A randomized clinical trial of chemotherapy with gemcitabine/cisplatin/nabpaclitaxel with or without the AXL inhibitor bemcentinib (BGB324) for patients with advanced pancreatic cancer.

Abstract

TPS473 Background: The Axl pathway coordinately mediates immune evasion and drug resistance in pancreatic cancer. Systemic Axl inhibition can enhance the efficacy of cancer therapy by blocking tumor cell proliferation, survival and drug resistance associated with epithelial-mesenchymal transition (EMT), and targeting innate immune suppression in the tumor microenvironment. Bemcentinib (BGB324) is a first in class, selective oral inhibitor of Axl. Our group has shown that bemcentinib therapy, in combination with gemcitabine, improved survival in multiple preclinical models of pancreatic cancer. Methods: This is a multicenter, randomized, phase 1b/2 clinical trial of nab-paclitaxel/gemcitabine/cisplatin with or without bemcentinib. Patients with metastatic pancreatic cancer, good performance status and preserved liver, kidney and hematologic function are eligible. The treatment schedule is as follows: Bemcentinib 100 or 200 mg daily, nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 intravenously on D1, 8 every 21 days. 3 -12 patients will be recruited in part 1 following a modified 3+3 dose finding scheme. Part 2 of the study is a 1:1 randomized phase 2 design enrolling 62 patients. The primary objective is to determine complete response rate. Secondary end points are overall response rate, PFS and adverse events. A parallel biomarker study will accompany the trial analyzing blood and tissue samples to determine the effect of chemotherapy and bemcentinib on 1) Axl pathway activity in tumor tissue, 2) changes in immune landscape including upregulation of immune cytokines, and immune cell infiltration into the tumor, 3) apoptosis and decreased proliferation of tumor and 4) to identify predictive biomarkers of response. Clinical trial information: NCT03649321.