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Clin Cancer Res. 2009 Nov 15;15(22):7061-8. doi: 10.1158/1078-0432.CCR-09-1241. Epub 2009 Nov 10.

Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies.

Author information

1
Division of Cancer Medicine, Department of Investigational Therapeutics (Phase 1 Program), Unit 455, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. dshong@mdanderson.org

Abstract

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.

PMID:
19903778
PMCID:
PMC2784003
DOI:
10.1158/1078-0432.CCR-09-1241
[Indexed for MEDLINE]
Free PMC Article
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