title: Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.
abstract: Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.
authors: Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, SW 430, Boston, MA 02215, USA.
authors: J
authors: J
authors: Drappatz
authors: E Q
authors: EQ
authors: Lee
authors: S
authors: S
authors: Hammond
authors: S A
authors: SA
authors: Grimm
authors: A D
authors: AD
authors: Norden
authors: R
authors: R
authors: Beroukhim
authors: M
authors: M
authors: Gerard
authors: D
authors: D
authors: Schiff
authors: A S
authors: AS
authors: Chi
authors: T T
authors: TT
authors: Batchelor
authors: L M
authors: LM
authors: Doherty
authors: A S
authors: AS
authors: Ciampa
authors: D C
authors: DC
authors: Lafrankie
authors: S
authors: S
authors: Ruland
authors: S M
authors: SM
authors: Snodgrass
authors: J J
authors: JJ
authors: Raizer
authors: P Y
authors: PY
authors: Wen
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007211:Indoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D000077767:Panobinostat; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D006877:Hydroxamic Acids; D007211:Indoles; D000068258:Bevacizumab; D000077767:Panobinostat