PO.CTP01.01 · 进行中的临床试验
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
作者与单位
摘要 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.