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

• Authors: Andres M. Lorza, H. Lee Moffitt Cancer Center and Research Institute; Harshan Ravi, H. Lee Moffitt Cancer Center and Research Institute; Rohit C. Philip, University of Arizona; Jean-Philippe Galons, University of Arizona; Theodore P. Trouard, University of Arizona; Nestor A. Parra, H. Lee Moffitt Cancer Center and Research Institute; Daniel D. Von Hoff, Translational Genomics Research Institute; William Read, Emory University; Raoul Tibes, Julius Maximilians University & Medical Center; Ronald L. Korn, Imaging Endpoints LLC; Natarajan Raghunand, H. Lee Moffitt Cancer Center and Research Institute
• Journal Title: Scientific Reports
• Volume: Volume 10, Number 1
• Publisher: Nature Portfolio | 2020-09-02, Pages 14449-14449
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41598-020-71246-w
• Subjects: Health Sciences, Oncology; Biology, Physiology; Engineering, Biomedical; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; Arterial input function; Contrast enhanced; I trial; Perfusion parameters; Targeting agent; Solid tumors; Therapy; Efficacy; Combination; Ombrabulin

Abstract

The 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 Cmax and a linear combination of (1) reduction in tumor fraction with AUC90s> 15.8 mM s, and, (2) increase in tumor fraction with ve< 0.3. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with ADC<1.1×10-3mm2/s, and, (2) increase in tumor fraction with ve< 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.