Background: TRC105 is an anti-endoglin chimeric monoclonal antibody that inhibits angiogenesis and tumor growth and is being studied in randomized Phase 2 trials with Bev. TRC105 is cleared through binding to endoglin expressed on proliferating endothelium when given as a single agent to cancer patients (Spencer et al, ASCO 2012). Preclinical data indicate that endoglin expression is increased in response to VEGF targeted treatment, and increased endoglin expression in response to Bev may increase the clearance of TRC105 when administered in combination to cancer patients.

Methods: Patients (pts) with solid tumors (ST) or ovarian cancer (OC) received 10 mg/kg/wk TRC105 as a single agent, and additional patients with ST (primarily ovarian and colorectal) received 10 mg/kg/wk TRC105 with Bev. Peak and trough levels were assessed by ELISA in 39 patients who received TRC105 alone and compared to that of 35 patients (largely Bev refractory) who received TRC105 and Bev. Pts administered TRC105 and Bev were considered a population sub-group and treated as a covariate. A population pharmacokinetic model of TRC105 disposition was built using rich sampling from the ST trial, with sparse data from OC and TRC105+Bev included in the base model. A two-compartment model with nonlinear elimination best fit the data, utilizing Michaelis-Menten parameters for saturable clearance.

Results: TRC105 peak and trough concentrations exceeded target serum concentrations of TRC105 known to saturate endoglin receptors in all pts dosed with 10 mg/kg/wk of TRC105 with and without Bev. The PK of TRC105 given with Bev had mean predicted (following 10,000 simulations) parameters of volume of distribution in the central compartment (VC), VMAX, and KM that were increased compared to population estimated parameters of TRC105 given as a single agent [VC= 44.5±2 (SE) (mL/kg) Pop mean estimate vs. 68.8±4 (mL/kg) Bev predicted; VMAX = 92.6±16 (μg/hr) vs. 297.5±40 (μg/hr) predicted, and KM= 5.91±2 (μg/mL) vs. 61.6±8.8 (μg/mL)]. All differences were significant (p<0.001). Observable data from patients administered the combination yielded PK parameters that were consistent with increased target-mediated clearance of TRC105 when given with Bev.

Conclusions: Peak and trough TRC105 serum levels exceed target serum concentrations when given at 10 mg/kg/wk as a single agent or with Bev. Central compartment distribution of TRC105 increased when given with Bev, which is consistent with increased endoglin expression on proliferating endothelium following Bev treatment. The maximum rate of elimination (Vmax) also increased, consistent with increased turnover; however the intrinsic clearance ratio of Vmax/Km remained the same, suggesting no change in endoglin turnover efficiency. Future studies will assess whether PK parameters correlate with responses to the combination of TRC105 and Bev in Bev refractory patients.