{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T01:23:16Z","timestamp":1778548996048,"version":"3.51.4"},"reference-count":31,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2012,5,17]],"date-time":"2012-05-17T00:00:00Z","timestamp":1337212800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>Amplification of the mesenchymal\u2010epithelial transition factor (<jats:italic>MET<\/jats:italic>) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR\u2010MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non\u2013ATP\u2010competitive, small\u2010molecule 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS:<\/jats:title><jats:p>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\u2010limiting toxicity in the first cycle of therapy (21 days).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>Thirty\u2010two patients received combination treatment. Tivantinib serum concentrations were not dose\u2010proportional. The most common (\u226520%) 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\u2010related 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p>Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer. Cancer 2012. \u00a9 2012 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.27575","type":"journal-article","created":{"date-parts":[[2012,5,17]],"date-time":"2012-05-17T16:04:39Z","timestamp":1337270679000},"page":"5903-5911","source":"Crossref","is-referenced-by-count":61,"title":["Phase 1 dose\u2010escalation trial evaluating the combination of the selective MET (mesenchymal\u2010epithelial transition factor) inhibitor tivantinib (ARQ 197) plus erlotinib"],"prefix":"10.1002","volume":"118","author":[{"given":"Jonathan W.","family":"Goldman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isett","family":"Laux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Chai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald E.","family":"Savage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dora","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward G.","family":"Garmey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard G.","family":"Just","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee S.","family":"Rosen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,5,17]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050753"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.07.9525"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040938"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099314"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050736"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.14.8924"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa044238"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1570"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710370104"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1141478"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1643"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604559"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-1173"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.31.0367"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-1002"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208146"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203859"},{"key":"e_1_2_7_19_2","first-page":"205","article-title":"Activation of Src by c\u2010Met overexpression mediates metastatic properties of colorectal carcinoma cells","volume":"6","author":"Herynk MH","year":"2007","journal-title":"J Exp Ther Oncol."},{"key":"e_1_2_7_20_2","first-page":"7926","article-title":"Both hepatocyte growth factor (HGF) and stromal\u2010derived factor\u20101 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy","volume":"63","author":"Jankowski K","year":"2003","journal-title":"Cancer Res."},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0145-2126(94)90003-5"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20604"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1993.7"},{"key":"e_1_2_7_24_2","first-page":"1635","article-title":"Hepatocyte growth factor (HGF) and receptor (c\u2010met) in normal and malignant astrocytic cells","volume":"19","author":"Welch WC","year":"1999","journal-title":"Anticancer Res."},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.21018"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.19.1635"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e3181ce3d1d"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e318168d9d4"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdn635"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.11.022"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.34.0570"},{"key":"e_1_2_7_32_2","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2011.29.15_suppl.tps217","article-title":"A phase III, randomized, double\u2010blind, placebo\u2010controlled study of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated subjects with locally advanced or metastatic, nonsquamous, non\u2010small cell lung cancer (NSCLC)","volume":"29","author":"Sandler A","year":"2011","journal-title":"J Clin Oncol."}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.27575","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.27575","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T12:16:26Z","timestamp":1760271386000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.27575"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,17]]},"references-count":31,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["10.1002\/cncr.27575"],"URL":"https:\/\/doi.org\/10.1002\/cncr.27575","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,17]]}}}