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A Phase I/II Study of LY900003, an Antisense Inhibitor of Protein Kinase C-, in Combination with Cisplatin and Gemcitabine in Patients with Advanced Non–Small Cell Lung Cancer

Miguel A. Villalona-Calero¹, Paul Ritch², Jose A. Figueroa³, Gregory A. Otterson¹, Robert Belt⁴, Edward Dow⁵, Sebastian George^6,, James Leonardo⁷, Spence McCachren⁸, G. Lance Miller⁹, Manuel Modiano¹⁰, Manuel Valdivieso¹¹, Richard Geary¹², Jennifer W. Oliver¹² and Jon Holmlund¹²

¹ The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; ² The Medical College of Wisconsin, Milwaukee, Wisconsin; ³ The Joe Arrington Cancer and Research Center, Lubbock, Texas; ⁴ Kansas City Hematology and Oncology Group, Westwood, Kansas; ⁵ Boston Hematology and Oncology, Boston, Massachusetts; ⁶ The Cancer and Blood Institute of the Desert, Rancho Mirage, California; ⁷ The East Carolina School of Medicine, Greenville, North Carolina; ⁸ The Thompson Cancer Survival Center, Knoxville, Tennessee; ⁹ Oklahoma Oncology, Inc., Tulsa, Oklahoma; ¹⁰ The Arizona Clinical Research Center, Tucson, Arizona; ¹¹ The University of Texas Southwestern Medical Center, Dallas, Texas; and ¹² ISIS Pharmaceuticals, Inc., Carlsbad, California

Purpose: Protein kinase C- has been implicated in malignant transformation and proliferation. Based on in vivo superadditive interaction between the protein kinase C- antisense oligonucleotide LY900003 (Affinitak, ISIS 3521) and cisplatin, we designed this phase I/II trial of LY900003 with cisplatin/gemcitabine

Experimental Design: The safety of the combination, as well as potential pharmacokinetic interactions, was evaluated in the phase I portion of the trial. The phase II portion evaluated the antitumor activity of the combination in previously untreated patients with stage IIIB/IV non–small-cell lung cancer (NSCLC).

Results: Seven patients received 18 cycles of the combination during the phase I portion. Dose-limiting toxicity was only observed in one of six evaluable patients (grade 3 fatigue). However, due to a relatively high frequency of thrombocytopenia, cisplatin 80 (mg/m²) and gemcitabine (1,000 mg/m²) were recommended for the phase II portion. Antitumor activity was observed in two patients (one with NSCLC and one with pancreatic carcinoma), and prolonged stabilization was observed in two others. No pharmacokinetic interactions occurred. In the phase II portion, 55 NSCLC patients received the combination at two gemcitabine doses [1,000 mg/m², n = 44 (original cohort); 1,250 mg/m², n = 11 (expanded cohort)]. Fourteen of 39 evaluable patients in the original cohort had a response rate (1 complete response and 13 partial responses; response, 36%), whereas 2 of 9 evaluable patients in the expanded cohort experienced partial response (combined response rate, 33%). The median time to treatment failure was 3.9 months, whereas the median time response to progression for the 48 patients with evaluable response was 4.4 months (confidence interval, 3.5–5.5 months). Intent to treat median survival time was 8.9 months. Forty-eight percent of the patients experienced catheter-related events.

Conclusions: LY900003 can be administered safely in combination with cisplatin and gemcitabine and is associated with antitumor activity in patients with advanced NSCLC. Better characterization of subsets of patients most likely to benefit from this combination therapy is needed.

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