Citations

2023 Background: TRC105 is a humanized antibody targeting CD105 (endoglin), a member of the TGFβ receptor superfamily. CD105 is expressed in glioma stem cells and circulating endothelial cells (CECs) in GBM patients (pts), increasing following VEGF inhibition. N1174 was conducted in recurrent bevacizumab (bev) naïve GBM pts to investigate the hypothesis that CD105 blockade+bev can delay development of bev resistance. Methods: After a ph I cohort (15 pts) established the ph II dose of TRC105 as 10 mg/kg IV over 4 hours every 7 days in combination with standard dose bev, the ph II trial used 1:1 randomization with 90% power and 0.10 type I error to detect a 3 month (mo) difference in progression-free survival (PFS) between the two arms. CECs including CD105 positive subsets were measured by flow cytometry at baseline and multiple time points. Results: Based on 101 evaluable ph II pts, there was no significant difference in PFS between TRC105+bev and bev only (2.9 vs 3.2 mo, respectively; HR=1.14, 95% CI 0.73-1.77, p=0.57), or overall survival (10.0 vs 7.4 mo; HR 1.02 95% CI 0.63-1.65, p=0.93). Response rate (complete or partial) was 12.2% (6/49) for TRC105+bev and 11.6% (5/43) for bev only. Overall incidence of grade (gr) 3+ toxicity was higher for TRC105+bev (67.3% vs 32.7%, p<0.001) mainly due to 14 pts with gr 3 anemia in the TRC105+bev arm vs 0 in the bev only pts. Gr 3+ non-heme toxicities were higher in pts receiving TRC105+bev vs bev only (50% vs 30.6%, p=0.07), mainly due to headache (6 vs 1 pts) and hyperglycemia (3 vs 0 pts). CECs remained stable in combination treated pts, suggesting a possible impact of the anti-CD105 blockade, but increased at progression in the bev only arm. There was no association between PFS and initial changes in CEC values, independent of treatment received. Conclusions: TRC105 plus bev did not prolong median PFS vs single agent bev in recurrent GBM pts, although it was associated with a non-significant prolongation of OS. These data and associated correlative analysis of CECs from study pts point against endoglin being a clinically significant factor for the development of bev resistance. Support: U10CA180821, U10CA180882. Clinical trial information: NCT01648348.