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

Andres 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

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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 Cmax and a linear combination of (1) reduction in tumor fraction with AUC90s> 15.8 mM s, and, (2) increase in tumor fraction with ve< 0.3. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with ADC<1.1×10-3mm2/s, and, (2) increase in tumor fraction with ve< 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.

Original languageEnglish (US)
Article number14449
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • General

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