title: Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas.
abstract: COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Pamela
authors.initials: P
authors.lastname: New
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Surasak
authors.initials: S
authors.lastname: Phuphanich
authors.forename: Jane B
authors.initials: JB
authors.lastname: Alavi
authors.forename: Louis B
authors.initials: LB
authors.lastname: Nabors
authors.forename: Steven
authors.initials: S
authors.lastname: Piantadosi
authors.forename: Joy D
authors.initials: JD
authors.lastname: Fisher
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D013754:Tetracyclines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D000927:Anticonvulsants; D013754:Tetracyclines; C117155:tetracycline CMT-3