PO.CTP01.01 · 进行中的临床试验
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
摘要 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 ).