Phase I study of terameprocol in patients with recurrent high-grade glioma.
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.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA. grossman@jhmi.edu
Stuart A
SA
Grossman
Xiaobu
X
Ye
David
D
Peereboom
Myrna R
MR
Rosenfeld
Tom
T
Mikkelsen
Jeffrey G
JG
Supko
Serena
S
Desideri
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D016896:Treatment Outcome
D000927:Anticonvulsants; D000970:Antineoplastic Agents; C076852:terameprocol; D009637:Masoprocol