Pharmacokinetic and Pharmacodynamic analysis of circulating biomarkers of anti-NRP1, a novel anti-angiogenesis agent, in two Phase I trials in patients with advanced solid tumors
Menée sur des échantillons sanguins prélevés sur des patients inclus dans deux essais cliniques de phase I d'un anticorps monoclonal anti-NRP1, cette étude évalue les caractéristiques pharmacodynamiques de biomarqueurs associés à la réponse thérapeutique
Purpose: MNRP1685A is a monoclonal antibody to neuropilin-1 (NRP1). We evaluated blood-based pharmacodynamic (PD) biomarkers of MNRP1685A in two Phase I studies to assess exposure/response relationships to inform target dose and regimen selection. Experimental Design: The Phase I studies evaluated escalating doses of MNRP1685A as a single agent or in combination with bevacizumab. Plasma Placental Growth Factor (P1GF), VEGF and circulating NRP1 (cNRP1) were evaluated at multiple time-points using meso-scale discovery (MSD) assays and ELISA, respectively. Plasma PlGF was also measured in a Phase I/II trial of bevacizumab in metastatic breast cancer (AVF0776). The association between PlGF and MNRP1685A dose was described by a sigmoid Emax model. cNRP1 and MNRP1685A PK profiles were described using a two-target quasi-steady state (QSS) model. Results: A dose and time dependent increase in plasma PlGF and cNRP1 was observed in all patients treated with MNRP1685A. PK/PD analysis showed that bevacizumab and MNRP1685A had an additive effect in elevating P1GF. Predictions based on the two-target QSS model showed that the free drug concentration to maintain greater than 90% saturation of membrane NRP1 (mNRP1) and cNRP1 is about 8 mug/mL. Conclusions: These data show that MNRP1685A inhibits the VEGF pathway in humans as assessed by an increase in plasma PlGF. MNRP1685A appears to enhance bevacizumab-mediated VEGF pathway blockade, as demonstrated by an increase in the magnitude of PlGF elevation when combined with bevacizumab. PK/PD analysis of biomarkers in the Phase I population allowed identification of doses at which apparent maximal pathway modulation was observed.
Clinical Cancer Research , résumé, 2012