Dose–response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin

Abstract

AbstractThe vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2–3 days post-crolibulin (13–24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug $${C}^{max}$$ C max and a linear combination of (1) reduction in tumor fraction with $${AUC}_{90s}>15.8$$ AUC 90 s > 15.8  mM s, and, (2) increase in tumor fraction with $${v}_{e}<0.3$$ v e < 0.3 . A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with $${\text{ADC}} < 1.1 \times 10^{ - 3} \;{\text{mm}}^{2} /{\text{s}}$$ ADC < 1.1 × 10 - 3 mm 2 / s , and, (2) increase in tumor fraction with $$v_{e}<0.3$$ v e < 0.3 . These findings are suggestive of cell swelling and decreased tumor perfusion 2–3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.