Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (Study 1), and a drug-drug interaction (DDI) study with proton pump inhibitor (PPI) esomeprazole (Study 2). Following a high-fat meal (Study 1), cabozantinib Cmax and AUCs were increased (40.5% and 57%, respectively) and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (Study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80 - 125% limits; the upper 90% CI for Cmax was 125.1%. Due to the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH altering agents with cabozantinib is not contraindicated.