Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-alpha delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas.
Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients 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 Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.
Grossman
Stuart A
SA
The New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD 21231, USA. grossman@jhmi.edu
Alavi
Jane B
JB
Supko
Jeffrey G
JG
Carson
Kathryn A
KA
Priet
Regina
R
Dorr
F Andrew
FA
Grundy
John S
JS
Holmlund
Jon T
JT
D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000209:etiology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D054735:Phosphorothioate Oligonucleotides; D011493:Protein Kinase C / Q000187:drug effects; D051571:Protein Kinase C-alpha; D016896:Treatment Outcome
D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; C488084:aprinocarsen