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Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent
Andres M Arias Lorza1, Harshan Ravi1, Rohit C Philip2
1Department of Cancer Physiology, Moffitt Cancer Center, SRB-4, Tampa, FL, 33612, USA.
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 [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.
Insights
Crolibulin treatment in advanced solid tumors reduced tumor perfusion and increased cell swelling, as measured by MRI. These findings correlate with drug levels and can guide future dosing strategies.
Area of Science:
- Oncology
- Radiology
- Pharmacology
Background:
- Crolibulin is a vascular disrupting agent targeting tumor vasculature.
- Phase 1 clinical studies evaluate safety, dosing, and preliminary efficacy of novel cancer therapeutics.
- MRI techniques like DCE-MRI and DW-MRI can non-invasively assess tumor microenvironment changes.
Purpose of the Study:
- To investigate the relationship between crolibulin pharmacokinetics and treatment-induced changes in tumor perfusion and water diffusivity.
- To correlate plasma drug concentrations with quantitative MRI parameters in patients with advanced solid tumors.
Main Methods:
- A Phase 1 clinical study (NCT00423410) involving 11 subjects with advanced solid tumors.
- Dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI) were used to assess tumor perfusion and water diffusivity (ADC).
- Multivariable linear regression models were employed to correlate crolibulin plasma levels with MRI-derived parameters.
Main Results:
- Higher plasma drug concentrations correlated with reduced tumor perfusion and increased cell swelling (indicated by ADC changes).
- Specific MRI parameters, including tumor fraction changes, showed significant correlations with crolibulin exposure.
- Findings suggest decreased tumor perfusion and cell swelling 2-3 days post-crolibulin treatment.
Conclusions:
- Quantitative MRI parameters, including ADC and DCE-MRI metrics, can serve as potential biomarkers for crolibulin's vascular effects.
- The developed multivariable regression models may inform optimal crolibulin dosing in future clinical trials.
- Understanding these pharmacodynamic effects is crucial for combination therapy strategies in oncology.
