Phase I Study of the c-raf-1 Antisense Oligonucleotide ISIS 5132 in Combination with Carboplatin and Paclitaxel in Patients with Previously Untreated, Advanced Non-small Cell Lung Cancer
| Autor: | Panos Fidias, Nathan A. Pennell, T Jesse Kwoh, Richard S. Geary, Geoffrey I. Shapiro, Anthony L. Boral, Joseph Paul Eder, Bruce E. Johnson, Thomas J. Lynch, Jeffrey G. Supko, Arthur T. Skarin |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Pulmonary and Respiratory Medicine Lung Neoplasms Maximum Tolerated Dose Paclitaxel endocrine system diseases medicine.medical_treatment Neutropenia Pharmacology Carboplatin chemistry.chemical_compound Clinical trials Pharmacokinetics Carcinoma Non-Small-Cell Lung Antineoplastic Combined Chemotherapy Protocols medicine Carcinoma Chemotherapy Humans Lung cancer Human subjects Aged business.industry Middle Aged Thionucleotides medicine.disease Proto-Oncogene Proteins c-raf chemistry Oncology Toxicity Female business |
| Zdroj: | Journal of Thoracic Oncology. 4(9):1156-1162 |
| ISSN: | 1556-0864 |
| DOI: | 10.1097/jto.0b013e3181b2793f |
| Popis: | Background A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c- raf -1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m 2 and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC fp ) of 5 mg · min/ml (dose level 1). The carboplatin dose was then increased to AUC fp 6 mg · min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m 2 (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion. Results Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC fp 6 mg · min/ml, paclitaxel 175 mg/m 2 , and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum. Conclusion ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study. |
| Databáze: | OpenAIRE |
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