Year of Grant: 2015
Acute myeloid leukemia (AML) is the most common type of blood cancer affecting adults with incidence rates increasing with age. While standard induction chemotherapy with anthracyclines plus cytarabine can lead to a complete remission in 50-75% of younger patients, the majority of AML patients eventually relapses and dies of recurrent disease. In particular, older patients who are not able to withstand intensive chemotherapy have a median survival of 5–10 months. As such, the survival rate for elderly patients with AML has not improved or changed substantially in the last years.
Typically, AML blasts co-express the tumor necrosis receptor/ligand pair CD27 and CD70. The CD70-CD27-interaction promotes proliferation of AML cells by inducing stem cell gene signature pathways such as the canonical Wnt-, JAK/STAT-, hedgehog-, and TTGF signaling to increase symmetric cell division and promote a malignant state. Testings have shown that the blocking of CD70/CD27-signalling by monoclonal antibodies helps reduce the expression of stem cell signature genes, inhibits Wnt pathway activation, promotes asymmetric cell division and differentiation and decreases AML cell growth and colony formation in vitro, resulting in increased survival in preclinical mice studies.
This proposed Phase I/II clinical trial seeks to combine and assess the safety and effectiveness of azacytidine (standard treatment) with humanized monoclonal antibody ARGX-110 in patients with high-risk myelodysplastic syndrome (MDS) and patients with untreated de novo AML unfit for intensive induction treatment. Modified with the Potelligent® technonology, ARGX-110 induces enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) to specifically bind CD70 expressing cells and inhibit CD27 ligation and signaling to target the disease initiating stem cells.
The phase I part of the protocol is a dose escalation of ARGX-110 starting with a loading dose followed by the combination with standard dose acazytidine to assess safety and tolerability. The established dose will be tested in an extension phase II study with 15 additional patients. The study will be accompanied by a strong translational analysis on the effect of ARGX-110 treatment on AML blasts and leukemia stem cells.
ARGX-110 has been tested in a non-randomized, open-label multicenter, Phase I study, which consisted of a dose escalation part followed by a safety expansion involving 60 patients with CD70-expressing solid tumors and hematological cancers. No dose limiting toxicity was observed.
BERN UNIVERSITY HOSPITAL: A phase I/II study of ARGX-110 in patients with relapsed/refractory acute myeloid leukemia
RTFCCR ACTIVE GRANTS
Cleveland Clinic Foundation, 2017
University of Cambridge, 2015
University of Edinburgh, 2015