Ahluwalia Manmeet S, Ozair Ahmad, Rudek Michelle, Ye Xiaobu, Holdhoff Matthias, Lieberman Frank S, Piotrowski Anna F, Nabors Burt, Desai Arati, Lesser Glenn, Huang Ru Chih, Glenn Steve, Khosla Atulya A, Peereboom David M, Wen Patrick Y, Grossman Stuart A
Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA; Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Cell Rep Med. 2024 Jul 16;5(7):101630. doi: 10.1016/j.xcrm.2024.101630. Epub 2024 Jul 1.
Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).
复发性高级别胶质瘤（rHGGs）的预后很差，特异性蛋白1（Sp1）调控蛋白的转录抑制剂静脉注射特拉美普科（每月5天）的最大耐受剂量（MTD）为1700毫克/天，血浆浓度-时间曲线下面积（AUC）中位数为31.3μg∗h/mL。鉴于持续全身暴露可能提高疗效以及每日静脉治疗的后勤保障具有挑战性，我们在此开展一项多中心1期试验（GATOR），研究口服特拉美普科用于rHGGs的情况。采用3+3剂量递增设计，我们招募了20名患者，年龄中位数为60岁（范围31-80岁），男性占70%，复发中位数为1次（范围1-3次）。空腹患者耐受1200毫克/天（n = 3）、2400毫克/天（n = 6）、3600毫克/天（n = 3）和6000毫克/天（n = 2）的口服剂量，且无重大毒性。然而，剂量增加并未导致全身暴露增加，包括在进食状态下（6000毫克/天，n = 4），最大AUC<5μg∗h/mL。这些发现促使开展试验，研究能提供持续全身水平转录抑制剂以发挥其治疗潜力的方法。本研究已在ClinicalTrials.gov注册（NCT02575794）。
