PO.CTP01.02 · 进行中的临床试验

ARV-393（一种PROTAC BCL6降解剂）作为单药治疗晚期非霍奇金淋巴瘤（NHL）患者或与glofitamab联合治疗弥漫性大B细胞淋巴瘤（DLBCL）患者的1期研究

Phase 1 study of ARV-393, a PROTAC BCL6 degrader, as monotherapy in patients with advanced non-Hodgkin lymphoma (NHL) or combined with glofitamab in patients with diffuse large B-cell lymphoma (DLBCL)

编号 CT268 展板 2 时间 4/21 02:00–05:00 区域 Section 51 主讲 Lela Creutz

分会场 Phase I and Phase II Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Martin Hutchings¹, Andrew Zelenetz², Jacob H. Christensen³, Almudena Cascales Hernandez⁴, Sarit Assouline⁵, Luis E. Malpica Castillo⁶, Shalin Kothari⁷, Dipenkumar Modi⁸, Miguel A. Canales Albendea⁹, Damian Cubillas¹⁰, Alejandro M. Garcia-Sancho¹¹, Catherine M. Diefenbach¹², John Kuruvilla¹³, Paolo F. Caimi¹⁴, Krish Patel¹⁵, Sean Landrette¹⁶, Eric Zhi¹⁶, Yuanyuan Zhang¹⁶, Roland Meier¹⁶, Mathew J. Matasar¹⁷

¹Rigshospitalet and University of Copenhagen, Copenhagen, Denmark,²Memorial Sloan Kettering Cancer Center, New York, NY,³Odense University Hospital, Odense, Denmark,⁴Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain,⁵McGill University, Montreal, QC, Canada,⁶The University of Texas MD Anderson Cancer Center, Houston, TX,⁷Yale School of Medicine and Yale Cancer Center, New Haven, CT,⁸Karmanos Cancer Institute/Wayne State University, Detroit, MI,⁹Clínica Universidad de Navarra, Pamplona, Spain,¹⁰START Center for Cancer Research, Madrid, Spain,¹¹Hospital Universitario de Salamanca, Salamanca, Spain,¹²Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY,¹³Princess Margaret Cancer Centre, Toronto, ON, Canada,¹⁴Cleveland Clinic, Cleveland, OH,¹⁵Sarah Cannon Research Institute, Nashville, TN,¹⁶Arvinas Operations, Inc., New Haven, CT,¹⁷Rutgers Cancer Institute of New Jersey, New Brunswick, NJ

摘要 Abstract

中文摘要

背景：尽管NHL治疗近期取得进展，许多患者仍会经历疾病进展或复发。需要具有新颖作用机制的药物和联合策略来改善临床结局。B细胞淋巴瘤6（BCL6）是免疫细胞（尤其是生发中心B细胞）的主转录调控因子，也是NHL中一个确立的致癌驱动因子。ARV-393是一种口服的蛋白水解靶向嵌合体（PROTAC）BCL6降解剂，可结合E3泛素连接酶和BCL6，诱导BCL6的泛素化及其随后的蛋白酶体降解。ARV-393单药在多种NHL细胞来源异种移植（CDX）和患者来源异种移植模型（包括DLBCL、转化型滤泡性淋巴瘤和淋巴结T滤泡辅助细胞淋巴瘤[nTFHL]模型）中强效抑制肿瘤生长并诱导肿瘤消退。此外，ARV-393与CD20×CD3双特异性抗体glofitamab联合给药，在人源化高级别B细胞淋巴瘤CDX模型中显示出联合抗肿瘤活性，与任一单药相比诱导了更深的肿瘤生长抑制和更多的肿瘤消退。这些临床前发现证明了ARV-393单药在NHL各亚型中的抗肿瘤活性，并提示与glofitamab存在机制性协同作用，支持在NHL中开展单药临床研究以及在DLBCL患者中开展这一无化疗联合方案的研究。方法：这项全球性、多中心、开放标签、首次人体、1期剂量递增与优化/扩展研究（NCT06393738）正在评估ARV-393作为单药治疗复发或难治性（R/R）NHL或与glofitamab联合治疗R/R DLBCL的安全性、耐受性、药代动力学、药效动力学和初步抗肿瘤活性，主要目标为确定用于进一步探索的临时剂量。符合ARV-393单药条件的患者为确诊R/R B细胞NHL、既往接受过≥2线系统治疗（包括利妥昔单抗）的成人，或既往接受过标准治疗的nTFHL患者。符合ARV-393联合glofitamab条件的患者为病理确诊R/R DLBCL、非特指型DLBCL或由滤泡性淋巴瘤转化而来的大B细胞淋巴瘤、既往接受过≥2线系统治疗的成人。ARV-393将以28天为周期每日一次口服单药给药，或在21天周期内与静脉注射glofitamab联合给药。各研究队列共将入组约255例患者。截至2026年1月，入组正在进行中。

查看英文原文 English abstract

Background: Despite recent advancements in NHL therapies, many patients experience disease progression or relapse. Agents with novel mechanisms of action and combination strategies are needed to improve clinical outcomes. B-cell lymphoma 6 (BCL6) is a master transcriptional regulator of immune cells, particularly of germinal center B cells, and an established oncogenic driver in NHL. ARV-393 is an oral PROteolysis TArgeting Chimera (PROTAC) BCL6 degrader that binds an E3 ubiquitin ligase and BCL6 to induce ubiquitination of BCL6 and its subsequent proteasomal degradation. ARV-393 monotherapy potently inhibited tumor growth and induced tumor regressions across NHL cell-derived xenograft (CDX) and patient-derived xenograft models, including models of DLBCL, transformed follicular lymphoma, and nodal T-follicular helper cell lymphoma (nTFHL). Furthermore, administration of ARV-393 with a CD20×CD3 bispecific antibody, glofitamab, demonstrated combinatorial antitumor activity in a humanized high-grade B-cell lymphoma CDX model, inducing deeper tumor growth inhibition and increased tumor regressions vs either monotherapy. These preclinical findings demonstrated single-agent ARV-393 antitumor activity across NHL subtypes and suggested mechanistic synergy with glofitamab, supporting clinical investigation of monotherapy in NHL and this chemotherapy-free combination in patients with DLBCL. Methods: This global, multicenter, open-label, first-in-human, phase 1 dose escalation and optimization/expansion study (NCT06393738) is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-393 as monotherapy in relapsed or refractory (R/R) NHL or in combination with glofitamab in R/R DLBCL, with a primary objective of determining provisional doses for further exploration. Patients eligible for ARV-393 monotherapy are adults with confirmed R/R B-cell NHL who previously received ≥2 lines of systemic therapy (including rituximab), or nTFHL who previously received standard of care therapy. Patients eligible for ARV-393 in combination with glofitamab are adults with pathologically confirmed R/R DLBCL, DLBCL not otherwise specified, or large B-cell lymphoma arising from follicular lymphoma who were treated with ≥2 prior lines of systemic therapy. ARV-393 will be administered orally once daily in 28-day cycles alone or in combination with intravenous glofitamab during 21-day cycles. Approximately 255 patients will be enrolled across study cohorts. As of January 2026, enrollment is ongoing.

利益披露 Disclosure

M. Hutchings, AbbVie ). AstraZeneca ). Bristol Myers Squibb ). Celgene ). Genentech ). Genmab ). Incyte ). Johnson & Johnson ). Merck ). Novartis ). Roche ). Pfizer ). Seattle Genetics ). Takeda ). A. Zelenetz, BeOne Independent Contractor, ). Curio Science Independent Contractor. Genentech/Roche Independent Contractor, ). BMS Independent Contractor. AstraZeneca Independent Contractor, ). Arvinas Independent Contractor, ). Adaptive Biotechnologies Independent Contractor. Gilead Independent Contractor. Lilly ). International Lymphoma Radiation Oncology Group (ILROG) Travel. J. H. Christensen, Takeda ), Travel. Johnson & Johnson ). Beigene Travel. A. Cascales Hernandez, None. S. Assouline, Novartis ), Other, Consultancy/Advisory board; Speaker. AstraZeneca Other, Consultancy/Advisory board. AbbVie Other, Consultancy/Advisory board. BeOne Other, Consultancy/Advisory board. Roche Other, Consultancy/Advisory board. L. E. Malpica Castillo, Dizal Pharma Employment, ). S. Kothari, Eli Lilly Independent Contractor. ADC Therapeutics Independent Contractor. AbbVie Independent Contractor. Genentech Independent Contractor. Foresight Diangostics Independent Contractor. Incyte Independent Contractor. Bristol Myers Squibb ). D. Modi, Genentech ), Other, Consulting/advisory role (spouse). Karyopharm ). Regeneron ), Other, Honorarium. Genmab ), Consulting/advisory role. AstraZeneca ), Other, Consulting advisory role (spouse); Expert testimony. ADC therapeutics; Incyte; BMS; Daichi Sankyo (spouse) Other, Consulting/advisory role. M. A. Canales Albendea, None.. D. Cubillas, None. A. M. Garcia-Sancho, Gilead/Kite ), Travel, Other, Honoraria, Consulting fees. AbbVie; BMS; Janssen; Roche Travel, Other, Honoraria, Consulting fees. AstraZeneca, Ideogen, Lilly, Roche, Sobi Other, Honoraria, Consulting fees. BeOne, Incyte, Kyowa Kirin, Takeda Other, Honoraria. C. M. Diefenbach, None. J. Kuruvilla, AbbVie Independent Contractor, Other, Honoraria. AstraZeneca Independent Contractor, ), Other, Honoraria. BeOne Independent Contractor, ), Other, Honoraria. BMS Independent Contractor, Other, Honoraria. Kite/Gilead Independent Contractor, Other, Honoraria. Merck Independent Contractor, ), Other, Honoraria. Roche Independent Contractor, ), Other, Honoraria. OmniaBio Independent Contractor. Amgen Other, Honoraria. Arvinas Other, Honoraria. Genmab Other, Honoraria. Incyte Other, Honoraria. Janssen Other, Honoraria. Lilly Other, Honoraria. Novartis Other, honoraria. Pfizer Other, Honoraria. P. F. Caimi, ADC Therapeutics ). ContaX Stock. Genentech ). Genmab ). Novartis Independent Contractor. Recordati ). Abcon Stock Option. BMS Independent Contractor. K. Patel, AbbVie ), Other, Consulting (institution and self). Adaptive Biotechnologies ), Other, Consulting (institution and self). Adicet ). AstraZeneca ), Other, Consulting (institution and self). Bristol-Myers Squibb Other, Consulting (institution and self) Speakers Bureau (self). CRISPR Therapeutics ). Fate Therapeutics ). Genentech/Roche Other, Consulting (institution and self). Kite Other, Consulting and speakers bureau (self). Indapta Therapeutics ). Janssen ), Other, Consulting (paid to institution). Lilly ), Other, Consulting (paid to institution and self). Loxo Oncology ). MEI Pharma ). Merck ), Consulting (institution and self). Nurix; Pharmacyclics; Sana Biotechnology; Xencor ). Pfizer ), Consulting (paid to self). Arcus Biosciences; Avencell Therapeutics; BeOne Medicine; Century Therapeutics; Foresight Diagnostics; Genmab; Legend Biotech; Lyell Immunopharma; Sanofi Other, Consulting (paid to institution). Caribou Biosciences Other, Consulting (paid to institution and self). S. Landrette, Arvinas Employment, Stock, Stock Option. Orphai Therapeutics Stock, Patent. Yale University Patent. E. Zhi, Arvinas Employment, Stock. Y. Zhang, Arvinas Employment, Stock, Stock Option. R. Meier, Arvinas Independent Contractor. M. J. Matasar, AbbVie Independent Contractor, Other, Advisory/Consultancy. ADC Therapeutics Independent Contractor. AstraZeneca Independent Contractor. Epizyme Independent Contractor. Johnson & Johnson Independent Contractor. Kite Independent Contractor. Regeneron Independent Contractor. Roche Independent Contractor, ), Other, Advisory/Consultancy. Pfizer Independent Contractor, Other, Advisory/Consultancy. Hutch-Med Independent Contractor. Merck Stock Option. Bayer ). GM Biosciences ). Immunovaccine Technologies ). Janssen ). Genentech ). Pharmacyclics ). Seattle Genetics ). Recursion Pharmaceuticals, Arnold & Porter Other, Expert Testimony. Allogene; Arvinas; Genmab; Genentech; Incyte Corporation; Merck; Novartis; Visionaries  Other, Advisory/Consultancy.

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