Phase i study of terameprocol in patients with recurrent high-grade glioma

Stuart A. Grossman, Xiaobu Ye, David Peereboom, Myrna R. Rosenfeld, Tom Mikkelsen, Jeffrey G. Supko, Serena Desideri

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Abstract

Terameprocol is a global transcription inhibitor that affects cell division apoptosis, drug resistance, hypoxia responsive genes, and radiation resistance in hypoxia. A multicenter, dose-escalation study was conducted in heavily pretreated patients with recurrent, measurable, high-grade gliomas. Terameprocol was administered intravenously for 5 consecutive days each month and discontinued for toxicity or progression. Patients taking enzyme-inducing antiseizure drugs (EIASDs) were escalated independently. Thirty-five patients with a median Karnofsky performance status of 80, median age of 46 years, and median of 2 prior treatment regimens were accrued. Doses of 750, 1100, 1700, and 2200 mg/day were administered. Terameprocol was reformulated to avoid acidosis related to the excipient and was well tolerated at 1700 mg/day. Hypoxia and interstitial nephritis were noted at 2200 mg/day. Concurrent administration of EIASD did not significantly affect the serum pharmacokinetics of the terameprocol. Although no responses were seen, stable disease was noted in 9 (28) of 32 evaluable patients, with 5 (13) continuing treatment for >6 months (<6, 8, 10, 10, and <21 months). The overall median survival was 5.9 months. This phase I study defined the toxicity of terameprocol, determined that EIASDs do not affect its pharmacokinetics, and identified 1700 mg/day as the dose for future studies. Preclinical and human data suggest that this novel transcription inhibitor is worthy of further study. The long-term stability noted in some patients and the lack of associated myelosuppression suggest that terameprocol could be safely combined with radiation and temozolomide in newly diagnosed high-grade gliomas.

Original languageEnglish (US)
Pages (from-to)511-517
Number of pages7
JournalNeuro-oncology
Volume14
Issue number4
DOIs
StatePublished - Apr 1 2012

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Keywords

  • glioblastoma
  • high grade glioma
  • phase I trial
  • terameprocol
  • transcription inhibitor

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Grossman, S. A., Ye, X., Peereboom, D., Rosenfeld, M. R., Mikkelsen, T., Supko, J. G., & Desideri, S. (2012). Phase i study of terameprocol in patients with recurrent high-grade glioma. Neuro-oncology, 14(4), 511-517. https://doi.org/10.1093/neuonc/nor230