A phase 3, randomized, double-blind, adaptive, placebo/paclitaxel-controlled study of AVB-S6-500 in combination with paclitaxel in patients with platinum-resistant recurrent ovarian cancer (GOG-3059/ENGOT OV-66/AVB500-OC-004).

TPS5605 Background: The AXL receptor and its activating ligand, GAS6, are important drivers of metastasis and therapeutic resistance in human cancers. This signaling axis represents an attractive target for therapeutic intervention, but the strong picomolar binding affinity between endogenous GAS6 and AXL and the promiscuity of small molecule AXL inhibitors have presented a barrier to specific and potent inhibition of AXL. AVB-S6-500 is a highly sensitive and specific inhibitor of AXL, with ̃200-fold higher affinity than wild-type (WT) AXL. AVB-S6-500 binds GAS6, the sole ligand of AXL, inhibiting its interaction with AXL thereby dramatically reducing AXL signaled invasion and migration of highly metastatic cells in vitro and inhibiting metastatic disease in nonclinical models of aggressive human cancers. A Phase 1b study in platinum resistant ovarian cancer showed no dose limiting toxicities and established a recommended Phase 2 dose of 15mg/kg administered every 2 weeks. Longer progression free survival (PFS) and overall survival (OS) times were observed in patients who had not been previously treated with bevacizumab. Furthermore, retrospective analyses demonstrated that serum soluble AXL to GAS6 ratio may identify patients more likely to respond to this therapy. Methods: Patients with high grade serous, platinum resistant ovarian cancer, who have received no more than 4 prior therapy regimens will be randomized 1:1 to AVB-500 + PAC or PAC + placebo. Patients will be stratified by recurrence after last platinum regimen (<3, 3-6 months), prior lines (1-2, 3-4), and prior bevacizumab (yes, no). The primary endpoint is PFS by RECIST v 1.1 as assessed by the investigator, with OS a key secondary endpoint. The study design is adaptive; with two interim analyses addressing conditional power in the bevacizumab treated subset, and in a serum soluble AXL, GAS6 biomarker subset, respectively, with interim results used to define the final target population. Simulations confirm a nominal one-sided type 1 error below 0.025, and show >90% statistical power for PFS under the following assumptions of PFS medians. Study recruitment began in Q1. Clinical trial information: NCT04729608.

Duke Scholars

Author Angeles Alvarez Secord Obstetrics and Gynecology, Gynecologic Oncology