Matthias Holdhoff1, Xiaobu Ye1, Jeffrey G Supko2, Louis B Nabors3, Arati S Desai4, Tobias Walbert5, Glenn J Lesser6, William L Read7, Frank S Lieberman8, Martin A Lodge9, Jeffrey Leal9, Joy D Fisher1, Serena Desideri1, Stuart A Grossman1, Richard L Wahl10, David Schiff11. 1. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA. 2. Massachusetts General Hospital, Boston, Massachusetts, USA. 3. University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA. 4. University of Pennsylvania, Philadelphia, Pennsylvania, USA. 5. Henry Ford Health System, Detroit, Michigan, USA. 6. Wake Forest University, School of Medicine, Winston-Salem, North Carolina, USA. 7. Emory University, Atlanta, Georgia, USA. 8. University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 9. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 10. Washington University School of Medicine, St. Louis, Missouri, USA. 11. University of Virginia Medical Center, Charlottesville, Virginia, USA.
Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: 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.
Background: 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. Methods: 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. Results: 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. Conclusions: 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: Lloyd S Gray; Edward Perez-Reyes; Juan Carlos Gomora; Juan Carlos Gamorra; Doris M Haverstick; Michael Shattock; Linda McLatchie; Jane Harper; Gavin Brooks; Tiffany Heady; Timothy L Macdonald Journal: Cell Calcium Date: 2004-12 Impact factor: 6.817
Authors: Martin A Lodge; Matthias Holdhoff; Jeffrey P Leal; Asim K Bag; L Burt Nabors; Akiva Mintz; Glenn J Lesser; David A Mankoff; Arati S Desai; James M Mountz; Frank S Lieberman; Joy D Fisher; Serena Desideri; Xiaobu Ye; Stuart A Grossman; David Schiff; Richard L Wahl Journal: J Nucl Med Date: 2016-09-29 Impact factor: 10.057
Authors: Barbara Dziegielewska; Eli V Casarez; Wesley Z Yang; Lloyd S Gray; Jaroslaw Dziegielewski; Jill K Slack-Davis Journal: Mol Cancer Ther Date: 2016-02-01 Impact factor: 6.261
Authors: Antonio Omuro; Kathryn Beal; Katharine McNeill; Robert J Young; Alissa Thomas; Xuling Lin; Robert Terziev; Thomas J Kaley; Lisa M DeAngelis; Mariza Daras; Igor T Gavrilovic; Ingo Mellinghoff; Eli L Diamond; Andrew McKeown; Malbora Manne; Andrew Caterfino; Krishna Patel; Linda Bavisotto; Greg Gorman; Michael Lamson; Philip Gutin; Viviane Tabar; Debyani Chakravarty; Timothy A Chan; Cameron W Brennan; Elizabeth Garrett-Mayer; Rashida A Karmali; Elena Pentsova Journal: J Clin Oncol Date: 2018-04-23 Impact factor: 44.544