PO.CTP01.01 · 进行中的临床试验
IPN60300（一种靶向ITGA2的首创ADC）的I/II期FIH研究，评估其在局部晚期实体瘤成人患者中的安全性、耐受性、PK、生物标志物、免疫原性和抗肿瘤活性
Phase I/II FIH study of IPN60300, a first-in-class ADC targeting ITGA2, to assess the safety, tolerability, PK, biomarkers, immunogenicity and antitumor activity in adults with locally advanced solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：整合素α-2（ITGA2）是异二聚体跨膜受体整合素α2/β1的组成部分，在细胞黏附和转导中发挥关键作用。尽管ITGA2在正常组织中表达水平较低，但在包括胰腺癌、胃癌和结直肠癌在内的各种实体瘤中显著过表达，通过细胞外基质信号传导和上皮-间质转化促进肿瘤进展。IPN60300是一种靶向ITGA2的新型抗体-药物偶联物（ADC），旨在将exatecan（一种强效拓扑异构酶I抑制剂）特异性递送至表达ITGA2的癌细胞。IPN60300由人源化Fc突变单克隆抗体组成，通过组织蛋白酶可裂解的连接子位点特异性偶联exatecan，药物-抗体比为8。IPN60300的临床前研究显示，其与ITGA2具有强特异性结合、增强的内化、旁观者活性载荷的细胞内释放、在各种小鼠癌症模型中显著抑制肿瘤生长、良好的药代动力学（PK）特征，以及与其他以exatecan（或其衍生物）为载荷的ADC已知安全性特征一致的可接受安全性特征。
方法：这是一项开放标签、多中心、I/II期首次人体（FIH）、剂量递增、剂量优化和剂量扩展研究，旨在评估IPN60300作为单药的安全性、耐受性、药代动力学（PK）、药效学（PD）、免疫原性和抗肿瘤活性。符合条件的成人参与者应确诊为选定的晚期胃肠道肿瘤（胆道癌、胰腺癌、结直肠癌、胃癌和食管癌），且为复发、难治或进展性疾病且无标准治疗可用。I期将按以下方式进行：
• Ia期（带回填的剂量递增）旨在确定最大耐受剂量和药理活性剂量范围。将采用贝叶斯最优区间设计进行剂量递增。
• Ib期（剂量优化）通过评估目标剂量水平下的安全性和初步抗肿瘤活性来评估最佳给药方案。约102名参与者将在美国、法国和西班牙的I期中接受IPN60300。根据I期结果，将通过方案修订纳入II期剂量扩展研究。Ia期招募正在进行中。
临床试验信息：NCT07213817
查看英文原文 English abstract
Background: Integrin alpha-2 (ITGA2), a component of the heterodimeric transmembrane receptor integrin alpha2/beta1, plays a key role in cell adhesion and transduction. Although ITGA2 is expressed at low levels across normal tissues, it is notably overexpressed in various solid tumors, including pancreatic, gastric and colorectal, where it contributes to tumor progression via extracellular matrix signaling and epithelial-mesenchymal transition. IPN60300, a novel antibody-drug conjugate (ADC) targeting ITGA2, is designed to specifically deliver exatecan, a potent topoisomerase I inhibitor, to ITGA2 expressing cancer cells. IPN60300 consists of a humanized Fc mutated monoclonal antibody site-specifically conjugated to exatecan via a cathepsin-cleavable linker, with a drug-to-antibody ratio of 8. Preclinical studies of IPN60300 showed strong specific binding to ITGA2, enhanced internalization, intracellular release of bystander-active payload, significant tumor growth inhibition across various murine cancer models, a favorable pharmacokinetic (PK) profile, and an acceptable safety profile consistent with the known safety profile of other ADCs that have exatecan (or its derivatives) as payload.
Methods: This is an open label, multicentre, phase I/II first-in-human (FIH), dose escalation, dose optimization, and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and anti-tumor activity of IPN60300 as a single agent. Eligible adult participants should have a confirmed diagnosis of selected advanced gastrointestinal tumors (biliary track cancer, pancreatic cancer, colorectal cancer, gastric cancer and oesophageal cancer) for whom relapsed, refractory or progressive disease and no standard treatment exists. Phase I will be conducted as follows:
• Phase Ia (dose escalation with backfills) is to determine the maximum tolerated dose and the pharmacologically active dose range. A Bayesian Optimal Interval design will be used for dose escalation.
• Phase Ib (dose optimisation) evaluates the optimal dosing regimen by assessing safety and preliminary anti-tumor activity at dose levels of interest.Approximately 102 participants will receive IPN60300 in phase I in the US, France and Spain. Based on results from phase I, a phase II dose expansion study will be included via protocol amendment. Enrolment for Phase Ia is ongoing.
Clinical trial information: NCT07213817
利益披露 Disclosure
M. R. Sharma,
Abbott Laboratories Stock, Other Business Ownership.
Bristol-Myers Squibb Stock Option, Other Business Ownership.
Lilly Stock Option, Other Business Ownership.
Merck Stock Option, Other Business Ownership.
Regeneron Stock Option, Other Business Ownership.
Amgen Stock Option, Other Business Ownership.
Gilead Sciences Stock Option, Other Business Ownership.
Johnson & Johnson / Janssen Stock Option, Other Business Ownership.
Vertex Stock, Other Securities.
Pfizer Stock Option, Other Business Ownership.
J. Zou,
Ipsen Employment.
B. Beaufils,
Ipsen Employment.
A. Courtin,
Ipsen Employment.
S. Colombo,
Ipsen Employment.
L. Domit,
Ipsen Employment.
X. Shi,
Ipsen Employment.
E. Leo,
Ipsen Employment.
S. Pant,
Oncomed LLC, Telperian Stock, Other Business Ownership.
Incyte ).
CG Pharmaceuticals ).
Bristol-Meyrs Squibb ).
Boehringer Ingelheim ).
Janssen ).
Pfizer ).
AstraZeneca ).
Arcus ).
Elicio ).
ImmunoMET ).
Amal Therapeutics ).
Jazz Therapeutics ).
Revolution Medicine ).
Immuneering ).