Tsimberidou Apostolia M, Vining David J, Arora Sukeshi P, de Achaval Sofia, Larson Jeffrey, Kauh John, Cartwright Carrie, Avritscher Rony, Alibhai Imran, Tweardy David J, Kaseb Ahmed O
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2025 Mar 17;31(6):965-974. doi: 10.1158/1078-0432.CCR-24-2920.
Signal transducer and activator of transcription 3 is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase I study of TTI-101, a first-in-class, selective small-molecule inhibitor of signal transducer and activator of transcription 3, in patients with advanced metastatic cancer.
Patients were treated with TTI-101 orally twice daily in 28-day cycles at four dose levels (DL): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day ("3+3" design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699).
Sixty-four patients were treated (median age, 63 years; male sex, 52%; median number of prior therapies, 3). No dose-limiting toxicities or fatal treatment-related adverse events (TRAE) were observed. Diarrhea (mostly grade 1/2) was the only TRAE observed in ≥30% of subjects. Five patients experienced grade 3 TRAEs that resolved. TTI-101 showed linear pharmacokinetics from DL1 to DL3, with the pharmacokinetics plateauing at DL3. The recommended phase II dose is 12.8 mg/kg/day (DL3). Of the 41 patients who were evaluable for response, five (12%) had confirmed partial responses (cPR) and 17 (41%) had stable disease. Three (18%) of the 17 patients with hepatocellular carcinoma had a cPR (median time to treatment failure, 10.6 months). Two other cPRs were noted in one patient with ovarian cancer and one patient with gastric cancer.
TTI-101 was well tolerated. cPRs were observed across tumor types. The antitumor activity of TTI-101 monotherapy in patients with advanced, metastatic solid tumors is promising. A phase II study of TTI-101 in hepatocellular carcinoma is currently underway.
信号转导与转录激活因子3是一种转录因子，对癌细胞的存活和免疫隔离至关重要。我们开展了一项针对TTI-101的I期研究，TTI-101是首个用于治疗晚期转移性癌症患者的、一流的信号转导与转录激活因子3选择性小分子抑制剂。
患者接受TTI-101口服治疗，每日两次，每28天为一个周期，共四个剂量水平（DL）：3.2（DL1）、6.4（DL2）、12.8（DL3）和25.6（DL4）mg/kg/天（“3+3”设计）。逐步使用三种TTI-101制剂（NCT03195699）。
64例患者接受了治疗（中位年龄63岁；男性占52%；既往治疗的中位次数为3次）。未观察到剂量限制毒性或致命的治疗相关不良事件（TRAE）。腹泻（大多为1/2级）是在≥30%的受试者中观察到的唯一TRAE。5例患者出现3级TRAE，但均已缓解。TTI-101在DL1至DL3呈现线性药代动力学，在DL3达到药代动力学平台期。推荐的II期剂量为12.8 mg/kg/天（DL3）。在41例可评估疗效的患者中，5例（12%）获得确认的部分缓解（cPR），17例（41%）病情稳定。17例肝细胞癌患者中有3例（18%）获得cPR（至治疗失败的中位时间为10.6个月）。在1例卵巢癌患者和1例胃癌患者中还观察到另外2例cPR。
TTI-101耐受性良好。在多种肿瘤类型中均观察到cPR。TTI-101单药治疗晚期转移性实体瘤患者的抗肿瘤活性前景良好。目前正在开展TTI-101治疗肝细胞癌的II期研究。
