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PO.CTP01.01 · 进行中的临床试验

EIU-104101：EVOLVE104（一种三特异性CD3×CD2×ULBP2/5/6 T细胞衔接器）在晚期尿路上皮癌和鳞状细胞癌中的首次人体1a/1b期研究

EIU-104101: A first-in-human phase 1a/1b study of EVOLVE104, a trispecific CD3×CD2×ULBP2/5/6 T cell engager, in advanced urothelial and squamous cell carcinomas

海报缩略图：EIU-104101：EVOLVE104（一种三特异性CD3×CD2×ULBP2/5/6 T细胞衔接器）在晚期尿路上皮癌和鳞状细胞癌中的首次人体1a/1b期研究
编号 CT079 展板 10 时间 4/20 09:00–12:00 区域 Section 51 主讲 Anthony Fiorino, MD;PhD
分会场 Phase I Clinical Trials in Progress
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作者与单位 Authors & Affiliations

Manish Sharma1, Alex Spira2, Meredith McKean3, Jacqueline Brown4, Thomas Marron5, Stella Martomo6, Xiaowei Guan6, Astha Bhatia6, Shaun O'Brien6, Oksana Sergeeva6, Keri Urwin6, Jay Fine6, Anthony S. Fiorino6

1START Midwest, Grand Rapids, MI,2Virginia Cancer Specialists and NEXT Oncology, Fairfax, VA,3SCRI Oncology Partners Group, Nashville, TN,4Winship Cancer Institute of Emory University, Atlanta, GA,5Tisch Cancer Center, Icahn School of Medicine at Mt Sinai, New York, NY,6EvolveImmune Therapeutics, Inc, Branford, CT

摘要 Abstract

中文摘要
背景：EVOLVE T细胞衔接器（TCE）结合肿瘤抗原以及T细胞上的CD3和CD2，从而通过CD2结合提供整合的共刺激。与第一代TCE相比，EVOLVE TCE展现出更优的T细胞激活和肿瘤细胞杀伤，且无过度的细胞因子释放或强直性T细胞激活，并可能带来诸如增强效力和活性持续时间等临床获益。UL16结合蛋白2、5和6（ULBP2/5/6）属于一类细胞表面蛋白，是NKG2D受体的配体。我们此前报道过细胞表面ULBP2/5/6不存在于重要器官中，而见于某些黏膜上皮。细胞表面ULBP2/5/6见于尿路上皮癌和鳞状细胞癌（SCC）。由于在恶性细胞上高表达而在正常组织中表达有限，ULBP2/5/6是颇具吸引力的癌症免疫治疗靶点。EVOLVE104是一种三特异性TCE，结合ULBP2/5/6以及T细胞上的CD3和CD2。EVOLVE104的临床前研究显示，与双特异性TCE相比，其对ULBP2/5/6阳性肿瘤细胞的T细胞激活和杀伤增强，且在临床前毒理学研究中未发现安全性问题。凭借这一临床前特征，EVOLVE104代表了一种实体瘤中重定向T细胞治疗的新方法。 方法：EIU-104101是一项首次人体1a/1b期研究，评估EVOLVE104单药在晚期实体瘤成人患者中的应用。符合条件的肿瘤类型包括膀胱尿路上皮癌以及膀胱、肺、食管、舌、皮肤和肛门生殖器区域（阴茎、肛门、阴道、外阴、宫颈和尿道）的SCC。受试者必须患有局部晚期或转移性疾病，且对标准治疗复发或难治。研究目的包括评估EVOLVE104的安全性、疗效、药代动力学和药效动力学，并确定推荐2期剂量（RP2D）。研究的1a期部分将采用贝叶斯最优区间（BOIN）剂量爬坡方案入组至多80名受试者，包括在被判定为安全的剂量水平进行回填，其关键目的是确定一个或多个推荐扩展剂量（RDE）。1b期包括两个扩展队列：队列A为单一适应证（将根据1a期观察结果确定）的剂量优化队列，其中40名受试者将按1:1随机分配至两个RDE以确定RP2D；队列B将在其他相关适应证中入组至多40名受试者。本研究于2025年10月开放，目前正在美国各中心积极入组。ClinicalTrials.gov标识号：NCT07217171。
查看英文原文 English abstract
Background: EVOLVE T cell engagers (TCEs) bind to a tumor antigen and to both CD3 and CD2 on T cells, thereby providing integrated costimulation via CD2 binding. EVOLVE TCEs demonstrate superior T cell activation and tumor cell killing compared to first generation TCEs, without excess cytokine release or tonic T cell activation, and may offer clinical benefits such as enhanced potency and duration of activity.UL16 binding proteins 2, 5 and 6 (ULBP2/5/6) belong to a family of cell surface proteins that are ligands for the NKG2D receptor. We have previously reported that cell-surface ULBP2/5/6 is not present in vital organs and found in some mucosal epithelia. Cell surface ULBP2/5/6 is found in urothelial carcinomas and squamous cell carcinomas (SCCs). With high expression on malignant cells and limited normal tissue expression, ULBP2/5/6 are intriguing targets for cancer immunotherapy.EVOLVE104 is a trispecific TCE that binds ULBP2/5/6 and both CD3 and CD2 on T cells. Preclinical studies with EVOLVE104 demonstrated enhanced T cell activation and killing of ULBP2/5/6-positive tumor cells compared to bispecific TCEs, and no safety concerns were identified in preclinical toxicity studies. With this preclinical profile, EVOLVE104 represents a novel approach to redirected T cell therapy in solid tumors. Methods: EIU-104101 is a first-in-human phase 1a/1b study evaluating EVOLVE104 monotherapy in adults with advanced solid tumors. Eligible tumor types include urothelial carcinoma of the bladder and SCCs of the bladder, lung, esophagus, tongue, skin, and anogenital region (penis, anus, vagina, vulva, cervix, and urethra). Subjects must have locally advanced or metastatic disease that has relapsed from, or is refractory to, standard-of-care therapies. Study objectives include assessing the safety, efficacy, pharmacokinetics and pharmacodynamics of EVOLVE104 and identifying the recommended phase 2 dose (RP2D).The phase 1a portion of the study will enroll up to 80 subjects using a Bayesian optimal interval (BOIN) dose-escalation scheme including backfill at dose levels deemed safe, with a key objective to identify one or more recommended doses for expansion (RDEs). Phase 1b includes two expansion cohorts: Cohort A, which will be a dose optimization cohort in a single indication (to be determined based on the phase 1a observations) in which 40 subjects will be randomized 1:1 to two RDEs to determine the RP2D; and Cohort B, which will enroll up to 40 subjects in other relevant indications.The study opened in October 2025 and is actively enrolling at US sites. ClinicalTrials.gov Identifier: NCT07217171.
利益披露 Disclosure
M. Sharma, Abbott Laboratories, Abbvie, Bristol-Myers Squibb, Lilly, Merck, Regeneron, Amgen, Gilead, Johnson & Johnson, Vertex, Pfizer Stock. AADi, Enlanza Therapeutics, Whitehawn Therapeutics, Pliant Therapeutics Independent Contractor. AstraZeneca, Bolt Biotherapeutics, Bristol-Myers Squibb, Compugen, Exelixis, Ikena, InhibRx, KLUS Pharma, Macrogenics, Merck, Pfizer ). Regeneron, Astellas, Genmab, Glaxo SmithKline, Seagen, NGM Biotherapeutics, Gilead, Abbvie, Johnson & Johnson, Cullinan Oncology, Debiopharm, Helsinn, Repare Therapeutics, Boundless Bio Therapeutics ). ALX oncology, Black Diamond Therapeutics, Bohringer Ingelheim, Deciphera, Incyte, Chiugai, Mirati Therapeutics, Pliant, Adcentrx, Alkermes, Arcus Biosciences, Third Arc Bio, Artios, Arvinas, BioNTech ). Ipsen, Day One Biopharmaceuticals, Context Therapeutics, Daiichi Sankyo, EvolveImmune Therapeutics, FoRx Therapeutics, Genentech, Roche, Exscienta, Halda Therapeutics, Iambic Therapeutics ). IDEAYA Biosciences, Kumquat Biosciences, Mbrace Therapeutics, Menarini, Monte Rosa, Mitsubishi Tanabe, NiKang Therapeutics, Opna Bio, Quanta Therapeutics, Takeda, Treeline Biosciences, Medlink Therap ). Vividion Therapeutics, VelaVigo Bio, Zymeworks ). A. Spira, CytomX Therapeutics, AstraZeneca, Merck, Takeda, Amgen, Jannsen Oncology, Novartis, Bristol Myers Squibb, Bayer, Prelude Therapeutics, Abbvie, Astella Pharma Other, Honoraria. Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Jannsen, Mersana, Daiichi Sankyo, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi Independent Contractor. Arrivent Biopharma, Synthekine, Glaxo SmithKline, Crispr Therapeutics, Revolution Medicine, AstraZeneca, Blueprint Medicines Independent Contractor. LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas, MedImmune, Novartis, Incyte, Abbvie, Ignyta, Takeda, Macrogenics, CytomX, Astex, Bristol-Myers Squibb, Loxo, Gritstone, Plexxikon ). Amgen, Loxo, ADCT, Janssen, Rubius, Synthekine, Mersana, Blueprint Medicines, Regeneron, Alkermes, Revolution Medicines, Medikine, Black Diamond Therapeutics, ). BluPrint Oncology, nala therapeutics, Scorpion Therapeutics, Prelude Therapeutics, Lilly, Lepu Biopharma, Tango Therapeutics ). M. McKean, Abbvie; Bristol-Myers Squibb; Castle Biosciences; Daiichi Sankyo; IDEAYA Biosciences; IQvia; Merck; Moderna Therapeutics; Pfizer; Pierre Fabre; Regeneron; Revolution Medicines Independent Contractor. Arcus Biosciences; Aulos Bioscience; Bayer; Bicycle Therapeutics; BioNTech; Boehringer Ingelheim; C4 Therapeutics; Daiichi Sankyo; Dragonfly Therapeutics; Erasca, Inc; GenVivo; Gilead Sciences ). IDEAYA Biosciences; Ikena Oncology; immatics; Immunocore; Iovance Biotherapeutics; Jazz Pharmaceuticals; Kezar Life Sciences; Krystal Biotech; Merck; Moderna Therapeutics; ). Nested Therapeutics; Novartis; NucMito Pharmaceuticals; OncoC4; Pfizer; Pierre Fabre; Prelude Therapeutics; Regeneron; Repimune; Sapience Therapeutics; Synthorx; Teva; TScan Therapeutics ). EvolveImmune Therapeutics ). J. Brown, Exelixis, Xencor, Merck, Medicenna, Surface Oncology, Pliant Therapeutics, Macrogenics, Duality Bio ). Exelixis, Xencor, Gilead Other, honoraria. T. Marron, AbbVie, Merck, EMD Serono, Geneos, Arrowhead, Storm, Replimmune, Avammune, Tubulis, NaturesToolbox, EvolveImmune, AN2 Therapeutics, Caris, Tatum, GE Healthcare, Astellas Other, Honoraria. Regeneron, Genentech, Bristol-Myers Squibb, Merck, Boehringer Ingelheim ). Nature's Toolbox Stock Option. S. Martomo, EvolveImmune Therapeutics Employment, Stock. X. Guan, Mineralys Employment. Kinnate Pharma Employment. EvolveImmune Therapeutics Independent Contractor. A. Bhatia, EvolveImmune Therapeutics Employment, Stock. Stemline Therapeutics Employment. Zentalis Pharmaceuticals Employment. S. O'Brien, Bristol-Myers Squibb Employment, Stock. EvolveImmune Therapeutics Employment, Stock. O. Sergeeva, EvolveImmune Therapeutics Employment, Stock. K. Urwin, EvolveImmune Therapeutics, Phylaxis, Proniras, Prolium, Ajax Therapeutics, Kanvas Bio, Extend Bio, Yarrow Independent Contractor. J. Fine, EvolveImmune Therapeutics Employment, g., Board of Directors, non-salaried role), Stock. Merck, Johnson & Johnson Stock. Halda Therapeutics, Empress Therapeutics Independent Contractor, Other, Consulting. A. S. Fiorino, EvolveImmune Therapeutics Employment, g., Board of Directors, non-salaried role), Stock. C4 Therapeutics Independent Contractor. Nova Anchora Independent Contractor. Confidential Independent Contractor. Confidential Independent Contractor.

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