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

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.

• Authors: Stuart A Grossman, Xiaobu Ye, David Peereboom, Myrna R Rosenfeld, Tom Mikkelsen, Jeffrey G Supko, Serena Desideri, Adult Brain Tumor Consortium
• Journal: Neuro-oncology (Neuro Oncol) Vol. 14 Issue 4 Pg. 511-7 (Apr 2012) ISSN: 1523-5866 [Electronic] England
• PMID: 22323663 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)

Chemical References

• Anticonvulsants
• Antineoplastic Agents
• terameprocol
• Masoprocol

Topics

• Adult
• Aged
• Anticonvulsants (administration & dosage, pharmacology)
• Antineoplastic Agents (pharmacokinetics, therapeutic use, toxicity)
• Brain Neoplasms (drug therapy)
• Disease Progression
• Dose-Response Relationship, Drug
• Female
• Glioma (drug therapy)
• Humans
• Male
• Masoprocol (analogs & derivatives, pharmacokinetics, therapeutic use, toxicity)
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy)
• Treatment Outcome