First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors

Didier Meulendijks; Wolfgang Jacob; Maria Martinez-Garcia; Alvaro Taus; Martijn P Lolkema; Emile E Voest; Marlies H G Langenberg; Tania Fleitas Kanonnikoff; Andres Cervantes; Maja J De Jonge; Stefan Sleijfer; Morten Mau-Sørensen; Marlene Thomas; Maurizio Ceppi; Georgina Meneses-Lorente; Ian James; Celine Adessi; Francesca Michielin; Keelara Abiraj; Birgit Bossenmaier; Jan H M Schellens; Martin Weisser; Ulrik Niels Lassen

doi:10.1158/1078-0432.ccr-15-1683

First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors

Didier Meulendijks, Wolfgang Jacob, Maria Martinez-Garcia, Alvaro Taus, Martijn P Lolkema, Emile E Voest, Marlies H G Langenberg, Tania Fleitas Kanonnikoff, Andres Cervantes, Maja J De Jonge, Stefan Sleijfer, Morten Mau-Sørensen, Marlene Thomas, Maurizio Ceppi, Georgina Meneses-Lorente, Ian James, Celine Adessi, Francesca Michielin, Keelara Abiraj, Birgit BossenmaierJan H M Schellens, Martin Weisser, Ulrik Niels Lassen

Institut for Klinisk Medicin

38 Citationer (Scopus)

Abstract

PURPOSE: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.

EXPERIMENTAL DESIGN: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.

RESULTS: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration-time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥ 400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days).

CONCLUSIONS: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.

Originalsprog	Engelsk
Tidsskrift	Clinical Cancer Research
Vol/bind	22
Udgave nummer	4
Sider (fra-til)	877-85
Antal sider	9
ISSN	1078-0432
DOI	https://doi.org/10.1158/1078-0432.ccr-15-1683
Status	Udgivet - 15 feb. 2016

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Meulendijks, D., Jacob, W., Martinez-Garcia, M., Taus, A., Lolkema, M. P., Voest, E. E., Langenberg, M. H. G., Fleitas Kanonnikoff, T., Cervantes, A., De Jonge, M. J., Sleijfer, S., Mau-Sørensen, M., Thomas, M., Ceppi, M., Meneses-Lorente, G., James, I., Adessi, C., Michielin, F., Abiraj, K., ... Lassen, U. N. (2016). First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors. Clinical Cancer Research, 22(4), 877-85. https://doi.org/10.1158/1078-0432.ccr-15-1683

First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors. / Meulendijks, Didier; Jacob, Wolfgang; Martinez-Garcia, Maria et al.
I: Clinical Cancer Research, Bind 22, Nr. 4, 15.02.2016, s. 877-85.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Meulendijks, D, Jacob, W, Martinez-Garcia, M, Taus, A, Lolkema, MP, Voest, EE, Langenberg, MHG, Fleitas Kanonnikoff, T, Cervantes, A, De Jonge, MJ, Sleijfer, S, Mau-Sørensen, M, Thomas, M, Ceppi, M, Meneses-Lorente, G, James, I, Adessi, C, Michielin, F, Abiraj, K, Bossenmaier, B, Schellens, JHM, Weisser, M & Lassen, UN 2016, 'First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors', Clinical Cancer Research, bind 22, nr. 4, s. 877-85. https://doi.org/10.1158/1078-0432.ccr-15-1683

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title = "First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors",

abstract = "PURPOSE: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.EXPERIMENTAL DESIGN: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.RESULTS: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration-time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥ 400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days).CONCLUSIONS: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.",

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doi = "10.1158/1078-0432.ccr-15-1683",

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pages = "877--85",

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publisher = "American Association for Cancer Research (A A C R)",

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TY - JOUR

T1 - First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors

AU - Meulendijks, Didier

AU - Jacob, Wolfgang

AU - Martinez-Garcia, Maria

AU - Taus, Alvaro

AU - Lolkema, Martijn P

AU - Voest, Emile E

AU - Langenberg, Marlies H G

AU - Fleitas Kanonnikoff, Tania

AU - Cervantes, Andres

AU - De Jonge, Maja J

AU - Sleijfer, Stefan

AU - Mau-Sørensen, Morten

AU - Thomas, Marlene

AU - Ceppi, Maurizio

AU - Meneses-Lorente, Georgina

AU - James, Ian

AU - Adessi, Celine

AU - Michielin, Francesca

AU - Abiraj, Keelara

AU - Bossenmaier, Birgit

AU - Schellens, Jan H M

AU - Weisser, Martin

AU - Lassen, Ulrik Niels

PY - 2016/2/15

Y1 - 2016/2/15

N2 - PURPOSE: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.EXPERIMENTAL DESIGN: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.RESULTS: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration-time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥ 400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days).CONCLUSIONS: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.

AB - PURPOSE: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.EXPERIMENTAL DESIGN: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.RESULTS: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration-time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥ 400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days).CONCLUSIONS: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/1078-0432.ccr-15-1683

DO - 10.1158/1078-0432.ccr-15-1683

M3 - Journal article

C2 - 26463709

SN - 1078-0432

VL - 22

SP - 877

EP - 885

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 4

ER -

First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors

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