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- Title
Dose–response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.
- 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
- 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 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.
- Subjects
APOPTOSIS; PHARMACOKINETICS; TUMORS; REGRESSION analysis; DIFFUSION magnetic resonance imaging
- Publication
Scientific Reports, 2020, Vol 10, Issue 1, pN.PAG
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-020-71246-w