Treatment of alograft vascular disease with the chemotherapeutic paclitaxel associated with lipid nanoparticles: randomized, double-blind, safety and feasibility pilot study

Abstract

In previous studies, we showed that lipid nanoparticles (LDE), with a structure similar to that of Low-Density Lipoprotein (LDL), are concentrated in hearts transplanted in rabbits. When rabbits with heart transplants were treated with the chemotherapeutic agent paclitaxel associated with LDE, there was a remarkable reduction in the inflammatory process and a marked reduction in coronary artery stenosis and vessel preservation. Previously, it had been shown in patients with advanced cancer and in patients with aortic atheromas that the association of paclitaxel with LDE drastically reduces the toxicity of this drug, which has excellent tolerability and safety. Allograft Vascular Disease (EVD) is the most important cause of heart transplant failure and no effective treatment for the disease is currently available. The results described above in rabbits with heart transplants and the safety of LDE-paclitaxel demonstrated in clinical studies lead us to propose the use of LDE-paclitaxel in the treatment of heart transplants in patients. In this double-blind, randomized pilot study, we aimed to assess the safety and feasibility of treatment with paclitaxel associated with lipid nanoparticles in coronary heart graft disease in patients with heart transplants. Primary objective: To evaluate the safety and feasibility of using LDE-paclitaxel in the treatment of EVD in patients with heart transplants. Secondary objectives: To evaluate the progression of EVD through coronary angiography, intracoronary ultrasound, computed tomography angiography of the coronary arteries and endomyocardial biopsy; to evaluate the ventricular function through two-dimensional color echocardiography, including tissue Doppler; to evaluate the variation of serum levels of inflammatory markers as an expression of the alteration of the inflammatory component related to atherosclerotic disease. Primary endpoint: 10% plaque reduction with 5% CI; secondary outcomes: rejection and infection rate. Twenty patients more than one year after heart transplantation, with coronary artery disease confirmed by coronary angiography, will be allocated into two groups: treated with LDE-paclitaxel and the placebo group, treated with LDE solution without paclitaxel. Patients will be treated every 3 weeks for 18 weeks (a total of 6 tri-weekly cycles) with paclitaxel plus LDE at a dose of 175 mg/m2 body surface area. After randomization, patients will undergo intravascular ultrasound or optical coherence tomography of the coronary arteries. Imaging tests will be repeated 1 month after the last dose and after 1 year of follow-up. Biochemical determinations to assess toxicity will be performed before and after every 2 infusions of LDE-paclitaxel, during treatment. Inflammatory markers will be determined before treatment, after 1 month of the last dose and after 1 year. Endomyocardial biopsy of the right ventricle will be performed before randomization, after 1 month of treatment completion and after 1 year. Fragments will be collected to analyze the presence of acute rejection, the presence of inflammatory factors, macrophages and lipoprotein receptors by immunohistochemistry and by quantification of protein and gene expression of these markers. (AU)