Seroutou, Abdelkader, Tian, Xianbin, Fernandez, Rose, Morozov, Alex, Sheng, Qing, Ramkumar, Thiruvamoor and Zubel, Angela (2017) 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. BMC Cancer, 17(1) (646). ISSN 1471-2407

Abstract

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.

Item Type:	Article
Keywords:	phase I; HER3; HER2; monoclonal antibody; LJM716
Date Deposited:	04 Oct 2017 00:45
Last Modified:	04 Oct 2017 00:45
URI:	https://oak.novartis.com/id/eprint/30349