Randomized phase III trial of gemcitabine/cisplatin (GC) and protein kinase C α (PKCα) antisense oligonucleotide aprinocarsen in patients (pts) with advanced stage non-small cell lung cancer (NSCLC)
Authors: L. Paz-Ares, J.-Y. Douillard, P. Koralewski, C. Manegold, E. F. Smit, J. M. Reyes, G. C. Chang, W. J. John, P. Peterson, D. R. Gandara
Journal: Journal of Clinical Oncology (2005)

7053 Background: Aprinocarsen (Ap; Affinitak) is an antisense oligonucleotide tailored to target PKCα mRNA, thereby inhibiting the intracellular signaling events that PKCα mediates. Based on promising phase (ph) II results (Yuen et al ASCO 2001, #1234), a ph III trial of GC with or without Ap was initiated in pts with NSCLC. The primary endpoint was overall survival (OS), with a planned enrollment of 350 pts/arm based on an OS hazard ratio (HR) of 0.769 (5% alpha, 80% power, 30% censoring). Methods: Patients who had stage IIIB/IV NSCLC, no prior chemotherapy, and ECOG performance status of 0 or 1 were eligible. Randomized pts received either G 1250 mg/m2 on d1,8 and C 80 mg/m2 on d1 (control arm) or same GC plus Ap ∼2 mg/kg/d, continuous iv infusion, on d1–15 (experimental arm) q21d. After study initiation, ph II results indicated the need for a second experimental arm with an altered dosing schedule: G on d4,11, C on d4, and same Ap; enrollment was amended to 1000 pts. Receipt of ph III results of a similar trial resulted in early termination of enrollment. Since only 49 pts were enrolled on the second experimental arm, results from the 2 experimental arms were combined for analysis. Results: The control arm and experimental arms were similar in baseline characteristics. As shown below, there was no difference in efficacy between the arms, and the experimental arms experienced greater toxicity with more discontinuations due to adverse events (AEs). (Safety data illustrating greatest differences between arms is shown in the table.) Conclusions: The addition of Ap to GC resulted in no improvement in response or OS while the toxicity profile increased. Although this study failed to demonstrate efficacy in NSCLC, studies of Ap in other tumor types or in alternative schedules may be warranted. Control Arm: GC (N=328) Experimental Arms: GC+Ap (N=342) Statistical Comparison Median number of cycles 4 3 Efficacy measures Median overall survival (months), 95% CI 10.4 (8.6–12.2) 10.0 (8.4–10.8) p=.613 HR=1.05 (0.88–1.25) Time to progressive disease (months), 95% CI 6.0 (5.3–6.3) 5.5 (5.0–6.0) p=.210 HR=1.13 (0.94–1.36) (N=289) (N=280) Total responders (CR + PR), Overall response rate 101 35.0% 81 28.9% p=.124 Safety measures, n (%) (N=321) (N=322) Serious AEs, pts with ≥1 127 (39.6) 182 (56.5) <.0001 Total deaths, on study 25 (7.8) 22 (6.8) .6530 Discontinuations due to AEs 38 (11.8) 65 (20.2) .0050 Gr 3/4 thrombocytopenia 94 (29.3) 191 (59.3) <.0001 Gr 3/4 epistaxis 4 (1.2) 19 (5.9) .0022 Gr 3/4 thrombosis/embolism 2 (0.6) 13 (4.0) .0068 Serious AE experienced by ≥2% pts Thrombocytopenia 18 (5.6) 35 (10.9) .0210 Febrile neutropenia 4 (1.2) 8 (2.5) .3831 Pyrexia 12 (3.7) 20 (6.2) .2037 Injection site infection 2 (0.6) 18 (5.6) .0003 Catheter complication 1 (0.3) 7 (2.2) .0686 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Aventis, Eli Lilly Eli Lilly Eli Lilly Eli Lilly