Dataset Information

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

ABSTRACT:

Background

Epidermal growth factor receptor (EGFR) is a well-known target for cancer treatment. However, the authorized anti-EGFR monoclonal antibodies generally cause several toxic effects, especially severe cutaneous toxicities as well as infusion reactions, and the clinical indications are limited. Here we developed Ametumumab, a fully human recombinant anti-EGFR monoclonal antibody.

Objectives

To assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Ametumumab.

Design

A first-in-human phase Ia dose escalation study of Ametumumab in patients with advanced solid malignancies.

Methods

An open-label, first-in-human dose escalation study was done in 22 patients with advanced malignancies who received six ascending dosages ranging from 75 to 750 mg/m². Following a single dosage and a 28-day dose-limiting toxicity (DLT) monitoring period, patients were given repeated doses weekly. Blood samples were taken to determine the PK parameters of Ametumumab and anti-drug antibody concentrations. Every 8 weeks, radiographic tumor evaluations were conducted.

Results

In this trial, no DLT was observed, and the maximum tolerated dose was not reached at doses up to 750 mg/m². There were no severe adverse events but mild and moderate adverse effects, such as headache, proteinuria, and rash. Single-dose PK results demonstrated a straightforward linear relationship with dosage escalation. The medication concentrations accumulated and attained steady-state after four rounds of injections. It was calculated that 10 patients with disease control would be observed in the 22 evaluable patients. The disease control rate was 45.5%.

Conclusion

The Ametumumab was well tolerated and safe in patients with advanced solid malignancies, exhibiting minimal immunogenicity, a long half-life, high levels of drug exposure in the blood, and preliminary effectiveness.

Registration

The trial was registered with CTR20170343 on 10 April 2017, The China Center for Drug Evaluation.

SUBMITTER: Li D

PROVIDER: S-EPMC10071157 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

Li Da D Pan Hong H Wang Wei W Xue Yanan Y Fang Yong Y Lou Haizhou H Pan Qin Q Jin Wei W Zheng Yu Y Han Weidong W Zhu Kongli K Zhao Xianfeng X Xu Rong R Han Jin J Pan Hongming H

Therapeutic advances in medical oncology 20230401

<h4>Background</h4>Epidermal growth factor receptor (EGFR) is a well-known target for cancer treatment. However, the authorized anti-EGFR monoclonal antibodies generally cause several toxic effects, especially severe cutaneous toxicities as well as infusion reactions, and the clinical indications are limited. Here we developed Ametumumab, a fully human recombinant anti-EGFR monoclonal antibody.<h4>Objectives</h4>To assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Ame ...[more]

PMID: 37025261

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Project description:PurposeIn this first-in-human dose escalation study, the safety and efficacy of IO-108, a fully human monoclonal antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2), was investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody.MethodsThe study included patients with histologically or cytologically confirmed advanced and relapsed solid tumors, with measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Patients were treated with escalating doses of IO-108 every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. Safety and tolerability were the primary objectives. Secondary and exploratory objectives included: pharmacokinetics, clinical efficacy, immunogenicity and biomarkers.ResultsOf 25 patients enrolled, 12 were treated with IO-108 monotherapy and 13 received combination therapy. IO-108 was well-tolerated up to the maximally administered dose of 1,800 mg every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. No dose-limiting toxicity was observed, and a maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 6 (50.0%) patients treated with IO-108 monotherapy and 6 (46.2%) patients treated with IO-108+pembrolizumab. All TRAEs were mild or moderate (Grade 1 or 2), and no TRAEs led to treatment discontinuation or death. IO-108 exhibited a dose-proportional increase in exposure. Full receptor occupancy (RO) in peripheral blood was achieved at doses ≥600 mg. The overall response rate was 9% (1/11) in the monotherapy and 23% (3/13) in the combination therapy. A patient with treatment-refractory Merkel cell carcinoma treated with IO-108 monotherapy achieved a durable complete response (CR) for more than 2 years. Pharmacodynamic gene expression changes reflecting increased tumor infiltration of T cells were associated with clinical benefits in both monotherapy and combination therapy. Additionally, baseline tumor inflammation gene signature (TIS) scores correlated with clinical benefit.ConclusionIO-108 is well tolerated and has led to objective response as monotherapy and in combination with pembrolizumab. The complete response and the pharmacodynamic changes in the monotherapy cohort demonstrate single agent activity of IO-108 and provide proof of concept that targeting myeloid-suppressive pathways through LILRB2 inhibition may potentiate the clinical efficacy of anti-PD-1 immune checkpoint inhibitors.Trial registration numberNCT05054348.

Dataset Information

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

Background

Objectives

Design

Methods

Results

Conclusion

Registration

Publications

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

Similar Datasets

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