PO.CTP01.01 · 进行中的临床试验

一项靶向CDH17的ADC（DB-1324）治疗晚期/转移性胃肠道肿瘤参与者的1/2期首次人体研究

A phase 1/2, first-in-human study of an ADC targeting CDH17 (DB-1324) in participants with advanced/metastatic gastrointestinal tumor

编号 CT086 展板 17 时间 4/20 09:00–12:00 区域 Section 51 主讲 Joe Wei, MBBS, FRACP, PhD

分会场 Phase I Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Lin Shen¹, Jifang Gong¹, Jermaine Coward², Rajiv Shinde³, Joe Wei⁴, Yanhong Deng⁵, Yanqiao Zhang⁶, Ming Lu⁷, Meili Sun⁸, Sreenivasa Chandana⁹, Davendra Sohal¹⁰, Ting Zhang¹¹, Hua Mu¹¹, Yuran Liang¹¹, Haiqing Hua¹¹, Xiaodong Sun¹¹, Yang Qiu¹¹, Jiajia Chen¹¹, Zhongyuan Zhu¹¹

¹Beijing Cancer Hospital, Beijing, China,²Icon Cancer Centre, South Brisbane, Australia,³Linear Clinical Research, Nedlands, Australia,⁴Scientia Clinical Research, Randwick, Australia,⁵The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China,⁶Harbin Medical University Cancer Hospital, Harbin, China,⁷Beijing GoBroad Hospital, Beijing, China,⁸Jinan Central Hospital, Jinan, China,⁹START Midwest, LLC, Grand Rapids, MI,¹⁰University of Cincinnati Medical Center, Cincinnati, OH,¹¹Duality Biologics, Shanghai, China

摘要 Abstract

中文摘要

背景：钙黏蛋白-17（CDH17）属于7D-钙黏蛋白超家族的一个亚类，是胃肠道（GI）癌症的生物标志物，其特征为在多种GI癌症中过表达但在健康成人正常组织中表达受控。因此，CDH17被认为是GI癌症的一个可能治疗靶点。DB-1324是一种抗CDH17抗体-药物偶联物（ADC），其中人源化抗体通过可裂解的四肽连接子与专有的拓扑异构酶I抑制剂载荷相连，药物-抗体比约为8。DB-1324的临床前研究显示，DB-1324特异性结合CDH17细胞外结构域，不与其他钙黏蛋白家族蛋白结合。它在人CDH17阳性小鼠癌症模型中显示出抗肿瘤活性和可接受的安全性特征，支持进一步的临床开发。方法：这是一项全球性、首次人体、1/2期研究，旨在评估DB-1324在晚期/不可切除或转移性GI肿瘤参与者中的安全性、耐受性、药代动力学和抗肿瘤活性（NCT07263594）。符合条件的参与者必须患有GI肿瘤（无论CDH17或其他生物标志物表达水平），且在标准全身治疗期间或之后复发或进展，或对标准治疗不耐受，或无标准治疗可用；东部肿瘤协作组体能状态（ECOG PS）≤1；并有充分器官功能的证据。将评估DB-1324的多个剂量水平，以在1期中确定最大耐受剂量，其中包括剂量递增、回填和剂量扩展。2期将由一个或多个队列组成，旨在确认1期中发现的早期疗效信号。DB-1324将作为单药静脉给药，直至疾病进展、临床获益丧失、不可接受的毒性、撤回同意或失访。该研究计划在包括但不限于澳大利亚、美国和中国在内的地点招募约127名参与者进入1期剂量递增和回填部分。该研究目前在多个中心开放并正在招募。

查看英文原文 English abstract

Background: Cadherin-17 (CDH17), belonging to a subclass of the 7D-cadherin superfamily, is a biomarker for gastrointestinal (GI) cancers characterized by its overexpression in multiple GI cancers but controlled expression in normal tissues from healthy adults. CDH17 is therefore considered a possible therapeutic target for GI cancers. DB-1324 is an anti-CDH17 antibody-drug conjugate (ADC) in which a humanized antibody is linked to a proprietary topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker, with a drug-antibody ratio of approximately 8. Preclinical studies of DB-1324 showed that DB-1324 specifically binds to the CDH17 extracellular domains, with no binding to other cadherin family proteins. It demonstrated antitumor activity in human CDH17-positive murine cancer models and an acceptable safety profile, warranting further clinical development. Methods: This is a global, first-in-human, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of DB-1324 in participants with advanced/unresectable, or metastatic GI tumors (NCT07263594). Eligible participants must have a GI tumor (regardless of CDH17 or other biomarker expression levels) that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment, or for which no standard treatment is available; have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1; and evidence adequate organ function. Multiple dose levels of DB-1324 will be evaluated to identify the maximum tolerated dose in Phase 1, which includes Dose Escalation, Backfill, and Dose Expansion. Phase 2 will consist of one or more cohorts intended to confirm early signals of efficacy identified in Phase 1. DB-1324 will be administered intravenously as monotherapy until disease progression, loss of clinical benefit, unacceptable toxicity, withdrawal of consent, or loss to follow up. The study plans to enroll approximately 127 participants in Phase 1 Dose Escalation and Backfill parts from locations including but not limited to Australia, United States and China. The study is currently open in multiple centers and is currently recruiting.

利益披露 Disclosure

L. Shen, None.. J. Gong, None.. J. Coward, None.. R. Shinde, None.. J. Wei, None.. Y. Deng, None.. Y. Zhang, None.. M. Lu, None.. M. Sun, None.. S. Chandana, None. D. Sohal, Ability Pharma; Amgen; Astellas; Astra Zeneca; Bexion; Bristol-Myers Squibb; Carisma; Genentech; Hengrui; Lilly; Medilink; Merck; Mirati; NextCure; Pfizer; Regeneron; Revolution Medicines; Roche. ). Takeda; Tempus; Tizona; Totus; Triumvira. ). Replimune; Elevar; Regeneron; Revolution Medicines; Ability Pharma Other, Consulting/Honoraria.. Astra Zeneca Other, Consulting/Honoraria; Speakers Bureau.. Incyte Other, Speakers Bureau. T. Zhang, Duality Biologics Employment. H. Mu, Duality Biologics Employment, Stock. Y. Liang, Duality Biologics Employment. H. Hua, Duality Biologics Employment, Stock. X. Sun, Duality Biologics Employment, Stock. Y. Qiu, Duality Biologics Employment, Stock. J. Chen, Duality Biologics Employment, Stock. Z. Zhu, Duality Biologics g., Board of Directors, non-salaried role), Stock.

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