© 2005 by the Society forNeuro-Oncology
Efficacy and toxicity of the antisense oligonucleotide aprinocarsendirected against protein kinase C-
delivered as a 21-day continuousintravenous infusion in patients with recurrent high-grade astrocytomas
The New Approaches to Brain Tumor Therapy CNSConsortium, Baltimore, MD 21231 (S.A.G., J.B.A., J.G.S., K.A.C., R.P.); Isis Pharmaceuticals, Inc., Carlsbad, CA 92008 (F.A.D.,J.S.G., J.T.H.)
3 Address correspondence to Stuart A. Grossman, The New Approaches to BrainTumor Therapy CNS Consortium, 1650 Orleans Street, Room G93, Baltimore, MD21231(grossman{at}jhmi.edu).
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Abstract |
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Protein kinase C alpha (PKC-
) is a cytoplasmic serine threoninekinase involved in regulating cell differentiation and proliferation.Aprinocarsen is an antisense oligonucleotide against PKC- that reducesPKC- in human cell lines and inhibits a human glioblastoma tumor cellline in athymic mice. In this phase 2 study, aprinocarsen was administered topatients with recurrent high-grade gliomas by continuous intravenous infusion(2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial.Their median age was 46 years (range, 28-68 years), median Karnofskyperformance status was 80 (range, 60-100), median tumor volume was 58cm3 (range, 16-254 cm3), and histology includedglioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), andanaplastic astrocytoma (n = 1). The number of prior chemotherapy regimensincluded none (n = 3), one (n = 10), and two (n = 8). No tumor responses wereobserved. Patients on this therapy rapidly developed symptoms of increasedintracranial pressure with increased edema, enhancement, and mass effect onneuroimaging. The median time to progression was 36 days, and median survivalwas 3.4 months. The observed toxicities were mild, reversible, and uncommon(grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and nocoagulopathy or CNS bleed-ing resulted from this therapy. Plasmaconcentrations of aprinocarsen during the infusion exhibited significantinterpatient variability (mean = 1.06 µg/ml; range, 0.34-6.08 µg/ml).This is the first study to use an antisense oligonucleotide or a specificPKC- inhibitor in patients with high-grade gliomas. No clinical benefitwas seen. The rapid deterioration seen in these patients could result fromtumor growth or an effect of aprinocarsen on blood-brain barrierintegrity.
Received April 14, 2004; Accepted May 17, 2004
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