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• W3081519394 abstract "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/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 $${C}^{max}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:msup> <mml:mrow> <mml:mi>C</mml:mi> </mml:mrow> <mml:mrow> <mml:mi>max</mml:mi> </mml:mrow> </mml:msup> </mml:math> and a linear combination of (1) reduction in tumor fraction with $${AUC}_{90s}>15.8$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:mrow> <mml:msub> <mml:mrow> <mml:mi>AUC</mml:mi> </mml:mrow> <mml:mrow> <mml:mn>90</mml:mn> <mml:mi>s</mml:mi> </mml:mrow> </mml:msub> <mml:mo>></mml:mo> <mml:mn>15.8</mml:mn> </mml:mrow> </mml:math> mM s, and, (2) increase in tumor fraction with $${v}_{e}<0.3$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:mrow> <mml:msub> <mml:mi>v</mml:mi> <mml:mi>e</mml:mi> </mml:msub> <mml:mo><</mml:mo> <mml:mn>0.3</mml:mn> </mml:mrow> </mml:math> . A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with $${text{ADC}} < 1.1 times 10^{ - 3} ;{text{mm}}^{2} /{text{s}}$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:mrow> <mml:mtext>ADC</mml:mtext> <mml:mo><</mml:mo> <mml:mn>1.1</mml:mn> <mml:mo>×</mml:mo> <mml:msup> <mml:mn>10</mml:mn> <mml:mrow> <mml:mo>-</mml:mo> <mml:mn>3</mml:mn> </mml:mrow> </mml:msup> <mml:mspace /> <mml:msup> <mml:mrow> <mml:mtext>mm</mml:mtext> </mml:mrow> <mml:mn>2</mml:mn> </mml:msup> <mml:mo>/</mml:mo> <mml:mtext>s</mml:mtext> </mml:mrow> </mml:math> , and, (2) increase in tumor fraction with $$v_{e}<0.3$$ <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML> <mml:mrow> <mml:msub> <mml:mi>v</mml:mi> <mml:mi>e</mml:mi> </mml:msub> <mml:mo><</mml:mo> <mml:mn>0.3</mml:mn> </mml:mrow> </mml:math> . 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." @default.
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• W3081519394 date "2020-09-02" @default.
• W3081519394 modified "2023-10-03" @default.
• W3081519394 title "Dose–response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin" @default.
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• W3081519394 doi "https://doi.org/10.1038/s41598-020-71246-w" @default.
• W3081519394 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7468301" @default.
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