PO.CTP01.01 · 进行中的临床试验
STRO-004 ST1：一项评估STRO-004在难治/复发转移性实体瘤成人患者中安全性、药代动力学及初步抗肿瘤活性的1期开放标签研究
STRO-004 ST1: Phase 1 open-label study to evaluate safety, pharmacokinetics, and preliminary anti-tumor activity of STRO-004 in adults with refractory/recurrent metastatic solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：复发或转移性实体瘤的治疗仍然是一项挑战，尤其是在标准治疗后疾病复发的患者中。组织因子（Tissue Factor，TF）是一种具有肿瘤选择性表达的跨膜糖蛋白，已被证实通过增强肿瘤血管生成和转移来促进肿瘤进展，使其成为抗体药物偶联物（ADC）的理想靶点（Li等，2022）。TF在多种实体瘤的细胞表面过表达，包括非小细胞肺癌（NSCLC）、头颈部鳞状细胞癌（HNSCC）、宫颈癌、结直肠癌（CRC）和胰腺癌（PDAC）（de Bono等，2022）。STRO-004是一种新型TF靶向ADC，采用位点特异性、β-葡萄糖醛酸酶可裂解的稳定连接子和exatecan载荷，药物-抗体比（DAR）=8。STRO-004经工程改造以增强血浆稳定性和药代动力学（PK），与第1代TF ADC相比，可提高疗效并降低脱靶毒性。临床前数据显示其在包括TF表达异质性或低表达在内的TF表达肿瘤模型中具有强效抗肿瘤活性。STRO-004与TF结合后，经受体介导的内化，在溶酶体内释放其exatecan载荷。exatecan的膜通透性使其能够扩散进入相邻的TF阴性细胞，从而产生旁观者杀伤效应。STRO-004还诱导免疫原性细胞死亡（ICD），激活抗原呈递细胞（APC），并可能驱动持久的抗肿瘤免疫。这些发现支持其与免疫疗法联合使用。
方法：STRO-004-ST1是一项首次人体（first-in-human）、1期、开放标签、多中心研究，评估STRO-004在难治或复发转移性实体瘤成人患者中的安全性、PK和抗肿瘤活性。该试验包括三部分：单药剂量爬坡（第1A部分）、单药队列扩展（第1B部分）以及与pembrolizumab联合的剂量爬坡（第1C部分）。符合条件的患者为既往接受过治疗的HNSCC、NSCLC、食管癌、胃癌、PDAC、CRC、子宫内膜癌、宫颈癌或尿路上皮癌的成人（>18岁），具有可测量疾病且有组织可供回顾性中心检测。STRO-004每3周静脉给药一次。第1A部分的终点包括最大耐受剂量（MTD）、剂量限制性毒性（DLT）、抗肿瘤活性和PK；疗效为第1B部分的主要终点。计划入组约200例患者。本研究（NCT07227168）在提交时已开放并正在入组。
查看英文原文 English abstract
Background: The treatment of recurrent or metastatic solid tumors remains a challenge, particularly in patients with relapsed disease following standard-of-care treatment. Tissue Factor (TF), a transmembrane glycoprotein with tumor-selective expression, has been implicated in promoting tumor progression through enhanced tumor angiogenesis and metastasis, making it an ideal target for an antibody-drug conjugate (ADC) (Li et al, 2022). TF is overexpressed on the cell surface of multiple solid tumors, including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), cervical, colorectal cancer (CRC), and pancreatic cancer (PDAC) (de Bono et al, 2022). STRO-004 is a novel TF-targeted ADC incorporating a site-specific beta-glucuronidase-cleavable, stable linker and an exatecan payload, with a drug-antibody ratio (DAR)=8. STRO-004 is engineered for enhanced plasma stability and pharmacokinetics (PK), leading to improved efficacy and reduced off-target toxicity compared with 1 st generation TF ADCs. Preclinical data demonstrate potent anti-tumor activity across TF-expressing tumor models, including those with heterogenous or low TF expression. Upon binding to TF, STRO-004 undergoes receptor mediated internalization, releasing its exatecan payload within the lysosome. The membrane-permeable nature of exatecan enables diffusion into adjacent TF-negative cells, resulting in bystander killing. STRO-004 also induces immunogenic cell death (ICD), activating antigen-presenting cells (APCs) and potentially driving durable anti-tumor immunity. These findings support combination with immunotherapies.
Methods: STRO-004-ST1 is a first-in-human, Phase 1, open-label, multicenter study evaluating the safety, PK, and anti-tumor activity of STRO-004 in adults with refractory or recurrent metastatic solid tumors. The trial includes three parts: Monotherapy Dose Escalation (Part 1A), Monotherapy Cohort Expansion (Part 1B) and Combination Dose Escalation with pembrolizumab (Part 1C). Eligible patients are adults ( > 18 years) with previously treated HNSCC, NSCLC, esophageal, gastric, PDAC, CRC, endometrial, cervical or urothelial cancer who have measurable disease and tissue available for retrospective central testing. STRO-004 is administered intravenously every 3 weeks.
Part 1A endpoints include maximum tolerated dose (MTD), dose-limiting toxicity (DLT), anti-tumor activity and PK; efficacy is the primary endpoint in Part 1B. Approximately 200 patients will be enrolled. The study (NCT07227168) is open and enrolling at time of submission.
利益披露 Disclosure
D. Sommerhalder,
Sutro BioPharma, AbbVie, Actrivon Therapeutics, ADC Therapeutics, Aprea Therapeutics, Ascentage Pharma Group, Astellas, Avenzo Therapeutics, Biomea Fusion, Boehringer Ingleheim, BJ Bioscience ).
BioNTech, Bristol-Myers Squibb, Compugen, Day One Biopharma, Dicerna/Novo Nordisk, Dren Bio Inc, Exelixis, Fate Therapeutics, Gilead Sciences, Glasko SmithKline, Haihe Pharmaceutical, Iconovir Bio ).
Ideaya Biosciences, Imuneering, Impact Therapeutics, Incendia, Kura Oncology, MediLink Therapeutics, Mirati Therapeutics, ModeX Therapeutics, Monopteros Therapeutics, Navire Pharma Inc, ).
Nimbus Therapeutics, NGM Biopharmaceuticals, OBI Pharma, OncoResponse Inc, Pfizer, Revolution Medicines, Step Pharmaceuticals, Symphogen, Tachyon Therapeutics, Teon Therapeutics, Tyligand Bioscience ).
Vincerx Pharma, Vividion Therapeutics, ZielBio Inc, Zymeworks ).
Texas Oncology Employment, Stock.
NEXT Oncology Stock.
Syneos Other, Honoraria.
Guidepoint Other, Consulting fees.
Abbvie, Cartography Biosciences, Revolution Medicines, Nimbus Therapeutics Other, Advisory Board Payments.
J. Reuss,
Sutro BioPharma, Genentech, Roche, Verastem, Nuvalent, Arcus, Revolution Medicines, Regeneron, Amgen, Duality Bio, AstraZeneca ).
AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Seagen, Gilead, Janssen, Novocure, Regeneron, Summit Therapeutics, Pfizer, Lilly, Natera, Merck, EMD Serono, Roche Diagnostics, Boehringer Ingleheim Other, Advisory Board/Consultant.
L. Pappas,
Sutro BioPharma ).
Astellas Pharma, Caris Life Sciences, Kestrel Therapeutics, Merus, Tallac Therapeutics Other, Advisor/Consultant.
Eli Lilly and Company, Moderna Other, Previous equity holder.
Bristol Myers Squibb, Takeda Pharmaceutical Company Other, Speaker.
M. A. Salkeni,
Arcus, AbbVie, Acrivon, Aprea, AstraZeneca, BeOne Beigene, Compugen, Daiichi, Eikon, FirstBio, Ideaya, FoRx, Ionova, Kumquat, MBrace, Stemline, Nested, OncoResponse, Oncoterna, Pheon, Pathos ).
Pasithea, Storm, Exilixis, Kronos, Agenus, Takeda, Merck, Hibercell, Coherus, Genmab, Ipsen, Sutro Biopharma ).
AbbVie, Daiichi, AstraZeneca Other, Advisory Board.
A. Vandross,
AbbVie, Adcentrix, Ascentage Pharma, Asana Bio (Kirilys), BioOneCure, Deiphera, Impact Therapeutics, Nanjing Immunophage Biotech, Chugai Pharamaceutical Company, Gilead, Lyvgen Biopharma, Medikine, ).
Mbrace Therapeutics, Nikang, Nitto Therapeutics, NGMBio, OncoResponse, PMV Pharmaceuticals, Pasithea Pharmaceuticals, Shuhai Yufan Biotechnologies, Iambic Therapeutics, Immunomedics ).
Institute de Recherches Internationales Servier (I.R.I.S), siRNAomics, Tachyon Therapeutics, Teon Therapeutics, Kura, Exilixis, Xilio Development, ZieBio, Vincerex, MBRACE Therapeutics ).
Bolt Therapeutics, Pliant Therapeutics, Vividion Therapeutics, Nested Therapeutics, Zumutor Biologics, Sutro Biopharma ).
Boxer Captital, AbbVie, Nikang, Iambic Therapeutics Other, Consultant.
Pliant Pharmaceuticals Other, Advisory Board.
J. T. Henry,
HCA Stock, Stock Option.
Sarah Cannon Research Institute Employment.
Abbiscko Therapeutics, ABL Bio, Accutar Biotech, ADC Therapeutics, Acepodia, Acrivon, Agenus, ALLink Biotherapeutics, Allucent, Alterome, Amgen, Artios, Astellas, AstraZeneca, Avenzo, Avistone, Bayer ).
Bicycle Therapeutics, BioAlta, Biohaven Pharmaceuticals, BioInvent Pharma, Biomea Fusion, Biosplice Thrapeutics, Black Diamond Therapeutics, Boehringer Ingelheim, Boundless Bio ).
Centessa Pharmaceuticals, Context Therapeutics, Cyteir, CytomX, D3 Bio, Dynamicure Biotechnology, Daiichi Sankyo, Deciphera, Dren Bio, Eikon Therapeutics, Eli Lilly and Company, Epizyme, Erasca ).
Exelixis, FujiFilm, Genentech, Glaxo Smithkline, GV20 Therapeutics, Halda Therapeutics, Harbour Biomed, Hutchison MediPharma, ICON plc, IDEAYA Biosciences, IGM Biosciences, Ikena ).
Immuneering Corporation, Immunitas, Immunogen, Incyte, Ingelheim, InSilico, Inspirna, iTEOS Therapeutics, Jazz Pharmaceuticals, Jacobio Pharmaceuticals, Jounce Pharma, Jubilant Therapeutics, Kineta ).
Kumquat Biosciences, Kura Oncology, Loxo Oncology, Marengo Therapeutics, MediLink Therapeutics, Merck and CO, Metabomed, Mirati, ModeX Therapeutics, Molecular Templates, Nammi Therapeutics ).
Navire Pharma, Nested Therapeutics, Nikang Pharmaceuticals, NGM Bio, Normunity AccelCo Inc, Novartis, Novelwise Pharmaceuticals, Oncorus, OnKure, Pfizer, Phanes, Pierre Fabre Medicamen, Poseida ).
Prelude Therapeutics, PureTech, Pyxis, Pyramid Biosciences, Quanta Therapeutics, Rascal Therapeutics, Regeneron, Rein Therapeutics, Relay Therapeutics, Roche, Ribon Therapeutics, Sapience ).
Sarah Cannon Development Innovations, Sarah Cannon Research Insitute, Seagen, Simcha Therapeutics, Siranomics, Stingthera, Sumitomo Pharma, Sutro Biopharma, Synthorx Inc, Systimmune ).
Tachyon Therapeutics, Tango Therapeutics, Takeda Pharmaceuticals, Tallac Therapeutics, Tarveda, Tesaro, TORL Biotherapeutics, Turning Point Therapeutics, Vista Therapeutics ).
Vironexis Biotherapeutics, Xencor ).
G. Hernandez,
Sutro BioPharma Employment, Stock, Stock Option.
M. Mangeshkar,
Sutro Biopharma Employment.
J. Oliver,
Sutro Biopharma Employment, Stock, Stock Option.
M. R. Patel,
Ion Pharma Other, Leadership.
Daiichi Sankyo, Kura Oncology, Accutar Biotech, Mitsubishi Tanabe Pharma, Shivanka Research, Johnson and Johnson/Janssen Other, Consulting/Advisory Role.
Agenus, Boehringer Ingelheim, Cyteir Therapeutics, Daiichi Sankyo, Genentech/Roche, Janssen, Loxo, Macrogenics, Merck, Moderna Therapteutics, Pfizer, Prelude Therapeutics ).
Seven and Eight Biopharmaceuticals, Syndax, Artios, Novartis, Nurix, TeneoBio, Zymeworks, Olema, Adagene, Astellas, Accutar Biotech, Compugen, Immunogen, Blueprint Pharmaceuticals, Cullinan Oncology ).
Immune-Onc Therapeutics, Immunitas, Ribon Therapeutics, Step Pharma, Bristol Myers Squibb/Celgene, Kineta, Hotspot Therapeutics, Conjupro Biotherapeutics, Allorion Therapeutics, Vividon Therapeutics ).
Georiamune, Kura Oncology, AstraZeneca, Zai Lab, AbbVie, Avenzo, D3 Bio, OnCusp Therapeutics, Apollo, Medlink, BioNTech SE, Abdera Therapeutics, Lilly, Sutro Biopharma, Systimmune, Incyte ).