Phase I Clinical Trial on Pleural Mesothelioma Using Neoadjuvant Local Administration of Paclitaxel-Loaded Mesenchymal Stromal Cells (PACLIMES Trial): Study Rationale and Design

Abstract

Background and rationale. Pleural mesothelioma (PM) is a rare and aggressive neoplasm that originates from the pleural mesothelium and whose onset is mainly linked to exposure to asbestos, which cannot be attacked with truly effective therapies with consequent poor prognosis. The rationale of this study is based on the use of mesenchymal stromal cells (MSCs) as a vehicle for chemotherapy drugs to be injected directly into the pathological site, such as the pleural cavity. Study design. The study involves the use of a conventional chemotherapeutic drug, Paclitaxel (PTX), which is widely used in the treatment of different types of solid tumors, including PM, although some limitations are related to pharmacokinetic aspects. The use of PTX-loaded MSCs to treat PM should provide several potential advantages over the systemically administered drug as reduced toxicity and increased concentration of active drug in the tumor-surrounding context. The PACLIMES trial explores the safety and toxicity of the local administration of Paclimes in chemonaive patients, candidates for pleurectomy. The secondary objective is to find the effective Paclimes dose for subsequent phase II studies and to observe and record the antitumor activity. Future direction. The experimental pre-clinical background and rationale are discussed as well.

Keywords: cell therapy; local delivery; phase I study; pleural mesothelioma.

Figure 1

In vitro evidence of PTX and PTX-loaded MSCs on different cell lines, including NCI-H28 (PM). (Panel 1) Effects on tumor cell proliferation. The effects of increasing concentrations of PMX (A) and PTX (B) were evaluated with a 7-day MTT test. The effect was expressed as a percentage of the optical density measured in control cultures that did not receive PTX (100% proliferation). Box (C) reports the IC50 values, expressed as mean ± standard deviation (SD) of independent “n” experiments. Means were compared with a Student’s t test (*** p < 0.001). (Panel 2) MSCsPTX lysate tested on NCI-H28 (PM-) (A) and CFPAC-1 (pancreatic cancer) (B) cells. The antiproliferative effect of the lysate was evaluated in comparison to the effect of pure PTX. The dose-dependent inhibition was normalized to the antiproliferative activity of unloaded MSCs lysate, as a control condition. The graphs show IC50 values of PTX (ng/mL) and MSCsPTX lysates (µL/well) and the estimated amount of PTX released from a single loaded cell (pg/cell). Values are expressed as the mean ± SD of a series of three independent experiments.

Figure 2

PACLIMES trial design. In the case of patients for whom a cyto-histological diagnosis of PM with concomitant pleural effusion will be available, endopleural drainage will be performed for fluid evacuation. Subsequently, we will proceed to the infusion through the drainage tube of 3/5 mL, containing a dose of PTX-loaded MV. The tube will be temporarily clamped, and the patient will be asked to change his decubitus. This procedure will be repeated in the following two days. Finally, at the end of the third infusion, we will proceed to talcum slurry. In the case of patients enrolled with a suspected PM diagnosis with associated pleural effusion, medical thoracoscopy will be performed and biopsies will be obtained. A drainage tube will be left in the cable until diagnosis confirmation (5 days). Then, the PTX-loaded MV will be infused as described above and followed by a powdery slurry. In any case, endopleural drainage will be removed two/three days after the powder and patients will be subjected to standard procedures.

Figure 3

Inclusion and exclusion criteria for patients’ enrolment.

Figure 4

Dose finding approach. (A) Dose levels; (B) Number of patients according to the 3 + 3 design trial.