title: Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas.
abstract: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG.
  
  
  
  Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB.
  
  
  
  Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB.
  
  
  
  MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Holdhoff
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Nabors
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Arati S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Walbert
authors.affiliation: Wake Forest University, School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Lesser
authors.affiliation: Emory University, Atlanta, Georgia, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Read
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lieberman
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Lodge
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Leal
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Joy D
authors.initials: JD
authors.lastname: Fisher
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Serena
authors.initials: S
authors.lastname: Desideri
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wahl
authors.affiliation: University of Virginia Medical Center, Charlottesville, Virginia, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schiff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020747:Calcium Channels, T-Type / Q000737:chemistry*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D020748:Mibefradil / Q000008:administration & dosage; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D020747:Calcium Channels, T-Type; D020748:Mibefradil; D003606:Dacarbazine; D000077204:Temozolomide
keywords: anaplastic glioma; glioblastoma; mibefradil; temozolomide; timed sequential therapy