Ko Andrew H, Coveler Andrew L, Schlechter Benjamin L, Bekaii-Saab Tanios, Wolpin Brian M, Clark Jeffrey W, Bockorny Bruno, Bai Li-Yuan, Lin Yu-Chin, Chiang Evelyn, Langecker Peter, Lin Shih-Yao
Division of Hematology/Oncology, University of California San Francisco, 1825 4th Street, San Francisco, CA, 941158, USA.
Division of Hematology/Oncology, University of Washington Medical Center, Seattle, WA, USA.
Invest New Drugs. 2024 Apr;42(2):221-228. doi: 10.1007/s10637-024-01430-6. Epub 2024 Mar 5.
AbGn-107 is an antibody-drug conjugate directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in a variety of gastrointestinal (GI) malignancies. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a GI cancer-specific Phase I trial. Standard 3 + 3 dose escalation was used evaluating intravenous doses ranging from 0.1 mg/kg every 4 weeks to 1.0 mg/kg every 2 weeks. Key eligibility included chemo-refractory locally advanced, recurrent, or metastatic gastric, colorectal, pancreatic, or biliary cancer, with ECOG PS 0-1; positive AG-7 expression was not required during dose escalation phase. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments every 8 weeks. Primary objectives included safety and determination of maximum tolerated dose; secondary objectives included efficacy defined by objective response rate. Thirty-nine patients were enrolled across seven dose levels during dose escalation phase. Based on safety profile and pharmacokinetic data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase, in which an additional seven patients were enrolled. Median number of lines of prior therapy was 3 (range 1-7). AbGn-107 was generally well-tolerated, with infections, cytopenias, hyponatremia, fatigue, abdominal pain, and diarrhea representing the most common grade 3 or higher treatment-emergent adverse events. One subject achieved a partial response, while 18 (46.2%) achieved a best response of stable disease. Disease control lasting > 6 months was observed in 6 subjects (13.0%), including 4 of 15 (26.7%) treated at the highest dose level. AbGn-107 showed a reasonable safety profile and modest clinical activity in this highly pretreated patient population. Further evaluation is required to assess the clinical validity of AG-7 as a suitable antigen for therapeutic targeting. Clinical Trial information: NCT02908451.
AbGn-107是一种抗体药物偶联物，靶向AG-7抗原，这是一种在多种胃肠道（GI）恶性肿瘤中表达的类Lewis A糖表位。基于AbGn-107在体外和体内临床前研究中显示出的有前景的抗肿瘤活性，我们开展了一项针对胃肠道癌症的I期试验。采用标准的3+3剂量递增法，评估静脉给药剂量范围为每4周0.1mg/kg至每2周1.0mg/kg。关键入选标准包括化疗难治性局部晚期、复发或转移性胃癌、结直肠癌、胰腺癌或胆管癌，东部肿瘤协作组（ECOG）体能状态评分为0-1；剂量递增阶段不要求AG-7表达阳性。患者接受治疗直至疾病进展或出现不可接受的毒性反应，每8周进行一次肿瘤评估。主要目标包括安全性评估和最大耐受剂量的确定；次要目标包括以客观缓解率定义的疗效评估。在剂量递增阶段，共有39名患者入组了7个剂量水平。基于安全性概况和药代动力学数据，选择每2周1.0mg/kg作为队列扩展阶段的给药方案，该阶段又有7名患者入组。既往治疗线数的中位数为3（范围1-7）。AbGn-107总体耐受性良好，感染、血细胞减少、低钠血症、疲劳、腹痛和腹泻是最常见的3级或更高等级的治疗中出现的不良事件。1名受试者达到部分缓解，18名（46.2%）受试者达到疾病稳定的最佳缓解。6名受试者（13.0%）观察到疾病控制持续超过6个月，包括在最高剂量水平治疗的15名受试者中的4名（26.7%）。在这个经过高度预处理的患者群体中，AbGn-107显示出合理的安全性概况和适度的临床活性。需要进一步评估以确定AG-7作为治疗靶点的合适抗原的临床有效性。临床试验信息：NCT02908451。
