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  • Dose-response assessment by...
    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

    Scientific reports, 09/2020, Volume: 10, Issue: 1
    Journal Article

    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 ). ADC maps were computed from DW-MRI. Pre-contrast T maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC ) and the Extended Tofts Model parameters k , v , and v were calculated. There was a strong correlation between higher plasma drug Formula: see text and a linear combination of (1) reduction in tumor fraction with Formula: see text mM s, and, (2) increase in tumor fraction with Formula: see text. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with Formula: see text, and, (2) increase in tumor fraction with Formula: see text. 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.