Title |
A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer
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Published in |
BMC Cancer, September 2017
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DOI | 10.1186/s12885-017-3641-6 |
Pubmed ID | |
Authors |
Kerry Lynn Reynolds, Philippe L. Bedard, Se-Hoon Lee, Chia-Chi Lin, Josep Tabernero, Maria Alsina, Ezra Cohen, José Baselga, George Blumenschein, Donna M. Graham, Ignacio Garrido-Laguna, Dejan Juric, Sunil Sharma, Ravi Salgia, Abdelkader Seroutou, Xianbin Tian, Rose Fernandez, Alex Morozov, Qing Sheng, Thiruvamoor Ramkumar, Angela Zubel, Yung-Jue Bang |
Abstract |
Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012). |
X Demographics
Geographical breakdown
Country | Count | As % |
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Spain | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Practitioners (doctors, other healthcare professionals) | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 65 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 13 | 20% |
Other | 7 | 11% |
Student > Ph. D. Student | 7 | 11% |
Student > Bachelor | 6 | 9% |
Student > Master | 5 | 8% |
Other | 14 | 22% |
Unknown | 13 | 20% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 19 | 29% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 9% |
Biochemistry, Genetics and Molecular Biology | 5 | 8% |
Nursing and Health Professions | 4 | 6% |
Economics, Econometrics and Finance | 4 | 6% |
Other | 8 | 12% |
Unknown | 19 | 29% |