Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies
| Autor: | Adel K. El Naggar, Jennifer J. Wheler, Lei Ye, John J. Wright, Razelle Kurzrock, Aung Naing, Chaan S. Ng, Rabia Khan, Steven I. Sherman, Said M. Sebti, Nizar M. Tannir, Robert F. Gagel, Robert A. Newman, Stacy L. Moulder, Michelle A. Blaskovich, David S. Hong, J. C. Trent |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Niacinamide Sorafenib Oncology Cancer Research medicine.medical_specialty Adolescent Maximum Tolerated Dose Pyridines Quinolones Pharmacology Article Papillary thyroid cancer Neoplasms Internal medicine Pancreatic cancer Antineoplastic Combined Chemotherapy Protocols medicine Farnesyltranstransferase Humans Aged Aged 80 and over business.industry Phenylurea Compounds Benzenesulfonates Proto-Oncogene Proteins c-ret Farnesyltransferase inhibitor Medullary thyroid cancer Cancer Middle Aged medicine.disease Rash Treatment Outcome Mutation Female Tipifarnib medicine.symptom business medicine.drug |
| Zdroj: | Clinical Cancer Research. 15:7061-7068 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-09-1241 |
| Popis: | Purpose: We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib. Experimental Design: A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth). Results: Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had 50 reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months). Conclusions: Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations. (Clin Cancer Res 2009;15(22):70618) |
| Databáze: | OpenAIRE |
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