Biomarker modulation in patients (pts) receiving TRC105 (T) and bevacizumab (B) in a phase Ib clinical trial

Abstract

BACKGROUND: Endoglin (END; CD105) is a membrane-bound cell surface receptor expressed on proliferating endothelial cells implicated in resistance to VEGF inhibition. T, an anti-End monoclonal antibody, potentiates anti-VEGF therapy in in vitro and in vivo models. The combination of T plus B was well tolerated and was active in pts who progressed on prior B treatment. METHODS: Pts with advanced refractory solid tumors were treated with escalating doses of T plus B. Pts received 1 week of B monotherapy prior to the addition of T. Thirty-eight biomarkers related to tumor growth, angiogenesis, and inflammation were analyzed using an optimized multiplex ELISA platform. Samples from 38 pts were collected at baseline (BL), 1 week (C1D8), 2 week (C1D15), 4 week (C2D1), and end of study (EOS). Biomarker concentrations on study were compared to baseline using the Wilcoxon signed rank test with statistical significance assumed at p<0.05. RESULTS: After 1 week of B monotherapy (C1D8), PlGF was elevated and ANG-2, soluble END (sEND), TSP2, and VEGFR1 were decreased. Following the addition of T, only Ang-2 remained significantly decreased, while the following analytes were significantly elevated at C1D15, C2D1 and EOS: CRP, sEND, E-Selectin, IL-6, PAI-1 (active and total), P-Selectin, SDF-1, TGF-b1, and VCAM-1. Increases in sEND and PlGF are consistent with observations from pts treated with either T or B alone, respectively. The inflammatory markers, CRP and IL-6, and TGFb-regulated proteins, PAI-1 active and sEND, all exhibited greater than a 5-fold increase on average at EOS. Interestingly, the elevation of the END ligand, TGFb1, in response to T plus B treatment, has not been observed in pts treated with either agent alone. CONCLUSIONS: Treatment of pts with either T or B alone is associated with modulation of multiple angiogenic and inflammatory biomarkers. However, the combination of both agents led to increases in many inflammatory and TGFb-related proteins that persisted throughout the study. The differences across the biomarker patterns from pts treated with T plus B suggest increased bioactivity for the combination and support the role of T potentiating anti-VEGF therapies in pts.