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

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 RamkumarAngela Zubel, Yung Jue Bang

Research output: Contribution to journalArticle

3 Citations (Scopus)

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. Trial registration:Clinicaltrials.govregistry number NCT01598077 (registered on 4 May, 2012).

Original languageEnglish
Article number646
JournalBMC Cancer
Volume17
Issue number1
DOIs
StatePublished - 12 Sep 2017

Fingerprint

Epidermal Growth Factor Receptor
Esophagus
Stomach Neoplasms
Squamous Cell Carcinoma
Neck
Head
Monoclonal Antibodies
Breast Neoplasms
Maximum Tolerated Dose
Logistic Models
Neoplasms
Hypokalemia
Diarrhea
Appointments and Schedules
Pharmacokinetics
Safety
Pharmaceutical Preparations

Keywords

  • HER2
  • HER3
  • LJM716
  • Monoclonal antibody
  • Phase I

Cite this

Reynolds, Kerry Lynn ; Bedard, Philippe L. ; Lee, Se Hoon ; Lin, Chia Chi ; Tabernero, Josep ; Alsina, Maria ; Cohen, Ezra ; Baselga, José ; Blumenschein, George ; Graham, Donna M. ; Garrido-Laguna, Ignacio ; Juric, Dejan ; Sharma, Sunil ; Salgia, Ravi ; Seroutou, Abdelkader ; Tian, Xianbin ; Fernandez, Rose ; Morozov, Alex ; Sheng, Qing ; Ramkumar, Thiruvamoor ; Zubel, Angela ; Bang, Yung Jue. / 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. In: BMC Cancer. 2017 ; Vol. 17, No. 1.
@article{0c6075533bb7431fbbcfa170aa877242,
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",
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. Trial registration:Clinicaltrials.govregistry number NCT01598077 (registered on 4 May, 2012).",
keywords = "HER2, HER3, LJM716, Monoclonal antibody, Phase I",
author = "Reynolds, {Kerry Lynn} and Bedard, {Philippe L.} and Lee, {Se Hoon} and Lin, {Chia Chi} and Josep Tabernero and Maria Alsina and Ezra Cohen and Jos{\'e} Baselga and George Blumenschein and Graham, {Donna M.} and Ignacio Garrido-Laguna and Dejan Juric and Sunil Sharma and Ravi Salgia and Abdelkader Seroutou and Xianbin Tian and Rose Fernandez and Alex Morozov and Qing Sheng and Thiruvamoor Ramkumar and Angela Zubel and Bang, {Yung Jue}",
year = "2017",
month = "9",
day = "12",
doi = "10.1186/s12885-017-3641-6",
language = "English",
volume = "17",
journal = "BMC cancer",
issn = "1471-2407",
publisher = "BioMed Central Ltd.",
number = "1",

}

Reynolds, KL, Bedard, PL, Lee, SH, Lin, CC, Tabernero, J, Alsina, M, Cohen, E, Baselga, J, Blumenschein, G, Graham, DM, Garrido-Laguna, I, Juric, D, Sharma, S, Salgia, R, Seroutou, A, Tian, X, Fernandez, R, Morozov, A, Sheng, Q, Ramkumar, T, Zubel, A & Bang, YJ 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, vol. 17, no. 1, 646. https://doi.org/10.1186/s12885-017-3641-6

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. / Reynolds, Kerry Lynn; Bedard, Philippe L.; Lee, Se Hoon; Lin, Chia Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M.; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung Jue.

In: BMC Cancer, Vol. 17, No. 1, 646, 12.09.2017.

Research output: Contribution to journalArticle

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

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

UR - http://www.scopus.com/inward/record.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

VL - 17

JO - BMC cancer

JF - BMC cancer

SN - 1471-2407

IS - 1

M1 - 646

ER -