Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors

ESMO Open

article

E. Borazanci¹  A.M. Schram²  E. Garralda³  I. Brana³  M. Vieito Villar³  A. Spreafico⁴  M. Oliva⁴  N.J. Lakhani⁵  K. Hoffman⁶  R.M. Hallett⁶  D. Maetzel⁶  F. Hua⁷  J. Hilbert⁷  P. Giblin⁶  J. Anido⁶  A. Kelly⁶  P.J. Vickers⁶  R. Wasserman⁶  J. Seoane³  L.L. Siu⁴  D.M. Hyman²  D.V. Hoff¹  J. Tabernero³ 

[1] HonorHealth;Memorial Sloan Kettering Cancer Center;Vall d’Hebron Hospital Campus and Institute of Oncology;Princess Margaret Cancer Centre;START Midwest;Northern Biologics, Inc.;Applied BioMath;Institució Catalana de Recerca i Estudis Avançats ,(ICREA), Universitat Autònoma de Barcelona;UVic-UCC

关键词: leukemia inhibitory factor;    monoclonal antibody;    solid tumors;    STAT3;    safety;   

DOI  :  10.1016/j.esmoop.2022.100530

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

Background Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors.Materials and methods Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers.Results 16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action.Conclusions MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.

【 授权许可】

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