A phase 1 study evaluating safety and pharmacokinetics of losatuxizumab vedotin (ABBV-221), an anti-EGFR antibody-drug c
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PHASE I STUDIES
A phase 1 study evaluating safety and pharmacokinetics of losatuxizumab vedotin (ABBV-221), an anti-EGFR antibody-drug conjugate carrying monomethyl auristatin E, in patients with solid tumors likely to overexpress EGFR James M. Cleary 1 & Emiliano Calvo 2 & Victor Moreno 3 & Dejan Juric 4 & Geoffrey I. Shapiro 1 & Carol Ann Vanderwal 5 & Beibei Hu 5 & Maryella Gifford 5 & David Barch 5 & Lisa Roberts-Rapp 5 & Peter J. Ansell 5 & Hao Xiong 5 & Christopher Ocampo 5 & Anthony W. Tolcher 6 Received: 9 January 2020 / Accepted: 30 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung cancer, 5 head and neck [HNC], 5 glioblastoma multiforme, 2 breast, 14 other). Tumor samples were evaluated for EGFR protein expression by immunohistochemistry, EGFR and EGFR ligand mRNA expression by RNAseq, and results compared with outcome. Most common adverse events were infusion-related reaction (22/45; 49%) and fatigue (20/45; 44%). While most infusion reactions were grade ≤ 2, four patients experienced grade ≥3 infusion reactions. Several infusion reaction mitigation strategies were explored. Because of the high incidence of infusion reactions, the trial was stopped and the maximum tolerated dose was not reached. The last cleared dose: 6 mg/kg/cycle. Nineteen patients (42%) had stable disease; 4 remained on study >6 months. One HNC patient with increased levels of EGFR and EGFR ligands (amphiregulin, epiregulin) achieved a confirmed partial response. Pharmacokinetic analysis of losatuxizumab vedotin showed exposures appeared to be approximately dose-proportional. The high frequency of infusion reactions necessitated early closure of this trial. The detailed mitigation strategies used in this protocol for infusion-related reactions may provide beneficial information for trial design of agents with high infusion reaction rates. Keywords EGFR . Phase 1 . Antibody-drug conjugate . Advanced cancer . Losatuxizumab vedotin Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00908-3) contains supplementary material, which is available to authorized users. * James M. Cleary [email protected] 1
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
2
START Madrid-CIOCC, Madrid, Spain
3
START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain
4
Massachusetts General Hospital Cancer Center, Boston, MA, USA
5
AbbVie, Inc., North Chicago, IL, USA
6
START San Antonio,
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