Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.

Abstract

276 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.

Immune-Based Therapies and the Role of Microsatellite Instability in Pancreatic Cancer

“…According to the preliminary results of a phase II study (COMBAT study) CD40 agonists can increase the survival of metastatic pancreatic cancer patients. The number of TREG (regulatory T-cells) cells are diminished by 50% whereas CD3 + -cells and CD8 + -T-cells increased 15-fold and 2-fold, respectively, in liver biopsies [ 149 ].…”

Harnessing the Immune System in Pancreatic Cancer

“…• Hidalgo et al presented interim pharmacodynamic data from the monotherapy portion of phase II COMBAT study where mPDA patients were treated with 5 days of BL-8040 lead-in, followed by 21-day cycles where patients received pembrolizumab D1 and BL-8040 thrice weekly [17]. Blood samples were obtained on D1 and D5 for flow cytometric analysis while liver biopsies, when available, were assessed to characterize dynamic changes in the nature of the immune cell infiltrate.…”