PO.CTP01.01 · 进行中的临床试验
一项SMARCA2降解剂PLX-61639在SMARCA4突变的局部晚期或转移性实体瘤患者中的1期首次人体研究
A Phase 1, first-in-human study of the SMARCA2 degrader, PLX-61639, in patients with SMARCA4-mutated, locally advanced or metastatic solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：SMARCA4和SMARCA2是BAF核小体重塑复合物的冗余组分，两者中至少一个对细胞存活至关重要。编码SMARCA4的基因突变发生于约10-15%的上皮性实体瘤中，包括10%的NSCLC，在这些肿瘤中该突变与不良预后相关。消除SMARCA4蛋白或导致功能丧失（LoF）的突变造成肿瘤细胞对SMARCA2的存活依赖。PLX-61639是一种口服、单价、选择性的SMARCA2直接降解剂，在SMARCA4缺陷肿瘤异种移植物中显示出抗肿瘤活性，同时不影响表达SMARCA4的正常组织。这项首次人体1期试验（NCT07284186）的目的是评估PLX-61639的安全性和PK，确定最大耐受剂量或最大给药剂量以及推荐扩展剂量，并对其在复发或难治性SMARCA4缺陷实体瘤患者中的抗肿瘤活性进行初步评估。
方法：这是一项PLX-61639的多中心、开放标签剂量递增研究，分3个部分进行：第1部分剂量递增、第2部分剂量优化和第3部分扩展。所有3个部分将招募多达155名患者。合格患者必须基于现有基因组分析具有SMARCA4 LoF突变或SMARCA4的IHC染色阴性，且对标准治疗方案无应答或复发。患者需具有充足的肝、骨髓、凝血、肾和心肺功能，ECOG PS 0或1，以及RECIST 1.1可测量疾病。排除具有种系SMARCA4缺陷或同时缺失SMARCA2和SMARCA4的肿瘤患者。入组患者将在其分配的剂量水平上以28天为周期口服PLX-61639，每日一次，直至疾病进展或不可接受的毒性。将在首个28天周期评估至少3名患者的剂量限制性毒性，安全审查委员会（SRC）将使用贝叶斯最优区间算法决定递增至下一个更高剂量水平、递减或在当前剂量水平扩展。经SRC认定可耐受的剂量水平将开放供NSCLC患者回填入组。第1部分完成后，第2部分将招募SMARCA4缺陷NSCLC患者，并将患者随机分配至两个剂量水平之一以确定推荐扩展剂量（RED）。试验的第3部分将包含一个多达25名SMARCA4缺陷实体瘤患者的扩展队列，在RED接受治疗。关键终点包括AE（含DLT）的发生率和严重程度，以及通过RECIST 1.1测量的抗肿瘤活性、扫描的体积分析和循环肿瘤DNA的变化。本研究（NCT7284186）于2025年12月开放入组并持续招募中。
查看英文原文 English abstract
Background: SMARCA 4 and SMARCA2 are redundant components of the BAF nucleosome remodeling complex, at least one of which is essential for cell survival. Mutations in the gene encoding SMARCA4, occur in approximately 10 - 15% of epithelial solid tumors, including 10% of NSCLC where they are associated with poor prognosis. Mutations that eliminate SMARCA4 protein or cause Loss of Function (LoF) create a dependency on SMARCA2 for tumor cell survival. PLX-61639 is an oral, monovalent, selective direct degrader of SMARCA2 that has shown anti-tumor activity in SMARCA4-deficient tumor xenografts while sparing SMARCA4 expressing normal tissues. The purpose of this First-in-Humans Phase 1 trial (NCT07284186) is to evaluate the safety and PK of PLX-61639, to define the maximum tolerated or maximum administered dose and recommended expansion dose and to make a preliminary assessment of its anti-tumor activity in patients with relapsed or refractory, SMARCA4-deficient solid tumors.
Methods: This is a multi-center, open-label dose escalation study of PLX-61639 conducted in 3 parts: Part 1 Dose Escalation, Part 2 Dose Optimization and Part 3 Expansion. Up to 155 patients will be enrolled across all 3 parts. Eligible patients must have SMARCA4 LoF mutations based on existing genomic profiling or negative IHC staining for SMARCA4 and have failed to respond or have relapsed after standard of care regimens. Patients are required to have adequate liver, bone marrow, coagulation, renal, and cardiopulmonary function, ECOG PS 0 or 1 and measurable disease by RECIST 1.1. Patients with germline SMARCA4 deficiency or tumors with loss of SMARCA2 and SMARCA4 are excluded. Enrolled patients will receive PLX-61639 orally, once daily in 28-day cycles at their assigned dose level until disease progression or unacceptable toxicity. A minimum of 3 patients will be evaluated for Dose-Limiting Toxicity in the first 28-day cycle and the decision to escalate to the next higher dose level, de-escalate or expand at the current dose level will be made by the Safety Review Committee (SRC) using a Bayesian Optimal Interval algorithm. Dose levels that have been deemed tolerated by the SRC will be open for backfill enrollment for patients with NSCLC. Upon completion of Part 1, Part 2 will enroll patients with SMARCA4-deficient NSCLC and randomize patients to one of two dose levels to determine the Recommended Expansion Dose (RED). Part 3 of the trial will comprise an expansion cohort of up to 25 patients with SMARCA4-deficient solid tumors treated at the RED. Key endpoints include the incidence and severity of AEs, including DLTs and anti-tumor activity as measured by RECIST 1.1, volumetric analysis of scans and changes in circulating tumor DNA. This study (NCT7284186) opened for enrollment in December, 2025 and is continuing to enroll.
利益披露 Disclosure
J. F. DiMartino,
Plexium Inc Employment, Stock, Stock Option.
A. Spira,
Plexium Inc ).
A. Rohatgi,
Astra-Zeneca ).
Gilead ).
Summit ).
Moderna ).
Appotomics ).
Solve Therapeutics ).
Medilink ).
Bristol-Myers-Squibb ).
Amgen Other, Consulting.
Janssen Other, Consulting.
M. R. Khawaja,
Plexium Inc ).
Kymera Therapeutics ).
Orionis Biosciences ).
Genentech ).
Alyssum Therapeutics ).
BeOne Therapeutics ).
Clasp Therapeutics ).
Eli Lilly ).
Springworks Therapeutics ).
Red Arrow Therapeutics Independent Contractor.
L. Alder,
BergenBio ).
ORIC Pharmaceuticals ).
Iambic Therapeutics ).
NTT Data ).
Phanes Therapeutics ).
FoundationOne Independent Contractor.
OncoHost Independent Contractor.
Regeneron Independent Contractor.
Eli Lilly Independent Contractor.
Genentech Independent Contractor.
MJH Life Sciences Independent Contractor.
Boehringer Ingelheim Independent Contractor.
Amgen Independent Contractor.
Nuvation Bio Independent Contractor.
I. Dagogo-Jack,
Astra-Zeneca Independent Contractor.
Boehringer Ingelheim Independent Contractor.
Bayer Independent Contractor.
BostonGene Independent Contractor.
Bristol Myers Squibb Independent Contractor.
Catalyst Independent Contractor.
Genentech Independent Contractor, ).
Gilead Independent Contractor.
Janssen Independent Contractor.
Merus Independent Contractor.
Novocure Independent Contractor.
Nuvalent Independent Contractor.
Pfizer Independent Contractor, ).
Roche Independent Contractor.
Sanofi-Genzyme Independent Contractor.
Syros Independent Contractor.
ThermoFisher Scientific Independent Contractor.
Xcovery Independent Contractor.
Novartis ).
Array ).
M. A. Villalona,
Amgen ).
Eli Lilly Independent Contractor.
D. Rasco,
Plexium Inc ).
A. Rock,
Plexium Inc ).
A. Dowlati,
Plexium Inc Independent Contractor, ).
R. Guo,
Prelude Therapeutics ).
Astra Zeneca ).