Safety of AK117, an anti-CD47 monoclonal antibody, in patients with advanced or metastatic solid tumors in a phase I study.
Authors: Gan Hui Kong , Coward Jermaine , Mislang Anna Rachelle Austria , Cosman Rasha , Nagrial Adnan , Jin Xiaoping , Li Baiyong , Wang Zhongmin Maxwell , Kwek Kon Yew , Xia Dennis , Xia Yu 
Published: June 2021

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Background: AK117 is a novel humanized IgG4 monoclonal antibody (mAb) targeting CD47, a macrophage immune checkpoint that allows tumor cells to evade immune destruction by phagocytic cells. CD47 is a target expressed in many cancers. However, the initial dose of anti-CD47 therapy may be limited by severe anemia due to ubiquitous CD47 expression on senescent red blood cells (RBCs). Here, we present encouraging preliminary AK117 safety and receptor occupancy (RO) data from an ongoing dose-escalation study in patients (pts) with advanced or metastatic solid tumors. Methods: This is a first-in-human, phase 1a/1b, multicenter, open label, single arm, dose escalation and dose expansion study of AK117 administered intravenously to adult pts with resistant/refractory advanced or metastatic solid tumors or lymphomas. In the dose escalation phase (phase 1a), an accelerated titration followed by a 3+3+3 design was used to assess the safety and tolerability of AK117 monotherapy (dose range 0.3 mg/kg to 45 mg/kg); and determine the maximum tolerated dose (MTD). AK117 was administered QW on a 28-day treatment cycle and dose limiting toxicity (DLT) observation period. Tumor assessments per RECIST v1.1 were performed once every 8 weeks (2 cycles). Results: As of 15 Feb 2021, 15 pts were enrolled in phase 1a with DLT evaluation of the 30 mg/kg cohort currently in progress. There were no DLTs up to 20 mg/kg QW AK117, inclusive. Five treatment-related adverse events (TRAEs) occurred in 4 subjects as shown in the table below. All pts with TRAEs continue to receive AK117, except the pt on 1 mg/kg AK117 who discontinued due to disease progression. G2 anemia and G1 thrombocytopenia occurred after Cycle 1 in a pt (liposarcoma, 10 mg/kg cohort), who had a medical history of anemia (hemoglobin 119 g/L at screening). No hematological TRAEs were seen in other pts, including those who received 20 mg/kg AK117 QW. There were no infusion-related reactions (IRRs) or grade ≥ 3 TRAEs. Target engagement in the periphery was confirmed by measuring CD47 RO of AK117 on RBCs and T lymphocytes. 100% RO on RBCs and T lymphocytes was achieved after the first dose and continued to Day 8 (prior to second dose) in the 10 mg/kg and 20 mg/kg cohorts. Conclusions: AK117 is safe and well-tolerated up to 20 mg/kg QW, inclusive, with no IRRs or severe TRAEs observed. There were no hematological TRAEs, except in a pt with baseline G1 anemia receiving 10 mg/kg AK117. Unlike other anti-CD47 therapies, AK117 does not require a lower ‘priming’ dose to prevent anemia. Safety evaluation of the 30 mg/kg dose level is in progress. Full and durable RO in the periphery was seen at 10 mg/kg and above. Further evaluation of AK117 in combination with AK104, an anti-PD-1/CTLA-4 bispecific antibody, shall commence imminently. Clinical trial information: NCT04349969. [Table: see text]