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Phase III Study of Gemcitabine and Cisplatin With or Without Aprinocarsen, a Protein Kinase C-Alpha Antisense Oligonucleotide, in Patients With Advanced-Stage Non–Small-Cell Lung Cancer

Luis Paz-Ares, Jean-Yves Douillard, Piotr Koralewski, Christian Manegold, Egbert F. Smit, José Miguel Reyes, Gee-Chen Chang, William J. John, Patrick M. Peterson, Coleman K. Obasaju, Michael Lahn, David R. Gandara

From the Servicio de Oncología Médica, Doce de Octubre University Hospital, Madrid, Spain; Centre René Gauducheau, Saint Herblain, France; Wojewodzki Szpital Specjalistyczny, Krakow, Poland; Heidelberg University Medical Center, Mannheim, Germany; VU University Medical Center, Amsterdam, the Netherlands; Instituto de Oncología, Clínica Las Condes, Santiago, Chile; Taichung Veterans General Hospital, Taichung, Taiwan, People’s Republic of China; Commonwealth Cancer Center, Richmond, KY; Eli Lilly and Co, Indianapolis, IN; University of California Davis Cancer Center, Sacramento, CA

Address reprint requests to L. Paz-Ares, MD, PhD, Servicio de Oncología Médica, Doce de Octubre University Hospital, Madrid, Spain; e-mail: lpaz.hdoc{at}salud.madrid.org

PURPOSE: To determine whether aprinocarsen, an antisense oligonucleotide directed against protein kinase C-alpha, when added to the chemotherapy regimen of gemcitabine and cisplatin improved survival in patients with advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients with previously untreated stage IIIB/IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned to either a control arm of gemcitabine 1,250 mg/m² on days 1 and 8 and cisplatin 80 mg/m² on day 1, or experimental arms consisting of the identical chemotherapy plus aprinocarsen 2 mg/kg/d as continuous infusion for 14 days, starting on either day 1 or 3 days before chemotherapy. Cycles were repeated every 21 days.

RESULTS: A total of 670 patients were randomly assigned between the control (n = 328) and experimental arms (n = 342). Due to the results from another phase III study of aprinocarsen in NSCLC, further enrollment was stopped, and the study was terminated early. The median number of cycles was four on the control arm and three on the combined experimental arms. Median overall survival was not different between the two groups (control, 10.4 months [95% CI, 8.6 to 12.2]; experimental, 10.0 months [95% CI, 8.4 to 10.8]; P = .613; hazard ratio = 1.05 [95% CI, 0.88 to 1.25]). Response rates (control arm, 35.0%; experimental arms, 28.9%; P = .124) and other time-to-event measures were not significantly different. Grade 3 and 4 toxicities were significantly increased for thrombocytopenia (P < .0001), epistaxis, and thrombosis/embolism in the experimental arms.

CONCLUSION: Adding aprinocarsen to gemcitabine and cisplatin regimen did not enhance survival and other efficacy measures in patients with advanced NSCLC.

Supported by Eli Lilly and Co, Indianapolis, IN.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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