Furthering the clinical development of navicixizumab in advanced epithelial ovarian cancer patients with a population pharmacokinetic model and exploratory exposure-safety-efficacy response analyses (225)

Abstract

Objectives: Cumulative data from navicixizumab clinical trials were analyzed to establish a population pharmacokinetic model, which was further used to characterize the relationships of navicixizumab exposure with safety and efficacy parameters. Methods: A population pharmacokinetic model was developed using data from clinical trials with navicixizumab in advanced cancer patients (B83-001), in combination with paclitaxel in advanced ovarian cancer patients (B83-002) and combination with standard of care in colorectal cancer patients (B83-003). Exposure-safety analyses focused on the relationship between navicixizumab exposures and systemic hypertension as measured with mean arterial pressure data and incidence of pulmonary hypertension assessed using peak tricuspid velocity data. For the purposes of this analysis, pulmonary hypertension was defined as peak tricuspid velocities >3.4 m/s. Exposure-efficacy analyses focused on objective response rates collected using RECIST version 1.1 and sum of the longest diameters of the target lesion. Results: The overall pharmacokinetic profile of navicixizumab was best described by a 2-compartment model with dose-proportional pharmacokinetics observed at doses ≥ 2.5 mg/kg. The effects of patient weight and patient antidrug antibody (ADA) status were identified as significant covariates in the model, where ADA positivity was associated with reduced clearance values. Changes in mean arterial pressure were concentration-dependent, where both Stage III/IV and ADA positive patients had lesser changes in mean arterial pressures. While peak tricuspid velocities were not related to navicixizumab concentrations, dose, disease stage, or disease indication, pulmonary hypertension was observed as being related to cumulative navicixizumab exposures as measured by AUC and total dose. Navicixizumab exposures were not significantly related to objective response rates. Ovarian stage III/IV cancer patients demonstrated a significant relationship between higher exposure and significantly greater reductions in target tumor size. Conclusions: A robust pharmacokinetic model was developed, demonstrating linear navicixizumab pharmacokinetics at doses ≥ 2.5 mg/kg. While the impact of ADA on navicixizumab clearance was statistically significant, the impact at therapeutically relevant doses was not clinically meaningful. Changes in mean arterial pressures with navicixizumab concentrations support a favorable adverse event profile in the ovarian patient population, while cumulative dose and exposures are associated with peak tricuspid velocities ≥ 3.4 m/s. When both ORR and changes in target tumor size were considered, cumulative navicixizumab exposures were associated with increased efficacy in ovarian cancer patients. Cumulative data reported herein support continued clinical development of navicixizumab, especially in ovarian cancer patients. Objectives: Cumulative data from navicixizumab clinical trials were analyzed to establish a population pharmacokinetic model, which was further used to characterize the relationships of navicixizumab exposure with safety and efficacy parameters. Methods: A population pharmacokinetic model was developed using data from clinical trials with navicixizumab in advanced cancer patients (B83-001), in combination with paclitaxel in advanced ovarian cancer patients (B83-002) and combination with standard of care in colorectal cancer patients (B83-003). Exposure-safety analyses focused on the relationship between navicixizumab exposures and systemic hypertension as measured with mean arterial pressure data and incidence of pulmonary hypertension assessed using peak tricuspid velocity data. For the purposes of this analysis, pulmonary hypertension was defined as peak tricuspid velocities >3.4 m/s. Exposure-efficacy analyses focused on objective response rates collected using RECIST version 1.1 and sum of the longest diameters of the target lesion. Results: The overall pharmacokinetic profile of navicixizumab was best described by a 2-compartment model with dose-proportional pharmacokinetics observed at doses ≥ 2.5 mg/kg. The effects of patient weight and patient antidrug antibody (ADA) status were identified as significant covariates in the model, where ADA positivity was associated with reduced clearance values. Changes in mean arterial pressure were concentration-dependent, where both Stage III/IV and ADA positive patients had lesser changes in mean arterial pressures. While peak tricuspid velocities were not related to navicixizumab concentrations, dose, disease stage, or disease indication, pulmonary hypertension was observed as being related to cumulative navicixizumab exposures as measured by AUC and total dose. Navicixizumab exposures were not significantly related to objective response rates. Ovarian stage III/IV cancer patients demonstrated a significant relationship between higher exposure and significantly greater reductions in target tumor size. Conclusions: A robust pharmacokinetic model was developed, demonstrating linear navicixizumab pharmacokinetics at doses ≥ 2.5 mg/kg. While the impact of ADA on navicixizumab clearance was statistically significant, the impact at therapeutically relevant doses was not clinically meaningful. Changes in mean arterial pressures with navicixizumab concentrations support a favorable adverse event profile in the ovarian patient population, while cumulative dose and exposures are associated with peak tricuspid velocities ≥ 3.4 m/s. When both ORR and changes in target tumor size were considered, cumulative navicixizumab exposures were associated with increased efficacy in ovarian cancer patients. Cumulative data reported herein support continued clinical development of navicixizumab, especially in ovarian cancer patients.