PDF(Pubmed)
Abstract：
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).
摘要：
复发性高级别胶质瘤（rHGs）预后不佳，其中IVterameprocol的最大耐受剂量（MTD）（5天/月），特异性蛋白1（Sp1）调节蛋白的转录抑制剂，为1,700mg/天，血浆浓度-时间曲线下的中位面积（AUC）为31.3μg*h/mL。鉴于持续的全身暴露和每日静脉治疗的挑战性后勤可能会增加疗效，在这里，我们研究多中心口服terameprocol治疗rHGs，第一阶段试验（GATOR）。使用3+3剂量递增设计，我们招募了20名患者，中位年龄60岁（范围31-80岁），70%男性,和中位数1次复发（范围1-3）。空腹患者耐受1,200毫克/天（n=3），2,400毫克/天（n=6），3,600毫克/天（n=3），和6,000毫克/天（n=2）口服剂量，无主要毒性。然而,增加剂量不会导致全身暴露增加，包括在美联储州(6,000毫克/天，n=4),最大AUC<5μg*h/mL。这些发现保证了研究提供持续全身水平的转录抑制剂以利用其治疗潜力的方法的试验。本研究在ClinicalTrials.gov（NCT02575794）注册。
