TY - JOUR
T1 - 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
AU - Reynolds, Kerry Lynn
AU - Bedard, Philippe L.
AU - Lee, Se Hoon
AU - Lin, Chia Chi
AU - Tabernero, Josep
AU - Alsina, Maria
AU - Cohen, Ezra
AU - Baselga, José
AU - Blumenschein, George
AU - Graham, Donna M.
AU - Garrido-Laguna, Ignacio
AU - Juric, Dejan
AU - Sharma, Sunil
AU - Salgia, Ravi
AU - Seroutou, Abdelkader
AU - Tian, Xianbin
AU - Fernandez, Rose
AU - Morozov, Alex
AU - Sheng, Qing
AU - Ramkumar, Thiruvamoor
AU - Zubel, Angela
AU - Bang, Yung Jue
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/9/12
Y1 - 2017/9/12
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Trial registration:Clinicaltrials.govregistry number NCT01598077 (registered on 4 May, 2012).
AB - Background: 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. Methods: 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. Results: 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. Conclusions: LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Trial registration:Clinicaltrials.govregistry number NCT01598077 (registered on 4 May, 2012).
KW - HER2
KW - HER3
KW - LJM716
KW - Monoclonal antibody
KW - Phase I
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UR - http://www.scopus.com/inward/citedby.url?scp=85029370515&partnerID=8YFLogxK
U2 - 10.1186/s12885-017-3641-6
DO - 10.1186/s12885-017-3641-6
M3 - Article
C2 - 28899363
AN - SCOPUS:85029370515
SN - 1471-2407
VL - 17
JO - BMC cancer
JF - BMC cancer
IS - 1
M1 - 646
ER -