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

Abstract

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/m 2 ) and gemcitabine (1,000 mg/m 2 ) 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/m 2 , n ‫؍‬ 44 (original cohort); 1,250 mg/m 2 , 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.

The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells

“…In summary, our current study provides supporting evidence to the therapeutic potential of safingol, which has been shown to act synergistically with a number of conventional chemotherapeutics (11,(17)(18)(19)(20)(21)(22)37). The effectiveness and synergism of safingol/irinotecan at 1:1 molar ratio could be attributed to the down-regulation of the PKC pathway.…”

“…Protein kinase C has emerged as an important target for anti-cancer drug development, and numerous small molecule inhibitors and anti-sense molecules have been developed and entered into clinical trials (37)(38)(39). Given the important role of PKC in tumorigenesis, cell proliferation, and drug resistance development, it is of interest to explore the role of PKC in mediating the synergistic effect of safingol/irinotecan combination given at 1:1 molar ratio.…”

Protein Kinase C (PKC) Isozymes and Cancer

“…These data all indicate that PKC is an important target for treatment of SCLCs and NSCLCs, but clinical trials using PKC -specific antisense oligonucleotides show no or low efficacy in patients [296][297][298]. Further, clinical trials using PKC -targeted antisense oligonucleotides aprinocarsen [296,297] and LY900003 [298] …”

“…Further, clinical trials using PKC -targeted antisense oligonucleotides aprinocarsen [296,297] and LY900003 [298] …”

Synthesis and Duplex‐Stabilizing Properties of Fluorinated N‐Methanocarbathymidine Analogues Locked in the C3′‐endo Conformation

“…[1] Furthermore, fluorinated nucleoside analogues been applied as antiviral [2] and anticancer agents. [3] We recently characterized the antisense properties of both isomers of 2'-fluorohexitol nucleic acid (FHNA) [4,5] and 2'-fluorocyclohexenyl nucleic acid (F-CeNA). [6] We found that fluorine incorporation can indeed have a beneficial effect on the properties of modified oligonucleotides as compared to those of the parent nonfluorinated counterparts.…”