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

David S. Hong, Said M. Sebti, Robert A. Newman, Michelle A. Blaskovich, Lei Ye, Robert F. Gagel, Stacy Moulder, Jennifer J. Wheler, Aung Naing, Nizar M. Tannir, Chaan S. Ng, Steven I. Sherman, Adel K. El Naggar, Rabia Khan, Jon Trent, John J. Wright, Razelle Kurzrock

Research output: Contribution to journalArticle

71 Scopus citations

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 ≥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.

Original languageEnglish (US)
Pages (from-to)7061-7068
Number of pages8
JournalClinical Cancer Research
Volume15
Issue number22
DOIs
StatePublished - Nov 15 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hong, D. S., Sebti, S. M., Newman, R. A., Blaskovich, M. A., Ye, L., Gagel, R. F., Moulder, S., Wheler, J. J., Naing, A., Tannir, N. M., Ng, C. S., Sherman, S. I., El Naggar, A. K., Khan, R., Trent, J., Wright, J. J., & Kurzrock, R. (2009). Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies. Clinical Cancer Research, 15(22), 7061-7068. https://doi.org/10.1158/1078-0432.CCR-09-1241