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

被引：26

作者：

Borazanci, E. ^{[1
]}

Schram, A. M. ^{[2
]}

Garralda, E. ^{[3
]}

Brana, I ^{[3
]}

Villar, M. Vieito ^{[3
]}

Spreafico, A. ^{[4
]}

Oliva, M. ^{[4
]}

Lakhani, N. J. ^{[5
]}

Hoffman, K. ^{[6
]}

Hallett, R. M. ^{[6
]}

Maetzel, D. ^{[6
]}

Hua, F. ^{[7
]}

Hilbert, J. ^{[7
]}

Giblin, P. ^{[6
]}

Anido, J. ^{[6
]}

Kelly, A. ^{[6
]}

Vickers, P. J. ^{[6
]}

Wasserman, R. ^{[6
]}

Seoane, J. ^{[3
,8
]}

Siu, L. L. ^{[4
]}

Hyman, D. M. ^{[2
]}

Hoff, D., V ^{[1
]}

Tabernero, J. ^{[3
,9
]}

机构：

[1] HonorHealth, Scottsdale, AZ USA

[2] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[3] Vall dHebron Hosp Campus & Inst Oncol VHIO, Barcelona, Spain

[4] Princess Margaret Canc Ctr, Toronto, ON, Canada

[5] START Midwest, Grand Rapids, MI USA

[6] Northern Biol Inc, Toronto, ON, Canada

[7] Appl BioMath, Concord, MA USA

[8] Univ Autonoma Barcelona UAB, Inst Catalana Recerca & Estudis Avancats ICREA, CIBERONC, Barcelona, Spain

[9] UVic UCC, IOB Quiron, Barcelona, Spain

来源：

ESMO OPEN | 2022年 / 7卷 / 04期

关键词：

leukemia inhibitory factor; monoclonal antibody; solid tumors; STAT3; safety; LIF; CELLS; IMPLANTATION; ACTIVATION; EXPRESSION; CANCER; MICE;

D O I：

10.1016/j.esmoop.2022.100530

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

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: 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 >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.

引用

页数：11

共 29 条

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