We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies.
- Authors
Hong, David S; Cabanillas, Maria E; Wheler, Jennifer; Naing, Aung; Tsimberidou, Apostolia M; Ye, Lei; Busaidy, Naifa L; Waguespack, Steven G; Hernandez, Mike; El Naggar, Adel K; El Naggar, Alder K; Bidyasar, Savita; Wright, John; Sherman, Steven I; Kurzrock, Razelle
- Abstract
<bold>Purpose: </bold>Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins.<bold>Patients and Methods: </bold>We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle.<bold>Results: </bold>We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue.<bold>Conclusions: </bold>Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.
- Subjects
ADENOCARCINOMA; ANTINEOPLASTIC agents; CELL differentiation; CELLULAR signal transduction; CLINICAL trials; COMPARATIVE studies; DOSE-effect relationship in pharmacology; RESEARCH methodology; MEDICAL cooperation; NEUROENDOCRINE tumors; PROTEINS; PYRIDINE; QUINOLONE antibacterial agents; RESEARCH; RESEARCH funding; THYROID gland tumors; TRANSFERASES; UREA; VITAMIN B complex; EVALUATION research; BENZENE derivatives; PROTEIN kinase inhibitors; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Journal of Clinical Endocrinology & Metabolism, 2011, Vol 96, Issue 4, p997
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2010-1899