Mahalingam Devalingam, Harb Wael, Patnaik Amita, Bullock Andrea, Watnick Randolph S, Vincent Melanie Y, Chen Jian Jenny, Wang Suming, Pestana Harold, Chao Judy, Mahoney James, Cieslewicz Michael, Watnick Jing
Northwestern University Medical School, Chicago, IL, USA.
Horizon Oncology Center, Lafayette, IN, USA.
Commun Med (Lond). 2024 Jan 13;4(1):10. doi: 10.1038/s43856-024-00433-x.
VT1021 is a cyclic peptide that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). TSP-1 reprograms the TME via binding to CD36 and CD47 to induce tumor and endothelial cell apoptosis as well as immune modulation in the TME.
Study VT1021-01 (ClinicalTrials.gov ID NCT03364400) used a modified 3 + 3 design. The primary objective was to determine the recommended Phase 2 dose (RP2D) in patients with advanced solid tumors. Safety, tolerability, and pharmacokinetics (PK) were assessed. Patients were dosed twice weekly intravenously in 9 cohorts (0.5-15.6 mg/kg). Safety was evaluated using CTCAE version 5.0 and the anti-tumor activity was evaluated by RECIST version 1.1.
The RP2D of VT1021 is established at 11.8 mg/kg. VT1021 is well tolerated with no dose-limiting toxicities reported (0/38). The most frequent drug-related adverse events are fatigue (15.8%), nausea (10.5%), and infusion-related reactions (10.5%). Exposure increases proportionally from 0.5 to 8.8 mg/kg. The disease control rate (DCR) is 42.9% with 12 of 28 patients deriving clinical benefit including a partial response (PR) in one thymoma patient (504 days).
VT1021 is safe and well-tolerated across all doses tested. RP2D has been selected for future clinical studies. PR and SD with tumor shrinkage are observed in multiple patients underscoring the single-agent potential of VT1021. Expansion studies in GBM, pancreatic cancer and other solid tumors at the RP2D have been completed and results will be communicated in a separate report.
VT1021是一种环肽，可诱导募集至肿瘤微环境（TME）的髓源性抑制细胞（MDSC）中血小板反应蛋白-1（TSP-1）的表达。TSP-1通过与CD36和CD47结合来重新编程TME，从而诱导肿瘤细胞和内皮细胞凋亡以及TME中的免疫调节。
VT1021-01研究（ClinicalTrials.gov标识符NCT03364400）采用改良的3+3设计。主要目的是确定晚期实体瘤患者的推荐2期剂量（RP2D）。评估了安全性、耐受性和药代动力学（PK）。患者每周静脉注射两次，共9个队列（0.5-15.6mg/kg）。使用CTCAE 5.0版评估安全性，使用RECIST 1.1版评估抗肿瘤活性。
VT1021的RP2D确定为11.8mg/kg。VT1021耐受性良好，未报告剂量限制性毒性（0/38）。最常见的药物相关不良事件是疲劳（15.8%）、恶心（10.5%）和输液相关反应（10.5%）。暴露量从0.5mg/kg到8.8mg/kg成比例增加。疾病控制率（DCR）为42.9%，28例患者中有12例获得临床益处，包括1例胸腺瘤患者出现部分缓解（PR，持续504天）。
在所有测试剂量下，VT1021均安全且耐受性良好。已选择RP2D用于未来的临床研究。在多名患者中观察到PR和肿瘤缩小的疾病稳定（SD），突出了VT1021的单药潜力。已完成在RP2D剂量下针对胶质母细胞瘤、胰腺癌和其他实体瘤的扩展研究，结果将在单独报告中公布。
