A Phase 1b Study Evaluating the Safety and Efficacy of AK117 (anti-CD47 monoclonal antibody) in Combination with Azacitidine in Patients with Treatment-Naïve Acute Myeloid Leukemia

Background: AK117 is a humanized IgG4 monoclonal antibody that specifically targets CD47, a “don’t eat me” signal excessively expressed on tumor cells such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). CD47 blockade effectively stimulates macrophage-mediated phagocytosis of AML cells, and when combined with azacitidine (AZA), it synergistically enhances the activation of "eat me" signals. Here, we report the data from a Phase 1b study of AK117 plus AZA in patients with treatment-naïve AML.

Methods: Patients newly diagnosed with AML who were deemed unfit for intensive chemotherapy were included in the study to receive combination therapy with AK117 and AZA. AK117 was administered intravenously (IV) following various dosing regimens (10-20 mg/kg once weekly [QW], or 30-45 mg/kg every 2 weeks [Q2W]), whereas AZA was administered subcutaneously (SC) at the standard dosage (75 mg/m², Day 1-7, every 4 weeks [Q4W]). The primary endpoints of the study were safety/tolerability, and composite complete remission (CCR) defined as the combination of complete remission (CR) and complete remission with incomplete hematologic recovery (CRi), based on the 2017 European Leukemia Net (ELN) response criteria.

Results: As of June 9, 2023, 40 patients were enrolled (median age: 63 years, 42.5% males, 72.5% with ECOG≥1). Most patients had abnormal hematologic conditions at baseline, including decreased hemoglobin, neutrophil count, and platelet count. Specifically, 80.0% of patients had Grade ≥3 anemia, 62.5% had Grade ≥3 neutrophil count decrease, and 50.0% had Grade ≥3 platelet count decrease. For the recommended phase 2 dose (RP2D) group, treated with a combination of AK117 30 mg/kg Q2W and AZA, 22 patients were enrolled (median age: 63 years, 31.8% males, 72.7% with ECOG≥1). After a median follow-up of 6.7 months (ranging from 0.2-20.7 months), anemia (a primary adverse event associated with CD47 blocking antibodies) occurred in 32.5% (13/40) of the patients. Other commonly observed treatment-emergent adverse events (TEAEs) (≥30%) included decreased white blood cell count (70.0%), decreased lymphocyte count (62.5%), decreased platelet count (55.0%), decreased neutrophil count (52.5%), pyrexia (52.5%), constipation (40.0%), and vomiting (37.5%). The most frequently reported Grade ≥3 TEAEs (≥20%) were decreased white blood cell count (52.5%), decreased platelet count (47.5%), decreased neutrophil count (45.0%), decreased lymphocyte count (25.0%), and anemia (25.0%). One patient (2.5%) discontinued treatment due to TEAE. The efficacy of AK117 was compared at different dosages, and ultimately, 30mg/kg Q2W was chosen as the RP2D. Out of 20 evaluable patients, 11 (55%) achieved a CCR, including 9 (45%) with a CR and 2 (10%) with a CRi. Stable disease (SD) was reported in 35% of the patients. The median time to response (TTR) was 1.31 months, while the median time to CR (TTCR) was 1.84 months. The median duration of response (DoR) and duration of CR (DoCR) were not reached.

Conclusions: The combination of AK117 and AZA exhibited a manageable safety profile with a low incidence of anemia, and demonstrated promising efficacy as a first-line treatment in AML patients who were unable to undergo intensive chemotherapy.