Abstract
Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700mg/day with median area under the plasma concentration-time curve (AUC) of 31.3μg∗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 1,200mg/day (n= 3), 2,400mg/day (n= 6), 3,600mg/day (n= 3), and 6,000mg/day (n= 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000mg/day, n= 4), with maximal AUC <5μg∗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).
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