范可尼贫血基因突变；ARID1A、ATM、ATR、BRIP1、BAP1、BARD1、CDK12、CHK1、CHK2、IDH1/2、MRE11A、NBN、PALB2、RAD50、RAD51、RAD51B/C/D、RAD54L的功能性改变）。主要目的是评估pidnarulex治疗后的Rad51应答。次要目的包括安全性（CTCAE v5.0）、客观缓解率（RECIST v1.1）、pidnarulex的药代动力学（PK），以及与临床应答相关的其他肿瘤DNA损伤和修复标志物（RPA32、pSer33-RPA32、gammaH2AX、53BP1、pSer8-RPA32、pKap1和pNBS1）。符合条件的成年人须经组织学确诊为实体瘤，ECOG≤2，器官功能充足，且肿瘤适合活检。Pidnarulex于每个28天周期的第1天和第8天以325 mg/m²静脉给药。对于≥3级非血液学毒性进行剂量减量，最多减量2次（DL-1：250 mg/m²；DL-2：200 mg/m²）。在基线和第1周期第2天（给药后24±2小时）强制采集肿瘤活检以进行药效学评估。采集血样用于PK分析（强制）和ctDNA（可选）。研究成功需要每个队列16份可评估活检，其中≥3例患者（19%）显示Rad51应答，从而在5%假阳性率下具有90%的把握度检测出真实的30%Rad51阳性应答率。由NCI合同编号HHSN261201500003I资助。

查看英文原文 English abstract

Background: Pidnarulex (CX-5461) is a first-in-class G-quadruplex-stabilizing agent that induces replication-dependent DNA damage, inhibits RNA polymerase I and topoisomerase II (Top2). Pidnarulex has demonstrated safety and preliminary efficacy in a prior phase I study ( NCT02719977 ), with partial responses in 4 of 32 patients and stable disease in 11 patients, including 4 with responses ≥6 months. The National Cancer Institute's (NCI) preclinical in vitro studies in homologous recombination (HR)-proficient (, OVCAR3) and HR-deficient (HRD) (A2780, IGROV1) cell lines show that pidnarulex (1 µM or 3 µM in vitro ;) significantly increased percentage of RPA32, pSer33-RPA32, 53BP1 and Rad51 nuclear foci 24 hours post-treatment, indicating DNA damage response activation. G4 stabilization (BG4 antibody) was observed in all 3 cell lines at both concentrations. This pilot study ( NCT06606990 ) aims to determine whether pidnarulex induces a Rad51 response, defined as the percentage of cells with ≥5 Rad51 positive nuclear foci in post-treatment tumor biopsies. Methods: This single-center pilot study aims to enroll 40 adult patients (age ≥18) distributed equally between 2 cohorts: with or without HRD-associated alterations (deleterious BRCA1/2; Fanconi anemia gene mutations; functional alterations in ARID1A, ATM, ATR, BRIP1, BAP1, BARD1, CDK12, CHK1, CHK2, IDH1/2, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B/C/D, RAD54L). The primary objective is assessing Rad51 response following pidnarulex treatment. Secondary objectives include safety (CTCAE v5.0), objective response rate (RECIST v1.1), pharmacokinetics (PK) of pidnarulex, and additional tumor DNA-damage and repair markers RPA32, pSer33-RPA32, gammaH2AX, 53BP1, pSer8-RPA32, pKap1, and pNBS1) associated with clinical response. Eligible adults must have histologically confirmed solid tumors, ECOG ≤2, adequate organ function, and tumor amenable to biopsy. Pidnarulex is administered at 325 mg/m² IV on days 1 and 8 of each 28-day cycle. Dose reductions occur for grade ≥3 non-hematologic toxicities, with a maximum of 2 reductions (DL-1: 250 mg/m²; DL-2: 200 mg/m²). Mandatory tumor biopsies are collected at baseline and on cycle 1 day 2 (24 ± 2 hours post-dose) for pharmacodynamic assessment. Blood samples are collected for PK analyses (mandatory) and ctDNA (optional). Study success requires 16 evaluable biopsies per cohort, with ≥3 patients (19%) showing a Rad51 response, providing 90% power to detect a true 30% Rad51-positive response rate at a 5% false-positive rate. Funded by NCI Contract No. HHSN261201500003I.

利益披露 Disclosure

J. Ahmed, None.. B. Ko, None.. S. J. Shin, None.. M. Hogu, None.. L. Rubinstein, None.. H. Gali, None.. D. F. Wilsker, None.. R. E. Parchment, None.. L. Kuhlmann, None.. S. Gore, None.. J. H. Doroshow, None.. A. P. Chen, None.

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