Dose–response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin
Andrés M. Arias Lorza, Harshan Ravi, Rohit C. Philip, Jean‐Philippe Galons, Theodore P. Trouard, Nestor A. Parra, Daniel D. Von Hoff, William L. Read, Raoul Tibes, Ronald L. Korn, Natarajan Raghunand
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.