Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma.
A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.
Department of Radiation Oncology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. prakash.chinnaiyan@moffitt.org
Prakash
P
Chinnaiyan
Sajeel
S
Chowdhary
Lisa
L
Potthast
Antony
A
Prabhu
Ya-Yu
YY
Tsai
Bhaswati
B
Sarcar
Soumen
S
Kahali
Steven
S
Brem
H Michael
HM
Yu
Amyn
A
Rojiani
Ryan
R
Murtagh
Edward
E
Pan
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000633:toxicity; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000032:analysis; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010982:Platelet-Derived Growth Factor / Q000032:analysis; D040901:Proteomics; D000077337:Vorinostat
D061067:Antibodies, Monoclonal, Humanized; D006877:Hydroxamic Acids; D018975:Insulin-Like Growth Factor Binding Protein 5; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D000068258:Bevacizumab; D000077337:Vorinostat; D000077146:Irinotecan; D002166:Camptothecin