6533b82dfe1ef96bd129161f

RESEARCH PRODUCT

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

Morten Mau SoerensenAndrés CervantesMaria Martinez-garciaStefan SleijferTania Fleitas KanonnikoffDidier MeulendijksMaja J.a. De JongeKeelara AbirajÁLvaro TausMarlene ThomasMaurizio CeppiUlrik LassenBirgit BossenmaierEmile E. VoestJan H.m. SchellensCeline AdessiMartin WeisserWolfgang JacobGeorgina Meneses-lorenteMarlies H.g. LangenbergMartijn P. LolkemaMartijn P. LolkemaFrancesca MichielinIan James

subject

AdultMale0301 basic medicineCancer Researchmedicine.medical_specialtyPathologyMaximum Tolerated DoseReceptor ErbB-3CmaxAntibodies Monoclonal HumanizedResearch SupportGastroenterologyClinical Trial Phase I03 medical and health sciencesPhase I0302 clinical medicinePharmacokineticsInternal medicineJournal ArticlemedicineHumansNon-U.S. Gov'tAdverse effectAgedAnalgesicsbusiness.industryResearch Support Non-U.S. Gov'tCancerMiddle AgedLumretuzumabmedicine.diseaseClinical TrialMulticenter StudyTreatment Outcome030104 developmental biologyOncology030220 oncology & carcinogenesisPharmacodynamicsMonoclonalFemaleColorectal NeoplasmsbusinessEx vivo

description

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. Clin Cancer Res; 22(4); 877–85. ©2015 AACR.

yearjournalcountryeditionlanguage
2016-02-15
https://www.fundanet.incliva.es/publicaciones/ProdCientif/PublicacionFrw.aspx?id=3080