@article{bed8945880c84a39a67bda2338c80999,
title = "A phase 1b study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors",
abstract = "Regorafenib 160 mg orally once daily (QD) 3 weeks on/1 week off is approved in colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma. We established the safety and pharmacokinetics (PK) of regorafenib combined with cetuximab in advanced refractory solid tumors. This was a phase 1, open-label, dose-escalation study (NCT01973868) in patients with advanced/metastatic solid tumors who progressed after standard therapy. Regorafenib was administered at various dose levels QD continuously or intermittently (3 weeks on/1 week off) combined with intravenous cetuximab 250 mg/m2 weekly. The primary objectives were safety, PK and maximum tolerated dose (MTD). The secondary objective was tumor response. Dose-limiting toxicities (DLTs) were evaluated in Cycle 1. Of 42 treated patients, 31 received regorafenib intermittently (120 mg, n = 8; 160 mg, n = 23) and 11 continuously (60 mg, n = 5; 100 mg, n = 6) plus cetuximab. The continuous arm was terminated due to low tolerable dose. In the intermittent arm, one DLT (grade 3 hand–foot skin reaction) was observed at 120 mg but none at 160 mg, therefore 160 mg/day was declared as the MTD in combination with cetuximab. The most common all-grade treatment-emergent adverse events were fatigue (52%), hypophosphatemia (48%) and diarrhea (40%). One grade 3 cetuximab-related dermatitis acneiform was observed. No clinically relevant drug–drug interactions were observed. Five patients (21%) had a partial response. Regorafenib 160 mg QD (3 weeks on/1 week off) plus standard dose of cetuximab was well tolerated with no unexpected toxicities and promising signs of efficacy.",
keywords = "cetuximab, metastatic colorectal cancer, phase 1, regorafenib",
author = "Colin Weekes and Lockhart, {A. Craig} and Lee, {James J.} and Isrid Sturm and Adriaan Cleton and Funan Huang and Lenz, {Heinz Josef}",
note = "Funding Information: Key words: regorafenib, cetuximab, metastatic colorectal cancer, phase 1 Abbreviations: AE: adverse event; AUC: area under the plasma concentration–time curve; Cmax: maximum observed drug concentration; CV: geometric coefficient of variation; DLT: dose-limiting toxicity; EGFR: epidermal growth factor receptor; HFSR: hand–foot skin reaction; IV: intravenous; mCRC: metastatic colorectal cancer; MTD: maximum tolerated dose; PK: pharmacokinetics; PR: partial response; QD: once daily; TEAE: treatment-emergent adverse event; VEGFR: vascular endothelial growth factor receptor. Additional Supporting Information may be found in the online version of this article. Conflict of interests: CW has received research funding from Bayer. JJL has received research funding from Merck and advisory board fees from AbbVie, Incyte and LOXO. IS is an employee of Bayer and owns Bayer stocks. AC is an employee of Bayer and owns stocks in Bayer, AstraZeneca and Pfizer. FH is an employee of Bayer and owns Bayer stocks. H-JL has received honoraria from Bayer, Bristol-Myers Squibb, Merck Serono and Roche, and advisory board and consulting fees from Bayer, Merck Serono and Roche. ACL has nothing to disclose. Grant sponsor: Bayer DOI: 10.1002/ijc.32317 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. History: Received 26 Oct 2018; Accepted 27 Feb 2019; Online 8 Apr 2019 Correspondence to: Colin Weekes, MD, PhD, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA, Tel.: +1 617-726-5130, E-mail: cdweekes@mgh.harvard.edu Funding Information: We would like to thank Zuzana Jirakova Trnkova and Susanne Reschke for their contribution to the study. We would also like to thank the patients, their families and participating in study centers. Our study was sponsored by Bayer. Editorial assistance in the preparation of this article was provided by Alex Coulthard and Katrin Gudmundsdottir of OPEN Health Medical Communications (London, UK), with financial support from Bayer. Publisher Copyright: {\textcopyright} 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC",
year = "2019",
month = nov,
day = "1",
doi = "10.1002/ijc.32317",
language = "English (US)",
volume = "145",
pages = "2450--2458",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "9",
}