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

• Published in: Scientific reports Vol. 10; no. 1; p. 14449
• Main Authors: Lorza, Andres M. Arias, Ravi, Harshan, Philip, Rohit C., Galons, Jean-Philippe, Trouard, Theodore P., Parra, Nestor A., Von Hoff, Daniel D., Read, William L., Tibes, Raoul, Korn, Ronald L., Raghunand, Natarajan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2020; Nature Publishing Group
• Subjects: 692/4028/67/2321; 692/4028/67/2328; Adult; Aged; Benzopyrans - administration & dosage; Blood Vessels - drug effects; Blood Vessels - pathology; Contrast Media - administration & dosage; Diffusion Magnetic Resonance Imaging; Dose-Response Relationship, Drug; Female; Fish; Gadolinium; Gadolinium - pharmacology; Genetic linkage; Genomics; Genotyping; Humanities and Social Sciences; Humans; Male; Marine organisms; Middle Aged; multidisciplinary; Neoplasms - classification; Neoplasms - diagnostic imaging; Neoplasms - drug therapy; Neoplasms - pathology; Neovascularization, Pathologic - diagnostic imaging; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Pharmacokinetics; Quantitative trait loci; Ruditapes philippinarum; Science; Science (multidisciplinary); Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-71246-w

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/m 2 ). ADC maps were computed from DW-MRI. Pre-contrast T 1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC 90s ) and the Extended Tofts Model parameters k trans , v e , and v p were calculated. There was a strong correlation between higher plasma drug C max and a linear combination of (1) reduction in tumor fraction with AUC 90 s > 15.8  mM s, and, (2) increase in tumor fraction with v e < 0.3 . A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with ADC < 1.1 × 10 - 3 mm 2 / s , and, (2) increase in tumor fraction with 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.