Phase I Dose-Escalation Study of the Anti-CD70 Antibody ARGX-110 in Advanced Malignancies

Abstract

The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies. Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels ( = 26). ARGX-110 was administered intravenously every 3 weeks until progression or intolerable toxicity. Dose-limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected. Dose-limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRR). Of the 20 SAEs reported, five events, all IRRs, were considered related to ARGX-110. ARGX-110 demonstrates dose proportionality over the dose range 1 to 10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10 to 13 days. The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related antitumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematologic malignancies. This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics, and preliminary antitumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies. .

New emerging targets in cancer immunotherapy: CD27 (TNFRSF7)

“…The afucosylation of the anti-CD70 mAb is intended to improve its ability to induce the ADCC of CD70-expressing tumour cells. The best achieved overall response was SD in 14/26 (54%) patients 46. Five patients (RCC, ovarian cancer, head and neck cancer, myoepithelial carcinoma and mesothelioma) had a PFS of >6 months 46.…”

“…The best achieved overall response was SD in 14/26 (54%) patients 46. Five patients (RCC, ovarian cancer, head and neck cancer, myoepithelial carcinoma and mesothelioma) had a PFS of >6 months 46. One patient with T-cell lymphoma achieved a complete haematological response 47…”

“…ARGX-110 (glycoengineered CD70 blocking mAb) showed a favourable safety profile without any dose-limiting toxicity and no immune-related AEs. Drug-related grade 3 AE (fatigue, anorexia and hypoxia) were observed in 2/26 patients 46…”

Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage-Specific Targets

“…In addition, ARGX-110 displays enhanced ADCC and ADCP while preserving a strong CDC ( 107 ). The first phase I study (NCT02759250) in patients with advanced solid tumors expressing CD70 provided evidence of good tolerability of ARGX-110 and antitumor activity at all dose levels ( 108 ). Currently, a phase I–II study is recruiting patients to evaluate ARGX-110 efficacy in AML (NCT03030612).…”

Unveiling a CD70-positive subset of cancer-associated fibroblasts marked by pro-migratory activity and thriving regulatory T cell accumulation

“…Ten percent was chosen based on inclusion criteria for Phase 1 clinical trials using CD70-targeting antibodies. 50 For CD4 staining, the percentage positive immune cells were scored 0 to 3C (<5%, 5-10%, 11-50%, >50% of immune cells stained). Tregs were divided into 3 groups (<5%, 5-10%, >10% of immune cells stained).…”