A phase I/II study of LY900003, an antisense inhibitor of protein kinase C-alpha, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer.

Abstract

PURPOSE:

Protein kinase C-alpha has been implicated in malignant transformation and proliferation. Based on in vivo superadditive interaction between the protein kinase C-alpha 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.

• Authors: Miguel A Villalona-Calero, Paul Ritch, Jose A Figueroa, Gregory A Otterson, Robert Belt, Edward Dow, Sebastian George, James Leonardo, Spence McCachren, G Lance Miller, Manuel Modiano, Manuel Valdivieso, Richard Geary, Jennifer W Oliver, Jon Holmlund
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 18 Pt 1 Pg. 6086-93 (Sep 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15447994 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Oligodeoxyribonucleotides, Antisense
• Oligonucleotides
• Oligonucleotides, Antisense
• Thionucleotides
• Deoxycytidine
• ISIS 3521
• PRKCA protein, human
• Protein Kinase C
• Protein Kinase C-alpha
• Cisplatin
• Gemcitabine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Area Under Curve
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cisplatin (administration & dosage)
• Cohort Studies
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Enzyme Inhibitors (pharmacology)
• Female
• Follow-Up Studies
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Middle Aged
• Oligodeoxyribonucleotides, Antisense (therapeutic use)
• Oligonucleotides (chemistry)
• Oligonucleotides, Antisense (pharmacology)
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase C-alpha
• Thionucleotides (therapeutic use)
• Treatment Outcome
• Gemcitabine