<h3>Objectives:</h3> AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). The purpose of this study was to evaluate safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the RP2D. <h3>Methods:</h3> Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg at q2 weeks in combination with weekly Pac 80mg/m<sup>2</sup>D1, 8, 15 q28 days or PLD 40mg/m<sup>2</sup>D1 q28 days and assessed for safety, pharmacokinetics, pharmacodynamics, and response (via RECIST v1.1, assessed by investigator). A safety review committee reviewed each cohort prior to escalation to the next higher dose level. <h3>Results:</h3> A total of 53 patients with platinum-resistant HGSOC ovarian adenocarcinoma (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. No patients experienced a dose-limiting toxicity (DLT). A total of 53% (28/53)of patients experienced a grade 3-4 adverse event. No grade 5 events were observed. The majority of events were related to known chemotherapy side effects. No subject discontinued study therapy due to an adverse event. Confirmed ORR with Pac+AVB-500 was 35% (8/23) and 15% (4/26) in the PLD+AVB-500 subgroup. ORR in the Pac subgroup after 1-2 prior lines was 40% with a platinum-free interval (PFI) ≥3 months, and 60% with a PFI of <3 months. Pac treated patients who had not been exposed to bevacizumab had a 60% ORR vs 15% in the Bev pre-treated subgroup. An exposure-response analysis identified serum AVB-500 C1D15 trough levels of >13.8mg/L as the minimal efficacious concentration (MEC). Among the Pac treated subgroup, the ORR was 39% vs 22% and median overall survival (OS) was 10.3 months vs 6.7 months in the MEC-high and MEC-low groups, respectively (Figure 1). Additionally, serum soluble AXL/GAS6 ratio was measured at baseline as an indicator of pathway activation. Among the Pac treated subgroup, the ORR was 42.9% vs 0% for those with ratios >0.773 compared to those with ratios ≤0.773. <h3>Conclusions:</h3> AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and targets GAS6/AXL pathway. AVB-500was found to be safe and tolerable in this Ph1B trial in combination with Paclitaxel or PLD. The RP2D was based upon PK/PD parameters. This Ph1B trial suggesteda higher ORR in the Pac treated subgroup, particularlywith C1D15 trough levels >13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analysis also suggested that improved response rates may be observed in patients who have not been exposed to bevacizumab. The serum soluble AXL/GAS6 ratio may serve as a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. Further development of AVB-500 15 mg/kg Q2W in combination with Pac is warranted in PROC.