title: Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma.
abstract: The average survival time for patients with recurrent glioblastoma is between 5 and 9 months. Phase I and II trials have shown a modest survival benefit with combination temozolomide and other chemotherapeutics. We conducted a phase I trial of dose-escalating temozolomide with bevacizumab and the proteasome inhibitor bortezomib for patients with recurrent disease. Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m2. Fixed doses of bortezomib and bevacizumab were given at standard intervals. Patients were monitored for dose-limiting toxicities (DLT) to determine the maximum-tolerated dose (MTD) of temozolomide with this regimen. No DLT were seen in the first two groups (25 and 50 mg/m2temozolomide). One patient in the 75 mg/m2group experienced a grade 4 elevation of ALT and three more patients were accrued for a total of six patients at that dose level. No other DLT occurred, thus making 75 mg/m2the MTD. Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m2in combination with bevacizumab and bortezomib for recurrent glioblastoma. Only one patient experienced a severe (Grade 4) elevation of ALT. This study will provide the framework for further studies to elicit effectiveness and better determine a safety profile for this drug combination.
authors: Department of Neurosurgery, Emory University School of Medicine, 1365 Clifton Rd NE, Suite B6200, Atlanta, GA, 30322, USA. jay.mccracken@emory.edu.
authors: D Jay
authors: DJ
authors: McCracken
authors: Emory University School of Medicine, Atlanta, GA, USA.
authors: Emma C
authors: EC
authors: Celano
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Alfredo D
authors: AD
authors: Voloschin
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors: William L
authors: WL
authors: Read
authors: Department of Neurosurgery, Emory University School of Medicine, 1365 Clifton Rd NE, Suite B6200, Atlanta, GA, 30322, USA.
authors: Jeffrey J
authors: JJ
authors: Olson
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use; D000069286:Bortezomib / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012189:Retrospective Studies; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D000068258:Bevacizumab; D000069286:Bortezomib; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Adjuvant chemotherapy; Brain/central nervous system cancers; Combination chemotherapy; Glioblastoma; Magnetic resonance imaging (MRI); Phase I-III trials brain/central nervous system cancers