Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas

Matthias Holdhoff, Xiaobu Ye, Jeffrey G. Supko, Louis B. Nabors, Arati S. Desai, Tobias Walbert, Glenn J. Lesser, William L. Read, Frank S. Lieberman, Martin Lodge, Jeffrey Pettit Leal, Joy D. Fisher, Serena Desideri, Stuart A Grossman, Richard L. Wahl, David Schiff

Research output: Contribution to journalArticle

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 modifed 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-?uorothymidine (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 signifcant 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.

Original languageEnglish (US)
Pages (from-to)845-852
Number of pages8
JournalNeuro-Oncology
Volume19
Issue number6
DOIs
StatePublished - 2017

Fingerprint

temozolomide
Mibefradil
T-Type Calcium Channels
Calcium Channel Blockers
Glioma
Maximum Tolerated Dose
Therapeutics
G1 Phase Cell Cycle Checkpoints
Bradycardia
Aspartate Aminotransferases

Keywords

  • Anaplastic glioma
  • Glioblastoma
  • Mibefradil
  • Temozolomide
  • Timed sequential therapy

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas. / Holdhoff, Matthias; Ye, Xiaobu; Supko, Jeffrey G.; Nabors, Louis B.; Desai, Arati S.; Walbert, Tobias; Lesser, Glenn J.; Read, William L.; Lieberman, Frank S.; Lodge, Martin; Leal, Jeffrey Pettit; Fisher, Joy D.; Desideri, Serena; Grossman, Stuart A; Wahl, Richard L.; Schiff, David.

In: Neuro-Oncology, Vol. 19, No. 6, 2017, p. 845-852.

Research output: Contribution to journalArticle

Holdhoff, M, Ye, X, Supko, JG, Nabors, LB, Desai, AS, Walbert, T, Lesser, GJ, Read, WL, Lieberman, FS, Lodge, M, Leal, JP, Fisher, JD, Desideri, S, Grossman, SA, Wahl, RL & Schiff, D 2017, 'Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas', Neuro-Oncology, vol. 19, no. 6, pp. 845-852. https://doi.org/10.1093/neuonc/nox020
Holdhoff, Matthias ; Ye, Xiaobu ; Supko, Jeffrey G. ; Nabors, Louis B. ; Desai, Arati S. ; Walbert, Tobias ; Lesser, Glenn J. ; Read, William L. ; Lieberman, Frank S. ; Lodge, Martin ; Leal, Jeffrey Pettit ; Fisher, Joy D. ; Desideri, Serena ; Grossman, Stuart A ; Wahl, Richard L. ; Schiff, David. / Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas. In: Neuro-Oncology. 2017 ; Vol. 19, No. 6. pp. 845-852.
@article{fc08c21ab94448a9879e12e3b309b974,
title = "Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas",
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 modifed 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-?uorothymidine (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 signifcant 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.",
keywords = "Anaplastic glioma, Glioblastoma, Mibefradil, Temozolomide, Timed sequential therapy",
author = "Matthias Holdhoff and Xiaobu Ye and Supko, {Jeffrey G.} and Nabors, {Louis B.} and Desai, {Arati S.} and Tobias Walbert and Lesser, {Glenn J.} and Read, {William L.} and Lieberman, {Frank S.} and Martin Lodge and Leal, {Jeffrey Pettit} and Fisher, {Joy D.} and Serena Desideri and Grossman, {Stuart A} and Wahl, {Richard L.} and David Schiff",
year = "2017",
doi = "10.1093/neuonc/nox020",
language = "English (US)",
volume = "19",
pages = "845--852",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas

AU - Holdhoff, Matthias

AU - Ye, Xiaobu

AU - Supko, Jeffrey G.

AU - Nabors, Louis B.

AU - Desai, Arati S.

AU - Walbert, Tobias

AU - Lesser, Glenn J.

AU - Read, William L.

AU - Lieberman, Frank S.

AU - Lodge, Martin

AU - Leal, Jeffrey Pettit

AU - Fisher, Joy D.

AU - Desideri, Serena

AU - Grossman, Stuart A

AU - Wahl, Richard L.

AU - Schiff, David

PY - 2017

Y1 - 2017

N2 - 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 modifed 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-?uorothymidine (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 signifcant 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.

AB - 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 modifed 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-?uorothymidine (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 signifcant 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.

KW - Anaplastic glioma

KW - Glioblastoma

KW - Mibefradil

KW - Temozolomide

KW - Timed sequential therapy

UR - http://www.scopus.com/inward/record.url?scp=85020300808&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020300808&partnerID=8YFLogxK

U2 - 10.1093/neuonc/nox020

DO - 10.1093/neuonc/nox020

M3 - Article

VL - 19

SP - 845

EP - 852

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 6

ER -