Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies. Clin Cancer Res 2009 Nov 15;15(22):7061-8
Date
11/12/2009Pubmed ID
19903778Pubmed Central ID
PMC2784003DOI
10.1158/1078-0432.CCR-09-1241Scopus ID
2-s2.0-72549092909 (requires institutional sign-in at Scopus site) 80 CitationsAbstract
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 > or =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 (> or =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.
Author List
Hong DS, Sebti SM, Newman RA, Blaskovich MA, Ye L, Gagel RF, Moulder S, Wheler JJ, Naing A, Tannir NM, Ng CS, Sherman SI, El Naggar AK, Khan R, Trent J, Wright JJ, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Benzenesulfonates
Farnesyltranstransferase
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Mutation
Neoplasms
Niacinamide
Phenylurea Compounds
Proto-Oncogene Proteins c-ret
Pyridines
Quinolones
Treatment Outcome
