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2680 Argx-110 Targeting CD70, in Combination with Azacitidine, Shows Favorable Safety Profile and Promising Anti-Leukemia Activity in Newly Diagnosed AML Patients in an Ongoing Phase 1/2 Clinical Trial

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Poster II
Hematology Disease Topics & Pathways:
Diseases, AML, Biological, antibodies, Therapies, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Adrian F Ochsenbein, MD1*, Carsten Riether, PhD2, Ulrike Bacher3*, Rouven Müller, MD4*, Sabine Höpner, PhD5*, Yara Banz6*, Magdalena Hinterbrandner, Msc7*, Mario Bargetzi, MD8, Markus G. Manz, MD9, Luc Van Rompaey, PhD10*, Mahan Moshir, MSc10*, Tim Delahaye, MSc10*, Domenica Gandini, MD, PhD10*, Ellen Erzeel10*, Anna Hultberg, PhD10*, Samson Fung, MD10, Hans De Haard, PhD10*, Nicolas Leupin, MD10 and Thomas Pabst, MD, PhD11

1Department of Clinical Research and Medical Oncology, University and University Hospital of Bern, Bern, Switzerland
2Department of Medical Oncology, Inselspital, University and University Hopsital of Bern, Bern, Switzerland
3Hematology and Hematology central Laboratory, University Hospital of Bern, Bern, Switzerland
4Department of Hematology and Oncology, Division of Hematology, University and University Hospital Zurich, Zürich, Switzerland
5Department of Clinical Research, University of Bern, Bern, Switzerland
6Institute of Pathology, University of Bern, Bern, Switzerland
7Tumorimmunology, Department of Clinical Research, University of Bern, Bern, Switzerland
8Division of Haematology and Transfusion Medicine, Cantonal Hospital Aarau, Aarau, Switzerland
9Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland, Zurich, Switzerland
10argenx, Zwijnaarde, Belgium
11Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, Switzerland

Outcomes in elderly patients with acute myeloid leukemia (AML) are still adverse, as the majority does not qualify for intensive therapy or allogenic stem cell transplantation (ASCT). DNA hypomethylating agents (HMAs) induce remissions and prolong survival in a fraction of these patients. However, overall prognosis remains dismal and all patients progress due to therapy-resistant leukemia stem cells (LSCs). We recently demonstrated that HMAs upregulate the expression of CD70 on primary human AML LSCs, potentially contributing to HMA resistance and that blocking the cell-autonomous CD70/CD27 signaling inhibits proliferation and myeloid differentiation of LSCs and contributes to HMA resistance. Consequently, combining HMA treatment with a blocking αCD70 monoclonal antibody potently reduced colony formation of AML LSCs in vitro and effectively eliminated human AML LCSs in xenograft experiments. Based on these results, we initiated an open-label, non-controlled, non-randomized Phase 1/2 trial combining the HMA azacitidine (AZA) with ARGX-110, a human monoclonal antibody targeting CD70, in newly diagnosed AML patients unfit for intensive chemotherapy (ARGX-110-1601, NCT03030612).

Trial design

ARGX-110 with optimized antibody-dependent cell-mediated cytotoxicity (ADCC), is administered intravenously at 1, 3, 10 or 20 mg/kg once every two weeks (Q2W), in combination with a standard dose of AZA (75 mg/m² subcutaneously for 7 days every 28 days). A 2-week lead-in of ARGX-110 enables studying the effect of αCD70 antibody monotherapy. Primary objectives in the Phase 1 include determining the maximum tolerated dose of ARGX-110 in combination with AZA and the recommended phase 2 dose (RP2D). Secondary objectives comprise safety, pharmacokinetics and anti-leukemic activity of ARGX-110 alone or in combination with AZA (including overall response rate (ORR), frequencies of LSCs and minimal/measurable residual disease (MRD)).


The trial is ongoing and as of 16th July 2018, 12 newly diagnosed AML patients were treated in the dose-escalation part of the trial, the results of which will be further updated in December 2018. The median age over the dose cohorts was 75 years (range 64-84) and included intermediate (N=6) and adverse (N=6) ELN risk groups. WHO subtypes were AML with recurrent genetic abnormalities (N=2), MDS-related changes (N=6), AML-NOS (N=3) and therapy-related myeloid neoplasms (N=1).

No dose-limiting toxicity was observed and the combination of ARGX-110 with a standard dose of AZA was well tolerated. Hematological toxicities, in line with expected AZA toxicities, were the most frequently reported adverse events (AEs).

At the cut-off, the ORR (complete remission [CR] + incomplete recovery [CRi] + partial remission [PR] + morphologic leukemia-free status [MLFS]) was 92% (11/12 patients); among the 11 evaluable subjects, the best response was CR/CRi for 9 patients (82%), 1 patient (9%) reached MLFS, and 1 (9%) PR, with 7 patients still on the trial (median duration on the trial at cut-off was 6.9 months [range: 2-14.4 months]). Significantly, 1 patient reached CR and was discontinued after 5 months to undergo ASCT. Five evaluable patients (45%) achieved MRD negativity by flow cytometry. Molecular MRD negativity was achieved in 3/8 patients with available results, two correlating with flow-MRD negativity. The mean time to response for the first 9 patients was 2.8 months and 3.4 months to reach best response. The 3 patients in the 20 mg/kg cohort did not all reach response at the time of cut-off. Based on pharmacokinetics, safety, and pharmacodynamic data, the RP2D of 10 mg/kg was established. Translational studies assessing LSC frequencies in bone marrow aspirates by limiting dilution colony assays and xenograft experiments revealed that ARGX-110 monotherapy and in combination with AZA significantly reduced LSC frequencies in AML patients.


ARGX-110 in combination with AZA is well tolerated and leads to a higher ORR compared to historical data for AZA alone. Clinical activity of the combination is observed in different AML subtypes and risk categories. Preliminary data indicate that ARGX-110 alone, and in combination with AZA, efficiently eliminates LSCs. These observations warrant further accelerated investigation of ARGX-110 in combination with AZA in AML patients unfit for intensive therapy.

Disclosures: Ochsenbein: argenx: Research Funding. Riether: argenx: Research Funding. Bacher: argenx: Research Funding. Höpner: argenx: Research Funding. Hinterbrandner: argenx: Research Funding. Van Rompaey: argenx: Employment. Moshir: argenx: Employment. Delahaye: argenx: Employment. Gandini: argenx: Employment. Erzeel: argenx: Employment. Hultberg: argenx: Employment. Fung: argenx: Consultancy. De Haard: argenx: Employment. Leupin: argenx: Employment.

*signifies non-member of ASH