PO.CTP01.01 · 进行中的临床试验
一项靶向ADAM9的ADC（DB-1317）用于特定晚期或转移性实体瘤受试者的1a/1b期首次人体研究
A Phase 1a/1b, first-in-human study of an ADC targeting ADAM9 (DB-1317) in participants with selected advanced or metastatic solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：解整合素金属蛋白酶9（ADAM9）在多种癌症类型中高表达，其表达水平与抑制性肿瘤微环境、转移和不良预后相关，使其成为一个有前景的治疗靶点。DB-1317是一种抗体药物偶联物（ADC），由抗ADAM9抗体经可裂解四肽连接子与拓扑异构酶I抑制剂连接而成，药物抗体比约为8。临床前研究表明，DB-1317可诱导ADAM9依赖性细胞毒性，兼具旁观者杀伤效应和抗体依赖性细胞毒性。此外，DB-1317在食蟹猴中给药剂量高达80 mg/kg仍具有良好耐受性。这些发现支持DB-1317的临床开发（Shengchao Lin，AACR 2025）。
方法：这项首次人体1a/1b期研究（NCT07141706）旨在评估DB-1317在特定不可切除晚期/转移性实体瘤受试者中的安全性、耐受性、药代动力学和初步抗肿瘤活性，且不强制要求最低ADAM9表达水平。研究计划从美国、澳大利亚和中国招募约223名受试者（1a期最多63名，1b期约160名）。在1a期（剂量递增部分），将招募在特定晚期/不可切除或转移性实体瘤标准治疗中进展或不耐受的受试者，以确定DB-1317的最大耐受剂量或最大给药剂量。特定实体瘤包括胃癌（GC）、结直肠癌（CRC）、胰腺导管腺癌（PDAC）、胆管癌、非小细胞肺癌和去势抵抗性前列腺癌。将通过静脉输注给予约五个递增剂量水平的DB-1317（第一个剂量水平采用加速滴定设计，后续剂量水平采用BOIN设计）。将评估剂量限制性毒性（DLT）。当某一剂量水平经安全监查委员会（SMC）确认安全后，可招募回填受试者以进一步评估DB-1317。若在1a期观察到这些肿瘤类型的初步抗肿瘤活性，1b期（剂量扩展部分）将包括一个GC随机扩展队列以及两个CRC和PDAC单臂扩展队列。1b期使用的剂量水平将由申办方和SMC根据1a期数据确定。截至2025年12月24日，已在澳大利亚和美国招募了7名受试者。
查看英文原文 English abstract
Background: A disintegrin and a metalloprotease 9 (ADAM9) is highly expressed in several cancer types and its expression level correlates with a suppressive tumor microenvironment, metastasis, and poor prognosis, making it a promising therapeutic target. DB-1317 is an antibody-drug conjugate (ADC) comprised of an anti-ADAM9 antibody linked to a topoisomerase I inhibitor via a cleavable tetrapeptide linker, with a drug-to-antibody ratio of approximately 8. Preclinical studies demonstrated that DB-1317 induced ADAM9-dependent cytotoxicity, exhibited both by-stander killing effect and antibody-dependent cellular cytotoxicity. In addition, DB-1317 is well-tolerated at a dose of up to 80 mg/kg in cynomolgus monkeys. These findings warrant clinical development of DB-1317 (Shengchao Lin, AACR 2025).
Methods: The first-in-human phase 1a/1b study (NCT07141706) aims to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activities of DB-1317 in participants with selected unresectable advanced/metastatic solid tumors, without mandatory requirement for a minimum ADAM9 expression level. The study is planned to enroll approximately 223 participants from the United States, Australia, and China (up to 63 in phase 1a and approximately 160 in phase 1b).In phase 1a (dose escalation part), participants who have progressed on/after or are intolerant to standard treatments for advanced/unresectable or metastatic selected solid tumors will be enrolled to identify the maximum tolerated dose or maximum administered dose of DB-1317. Selected solid tumors include gastric cancer (GC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, non-small cell lung cancer, and castrate-resistant prostate cancer. Approximately five ascending dose levels of DB-1317 (accelerated titration design for the first dose level and a BOIN design for subsequent dose levels) will be administered by intravenous infusion. The dose-limiting toxicities (DLT) will be assessed. When a dose level is confirmed to be safe by the Safety Monitoring Committee (SMC), backfill participants may be enrolled to further evaluate DB-1317. Phase 1b (dose expansion part) will include one randomized expansion cohort in GC and two single-arm expansion cohorts in CRC and PDAC, if preliminary anti-tumor activities in these tumor types are observed in phase 1a part. Dose levels used in phase 1b part will be determined by sponsor and SMC based on phase 1a data. As of Dec 24, 2025, 7 participants have been enrolled in Australia and the United States.
利益披露 Disclosure
C. Lemech, None..
A. Spira, None.
D. Sommerhalder,
IQVIA Stock Option.
Texas Oncology Employment.
Guidepoint; Nimbus Therapeutics; Revolution Medicines; Abbvie; Cartography Bio Independent Contractor.
Abbvie; Acrivon Therapeutics; ADC therapeutics; Alentis Therapeutics; Aprea Therapeutics; Ascentage Pharma; Astellas; AstraZeneca; Avenzo Therapeutics; Axion Bio Inc; Biomea Fusion; BioNTech ).
BJ Bioscience; Boehringer Ingelheim; Bristol Myers Squibb; Compugen; Day One Biopharmaceuticals; Dewpoint Therapeutics Inc; Dicerna Pharmaceuticals/Novo Nordisk; Exelixis; Fate Therapeutics ).
Gilead Sciences; GSK; Haihe Pharmaceutical; IconOvir Bio; Ideaya Biosciences; Immuneering; IMPACT Therapeutics; Incendia Therapeutics; Ipsen; Kura Oncology; Medlink Therapeutics ).
Mirati Therapeutics/Bristol Myers Squibb; ModeX Therapeutics; Monopteros Therapeutics; Navire Pharma;NGM Bio; Nimbus Therapeutics; Normunity Inc; OncoResponse; OBI Pharma ).
ProteinQure; Pfizer;ProteinQure;Revolution Medicines;Step Pharma;Sutro Biopharma ).
Symphogen; Systimmune; Tachyon Therapeutics; Teon Therapeutics; ).
Tyligand Bioscience;VelaVigo Pharma Co;Vincerx Pharma; Vividion Therapeutics ).
ZielBio;Zymeworks ).
S. Fu,
Abbisko; Antengene; BeiGene; BeyongSpring Pharmaceuticals, Inc.; LLC.; Biotheus Inc; Boehringer Ingelheim; Coherent Biopharma, LLC; Crossignal Therapeutics, Inc.; CUE Biopharma, Inc. ).
DEKA Biosciences; Eli Lilly & Co.; Exelixis; Fore Biotherapeutics; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics, Co., Ltd.; Jazz Pharmaceuticlals; K-Group Beta; ).
Lantern Pharma Inc.; Lyvgen Biopharm, Co., Ltd.; MacroGenics; MediLink Therapeutics, Co. Ltd.; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc. ).
NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Nykode Therapeutics AS.; Parexel International, LLC; PharmaMar USA, Inc.; Pionyr Immunotherapeutics, Inc.; ).
PureTech Health, LLC; Qurgen, Inc.; Shanghai Huaota Biopharmaceutical Co., Ltd.; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon ).
Taiho Oncology and NCCN; Tigermed Group, LLC; TransCode Therapeutics, Inc.; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; Virogin Biotech, Ltd. ).
Cancer Prevention Research Institute of Texas (CPRIT) Precision Oncology Decision Support Core (RP150535); Clinical and Translational Science Award Grant (CTSA) 1UM1TR0045906. ).
F. Ge,
Duality Biologics Employment.
H. Mu,
Duality Biologics Employment, Stock.
Y. Yang,
Duality Biologics Employment.
Y. Qiu,
Duality Biologics Employment, Stock.
J. Chen,
Duality Biologics Employment, Stock.
R. Shi,
Duality Biologics Employment, Stock.
Z. Zhu,
Duality Biologics g., Board of Directors, non-salaried role), Stock.
R. Xu, None.