title: Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer.
abstract: The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen, gemcitabine, and carboplatin in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.
authors.affiliation: Milwaukee Medical College, Milwaukee, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ritch
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Jacob David
authors.initials: JD
authors.lastname: Bitran
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.forename: Alex
authors.initials: A
authors.lastname: Makalinao
authors.forename: David
authors.initials: D
authors.lastname: Irwin
authors.forename: Rogerio
authors.initials: R
authors.lastname: Lilenbaum
authors.forename: Patrick
authors.initials: P
authors.lastname: Peterson
authors.forename: William J
authors.initials: WJ
authors.lastname: John
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D003841:Deoxycytidine; D016190:Carboplatin; D012264:Ribonucleotide Reductases; D011493:Protein Kinase C; C488084:aprinocarsen; D000093542:Gemcitabine