NOX-A12 is an inhibitor of the chemokine CXCL12 for treatment of solid tumors. Binding of CXCL12 by NOX-A12 prevents receptor engagement and blocks the ability of CXCL12 to form a chemotactic concentration gradient. The Opera study (NCT03168139) is a Phase 1/2 study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination of NOX-A12 with pembrolizumab in metastatic microsatellite-stable colorectal (CRC) and pancreatic (PaC) cancer.
Patients received 300 mg NOX-A12 twice weekly during the two-week monotherapy phase. Biopsies were taken from liver metastases before treatment and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In the combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab.
20 patients were recruited, thereof 11 with CRC and 9 with PaC. 15 of the patients (75%) are male, with a median age of 62 (CRC) and 68 years (PaC). Patients were heavily pretreated with a median of 5 (CRC) and 3 lines (PaC) of prior treatment. Known best responses to last prior treatment was PD for 16 out of 20 patients. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. Thus far, 5 of the patients (25%) achieved a stable disease (3 CRC and 2 PaC). Interestingly, some of the patients with SD or clinical benefit also showed a favorable tissue cytokine response upon NOX-A12 monotherapy. Higher changes of CXCL12 levels in tissue observed upon monotherapy – indicating more complete CXCL12 neutralization – correlated with a favorable cytokine profile.
NOX-A12 alone and combined with pembrolizumab was safe and well tolerated. Changes in the cytokine signature in tumor tissue suggest that NOX-A12 modulates the tumor microenvironment and induces an immune-stimulatory Th1-like signature in multiple patients of which some show signs of disease stabilization or clinical benefit. The observed time of treatment compares favorably with the expected clinical course of such end-stage and heavily pre-treated patient population.
EudraCT: 2016-003657-15.
Noxxon Pharma.
Noxxon Pharma AG.
N. Halama, U. Prüfer: Research funded by Noxxon Pharma AG. A. Frömming, D. Beyer, D. Eulberg, J. Jungnelius, A. Mangasarian: Employee of Noxxon Pharma AG.