Modulation of angiogenic biomarkers in patients receiving high-dose TRC105

Abstract

BACKGROUND: TRC105, an anti-CD105 monoclonal antibody, has completed phase 1 testing and is being studied in multiple phase 2 trials. We previously reported that low dose TRC105 (0.01-1.0 mg/kg) modulated the expression of soluble angiogenic biomarkers in patients [J Clin Oncol 29: 2011 (suppl; abstr 10565)]. In this report, we evaluated angiogenic biomarkers in patients receiving higher doses of TRC105 including the recommended phase 2 dose. METHODS: Patients with advanced refractory solid tumors were treated with escalating doses of TRC105 until disease progression. Serial plasma samples were analyzed via an optimized multiplex ELISA platform. 36 biomarkers related to tumor growth, angiogenesis, and inflammation were assayed at baseline (BL), after 1 month (C2D1), concurrent with radiological restaging near the end of cycle 2 (C2D22), and at end of study (EOS). RESULTS: 32 patients treated with TRC105 at doses of 0.3 to 15 mg/kg were evaluated for biomarker expression. Wilcoxon signed rank tests indicated that the following analytes were significantly different at C2D1 when compared with baseline (p<0.05): Ang-2, IGFBP-3, total PAI-1, PDGF-AA, PDGF-BB, TSP-1, VEGF-D were all down-regulated; and E-Cadherin, soluble CD105, E-Selectin, IL-6, OPN, TSP-2, vWF were all up-regulated. At EOS, significant increases from C2D1 were observed for the following analytes: Ang-2, CRP, ICAM-1, IGFBP-1, IL-6, TSP-2, and VCAM-1 (p<0.05). Additionally, dose-dependent increases in soluble CD105 at C2D1 were observed (p<0.0001, r=0.9), suggesting direct target modulation by TRC105. CONCLUSIONS: TRC105 therapy is associated with early down-regulation of certain key angiogenic biomarkers and a dose-dependent increase in sCD105. Increases in many initially down-regulated angiogenic factors were observed at the time of progression, suggesting possible mechanisms for acquired resistance to TRC105. Further analysis of TRC105 in specified patient populations is underway and may provide more insight into the biological effects of this drug.