Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas
| Autor: | Serena Desideri, William L. Read, Stuart A. Grossman, Glenn J. Lesser, Arati Desai, Matthias Holdhoff, Louis B. Nabors, David Schiff, Frank S. Lieberman, Jeffrey G. Supko, Joy D. Fisher, Jeffrey P. Leal, Tobias Walbert, Martin A. Lodge, Xiaobu Ye, Richard L. Wahl |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research medicine.medical_specialty Maximum Tolerated Dose medicine.drug_class Dacarbazine Urology Clinical Investigations Standardized uptake value Calcium channel blocker 03 medical and health sciences Calcium Channels T-Type Young Adult 0302 clinical medicine Glioma Antineoplastic Combined Chemotherapy Protocols Temozolomide Medicine Humans neoplasms Survival rate Aged Aged 80 and over Mibefradil business.industry Brain Neoplasms Middle Aged medicine.disease digestive system diseases Survival Rate Regimen 030104 developmental biology Oncology 030220 oncology & carcinogenesis Anesthesia Female Neurology (clinical) Neoplasm Grading Neoplasm Recurrence Local business medicine.drug Follow-Up Studies |
| Zdroj: | Neuro-oncology. 19(6) |
| ISSN: | 1523-5866 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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