PMID- 22605616
OWN - NLM
STAT- MEDLINE
DCOM- 20130306
LR  - 20181202
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Linking)
VI  - 118
IP  - 23
DP  - 2012 Dec 1
TI  - Phase 1 dose-escalation trial evaluating the combination of the selective MET 
      (mesenchymal-epithelial transition factor) inhibitor tivantinib (ARQ 197) plus 
      erlotinib.
PG  - 5903-11
LID - 10.1002/cncr.27575 [doi]
AB  - BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Tivantinib plus 
      erlotinib was well tolerated with encouraging clinical activity, especially in 
      patients with nonsmall cell lung cancer.
CI  - Copyright (c) 2012 American Cancer Society.
FAU - Goldman, Jonathan W
AU  - Goldman JW
AD  - David Geffen School of Medicine, University of California Los Angeles Medical 
      Center, Los Angeles, California, USA. jwgoldman@mednet.ucla.edu
FAU - Laux, Isett
AU  - Laux I
FAU - Chai, Feng
AU  - Chai F
FAU - Savage, Ronald E
AU  - Savage RE
FAU - Ferrari, Dora
AU  - Ferrari D
FAU - Garmey, Edward G
AU  - Garmey EG
FAU - Just, Richard G
AU  - Just RG
FAU - Rosen, Lee S
AU  - Rosen LS
LA  - eng
SI  - ClinicalTrials.gov/NCT00612703
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120517
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (ARQ 197)
RN  - 0 (Pyrrolidinones)
RN  - 0 (Quinazolines)
RN  - 0 (Quinolines)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Erlotinib Hydrochloride
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/drug therapy
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Proto-Oncogene Proteins c-met/*antagonists & inhibitors
MH  - Pyrrolidinones/*administration & dosage/adverse effects/pharmacokinetics
MH  - Quinazolines/*administration & dosage
MH  - Quinolines/*administration & dosage/adverse effects/pharmacokinetics
EDAT- 2012/05/19 06:00
MHDA- 2013/03/07 06:00
CRDT- 2012/05/19 06:00
PHST- 2011/08/22 00:00 [received]
PHST- 2011/10/20 00:00 [revised]
PHST- 2012/02/09 00:00 [accepted]
PHST- 2012/05/19 06:00 [entrez]
PHST- 2012/05/19 06:00 [pubmed]
PHST- 2013/03/07 06:00 [medline]
AID - 10.1002/cncr.27575 [doi]
PST - ppublish
SO  - Cancer. 2012 Dec 1;118(23):5903-11. doi: 10.1002/cncr.27575. Epub 2012 May 17.