Assessment of Pharmacodynamic Vascular Response in a Phase I Trial of Combretastatin A4 Phosphate

Abstract

Purpose: Clinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume. Patients and Methods: Patients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)–labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided. Results: PET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, −49% at ≥ 52 mg/m2; P = .0010). Significant reductions were also seen in tumor blood volume (mean change, −15% at ≥ 52 mg/m2; P = .0070). Although by 24 hours there was tumor vascular recovery, for doses ≥ 52 mg/m2 the reduction in perfusion remained significant (P = .013). Thirty minutes after CA4P administration borderline significant changes were seen in spleen perfusion (mean change, −35%; P = .018), spleen blood volume (mean change, −18%; P = .022), kidney perfusion (mean change, −6%; P = .026), and kidney blood volume (mean change, −6%; P = .014). No significant changes were seen at 24 hours in spleen or kidney. Conclusion: CA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.