PO.CTP01.02 · 进行中的临床试验
CAN016：一种HER2靶向双载荷ADC的I期临床开发
CAN016, a HER2-targeted dual-payload ADC, phase 1 clinical development
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
HER2扩增、突变和过表达已在多种类型的癌症中被报道。基于这些发现，靶向单克隆抗体（如Herceptin）和ADC（如Enhertu）已获批，拓展了癌症治疗的格局。然而，对此类靶向疗法（尤其是对Enhertu）的耐药性仍是一项关键的临床挑战。CAN016是通过CanWell专有的StarLinker™技术，将两种不同作用机制（MOA）的载荷——Exatecan和MMAE——偶联而成的首个HER2靶向ADC。这一双载荷策略的特点在于增强抗肿瘤效力、克服肿瘤异质性并逆转耐药。在临床前研究中，CAN016在体外表现出与trastuzumab相似的结合和内化特征，并在体内展现出稳健的剂量依赖性抗肿瘤活性。在HER2高表达、HER2低表达乃至Enhertu耐药的CDX和PDX模型中，这些效果均优于Enhertu。与各自相应的单载荷HER2 ADC相比，CAN016在单药或联合（同步/序贯给药方案）中均显示出高于类似ADC的疗效。DMPK和GLP非人灵长类（NHP）研究证实其具有良好的PK和安全性特征，HNSTD为20 mg/kg。研究人群：符合条件的患者年龄≥18岁，患者须为HER2靶向ADC治疗失败者；预期寿命≥3个月，ECOG体能评分为0或1；依据RECIST 1.1版具有可测量病灶。临床试验设计：本I/II期首次人体（FIH）研究由两部分组成。剂量递增阶段以0.75mg/kg为起始剂量，采用加速滴定法。若观察到≥2级不良事件（AE），则切换至3+3设计以进一步评估MTD和/或RP2D。一旦确定MTD/RP2D，将进一步招募患者以评估CAN016在不同晚期实体瘤（包括乳腺癌、NSCLC、胃癌等）中的初步疗效。I期的主要终点是评估CAN016的安全性和耐受性并确定MTD/RP2D；II期是评估初步临床疗效。结论：CAN016在临床前研究中代表了一种针对HER2阳性/突变实体瘤的有前景的治疗药物，尤其是在ADC治疗后的情境中。IND申请已提交至美国FDA和中国CDE。
查看英文原文 English abstract
HER2 amplification, mutation and overexpression have been reported in various types of cancers. Based on those findings, targeted monoclonal antibodies (such as Herceptin) and ADC (such as Enhertu) have been approved, expending the landscape of cancer therapy. However, resistance to such targeted therapies, especially to Enhertu, remains a critical clinical challenge. CAN016 is developed as the first HER2 targeting ADC coupling with two distinct MOA payloads-Exatecan and MMAE, via CanWell's proprietary StarLinker™ technology. This dual-payload strategy features in enhancing antitumoral potency, overcoming tumor heterogenicity, and reversing the resistance. Preclinically, CAN016 exhibited similar binding and internalization profiles as trastuzumab in vitro and demonstrated robust dose-dependent anti-tumor activities in vivo. These effects were superior over Enhertu in HER2-high, HER2-low and even Enhertu-resistant CDX and PDX models. Compared to each of respective single-payload HER2ADCs, CAN016 showed greater efficacies than analog ADCs in monotherapy or in combination (concurrent/sequential schedules). DMPK and GLP NHP studies confirmed a favorable PK and safety profile with the HNSTD of 20 mg/kg. Study population: Eligible patients ≥ 18 years old, patients must have failed to HER2-targeted ADC;life expectancy ≥ 3 months with ECOG performance score 0 or 1; measurable lesion as per RECIST version 1.1. Clinical trail design: his phase I/II FIH study consists of two parts. Dose escalation, with a starting dose of 0.75mg/kg by accelerated titration. If ≥ grade 2 AEs were observed then switch to the 3+3 design for further assessing the MTD and/or RP2D. Once the MTD/RP2D was determined, further patients will be recruited to evaluate the preliminary efficacy of CAN016 in different advanced solid tumors including breast cancer, NSCLC, gastric cancer etc. The primary endpoint for phase I is to assess the safety and tolerability of CAN016 and determine the MTD/RP2D; for phase II is to evaluate the preliminary clinical efficacy. Conclusion: CAN016 represents a promising therapeutic for HER2-positive/mutant solid tumors in preclinical study, particularly in the post-ADC setting. IND applications have been submitted to the US FDA and China CDE.
利益披露 Disclosure
X. G, None..
F. Tan, None..
G. Massimini, None..
Y. Fan, None..
S. Wang, None..
W. Geng, None..
S. Wang, None..
Y. Yang, None..
P. Xu, None..
X. Chen, None..
Y. Luo, None..
J. Huang, None..
H. N. Yu, None..
B. Xu, None.