Dose-specific clearance of TRC105 (anti-CD105 antibody) in advanced solid tumor patients.
3042^ Background: CD105 is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels. TRC105 is an anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with advanced solid tumors and normal organ function were treated with escalating doses of intravenously administered TRC105 and assessed for safety and pharmacokinetics (PK). PK parameters for determining dose-linearity were estimated following single doses on in 16 patients at 3, 10 and 15 mg/kg and correlated with safety. Results: TRC105 was tolerated at 10 mg/kg weekly and 15 mg/kg every 2 weeks, but hyproliferative anemia was dose-limiting at 15 mg/kg weekly and was associated with TRC105 accumulation in serum from target saturation. Preliminary evidence of activity was observed with 21 of 45 evaluable patients progression-free at 2 months, including two ongoing responders. The AUC-single dose relationship of TRC105 revealed supra-proportionality in serum exposure at 15 mg/kg compared to 3 and 10 mg/kg. Dose proportionality using a power model revealed a nonlinear pharmacokinetic process (log[AUC] = 0.125*Dose+2.67, r2 = 0.92, ANOVA p<0.0035). The steady state volume of distribution was low (≈ 5.40 L/70kg) indicating TRC105 was confined to the vasculature with a low capacity target (i.e., low relative abundance) making it susceptible to saturation. The post-infusion Cmax however was linearly related to dose (r = 0.85) which suggested the nonlinearity in clearance was attributed to target-mediated disposition. The nonlinear disposition in the presence of low distribution indicated TRC105 bound avidly to endothelial cells. Concentrations expected to saturate CD105 binding were achieved continuously at 15 mg/kg dosed every 2 weeks and 10 mg/kg/wk. TRC105 accumulated at 15 mg/kg/wk as the accumulation factor at 56 days was 1.77-fold over single doses on C1D1. Conclusions: TRC105 clearance decreased above the MTD resulting in drug accumulation and hypoproliferative anemia with weekly dosing. The nonlinearity in clearance was attributed to saturating target-mediated disposition, consistent with binding to proliferating endothelial cells.