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
Publication Date
7-16-2024
Content Type
Article
PubMed ID:
Citation
Ahluwalia, M. S., Ozair, A., Rudek, M., Ye, X., Holdhoff, M., Lieberman, F. S., Piotrowski, A. F., Nabors, B., Desai, A., Lesser, G., Huang, R. C., Glenn, S., Khosla, A. A., Peereboom, D. M., Wen, P. Y., & Grossman, S. A. (2024). A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR). Cell reports. Medicine, 5(7), 101630. https://doi.org/10.1016/j.xcrm.2024.101630
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