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

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...

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Autores: Borazanci, Erkut H.|||0000-0001-5136-5462, Schram, Alison|||0000-0002-6070-2413, Garralda, Elena|||0000-0002-4412-7842, Braña, Irene|||0000-0002-1068-9601, Vieito, María|||0000-0001-7531-343X, Spreafico, Anna|||0000-0002-3034-3042, Oliva, Marc|||0000-0001-5352-8130, Lakhani, Nehal J., Hoffman, K., Hallett, Robin M.|||0000-0002-2695-4190, Maetzel, Dorothea|||0000-0003-1720-802X, Hua, Fei, Hilbert, J., Giblin, Patricia|||0000-0002-4646-8384, Anido, Judit|||0000-0002-5569-8923, Kelly, A., Vickers, P.J., Wasserman, Robert, Seoane Suárez, Joan|||0000-0002-6541-5974, Siu, Lillian L.|||0000-0002-3500-0540, Hyman, David M., Von Hof, Daniel|||0000-0003-4723-7681, Tabernero, Josep|||0000-0002-2495-8139
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:292133
Acceso en línea:https://ddd.uab.cat/record/292133
https://dx.doi.org/urn:doi:10.1016/j.esmoop.2022.100530
Access Level:acceso abierto
Palabra clave:Leukemia inhibitory factor
Monoclonal antibody
Solid tumors
STAT3
Safety
Descripción
Sumario: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. 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. Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS.

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