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Phase 1 dose-escalation trial evaluating the combination of the selective MET (mesenchymal-epithelial transition factor) inhibitor tivantinib (ARQ 197) plus erlotinib†
Article first published online: 17 MAY 2012
Copyright © 2012 American Cancer Society
Volume 118, Issue 23, pages 5903–5911, 1 December 2012
How to Cite
Goldman, J. W., Laux, I., Chai, F., Savage, R. E., Ferrari, D., Garmey, E. G., Just, R. G. and Rosen, L. S. (2012), Phase 1 dose-escalation trial evaluating the combination of the selective MET (mesenchymal-epithelial transition factor) inhibitor tivantinib (ARQ 197) plus erlotinib. Cancer, 118: 5903–5911. doi: 10.1002/cncr.27575
Clinical trials ID number NCT00612703, at ClinicalTrials.gov
- Issue published online: 19 NOV 2012
- Article first published online: 17 MAY 2012
- Manuscript Accepted: 9 FEB 2012
- Manuscript Revised: 20 OCT 2011
- Manuscript Received: 22 AUG 2011
- nonsmall cell lung cancer;
- ARQ 197;
- proto-oncogene proteins c-MET
Amplification of the mesenchymal-epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR-MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non–ATP-competitive, small-molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib.
Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose-limiting toxicity in the first cycle of therapy (21 days).
Thirty-two patients received combination treatment. Tivantinib serum concentrations were not dose-proportional. The most common (≥20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment-related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD.
Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer. Cancer 2012. © 2012 American Cancer Society.