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

Our plain-English summary of Phase I Clinical Trial on Pleural Mesothelioma Using Neoadjuvant Local Administration of Paclitaxel-Loaded Mesenchymal Stromal Cells (PACLIMES Trial): Study Rationale and Design, by G.M. Stella, D. Lisini, P. Pedrazzoli, et al (Cancers, 2024).

The study

• Authors: G.M. Stella, D. Lisini, P. Pedrazzoli, G. Galli, C. Bortolotto, G. Melloni, G. D'Ambrosio, C. Klersy, A. Grosso, F. Paino, S. Tomaselli, L. Saracino, G. Alessandri, A. Pessina, E. Grignani, V. Rosti, A.G. Corsico, P. Comoli, F. Agustoni
• Journal: Cancers
• Published: 2024;16(19)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article is a study protocol. It describes the plan for a phase I trial called PACLIMES and reports no results from patients. The trial is open-label, non-randomized and run at a single center. It tests Paclimes, which is mesenchymal stromal cells taken from fat tissue and loaded with the chemotherapy drug paclitaxel. Chemotherapy-naive patients with pleural mesothelioma who are candidates for pleurectomy will receive the cells through a chest tube into the pleural space three times over 72 hours, before talc is instilled. The main aim is to measure safety, toxicity and the maximum tolerated dose using a "3 + 3" dose-escalation design with 9 to 18 patients. Relapse-free survival is a secondary aim. Tumor damage will be compared with surgical samples from a retrospective group of 10 mesothelioma cases from 2018 to 2021. As background, the authors reported laboratory tests in which paclitaxel was about 13 times more active than PMX against NCI-H28 mesothelioma cells. The authors expected the approach to cause less toxicity than paclitaxel given into the bloodstream. Paclimes had never been tested in humans.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Study protocol (rationale and design) for a phase I, open-label, non-randomized, single-center, dose-escalation trial; no trial results are reported
• Who was studied: Planned enrollment of 9 to 18 chemotherapy-naive patients with pleural mesothelioma who are candidates for pleurectomy. The article describes them in places as having advanced disease and elsewhere as having early-stage disease and being candidates for surgery. The trial was approved by the ethics committee of IRCCS Policlinico San Matteo, Pavia, Italy (23 August 2023). A retrospective comparison group of 10 pleural mesothelioma cases from 2018 to 2021 will also be used.
• Exposure: Not an asbestos exposure study. The intervention is Paclimes: mesenchymal stromal cells isolated from fat tissue obtained by liposuction and loaded with paclitaxel. It is given as three administrations of 1.2 × 10^8 cells over 72 hours into the pleural space through a chest tube. Each treatment is estimated to provide 6 to 12 µg of paclitaxel.
• Main results:
  • No patient results: the article sets out the trial's planned objectives. The primary objective is safety, toxicity and the maximum tolerated dose; the secondary objective is relapse-free survival.
  • Background laboratory (in vitro) data presented by the authors: paclitaxel was approximately 13 times more active than PMX (described in the article as an antifolate) against NCI-H28 mesothelioma cells.
  • Background laboratory data: the authors estimated that each loaded cell carried an average of 0.15 pg of paclitaxel.
  • Background mouse experiments by the authors' group, cited to earlier work: both paclitaxel-loaded cells given locally and free paclitaxel given into the abdomen reduced the growth of a human mesothelioma grown under the skin of nude mice (p less than 0.02).
• The authors' conclusion: The authors stated that, compared with free paclitaxel, the approach would offer potential advantages, including a reduction in systemic toxicity and a smaller amount of drug needed. They expected the trial to open the way to a new approach to managing malignant pleural effusions.
• Limitations the authors state:
  • The study hypothesis is limited because it is difficult to develop preclinical models that simulate the clinical setting of these patients.
  • Because patients with early-stage disease are hard to identify and enroll, the trial uses a retrospective comparison group instead of a randomized control group.
  • The threshold for a meaningful difference in tissue markers (more than 0.5 standard deviation) was chosen arbitrarily, based on the literature.
  • No formal clinical studies have examined how paclitaxel interacts with other medicines.

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, Pleural Mesothelioma, Neoplasm, Mesothelium, Prognosis, Chemotherapy, Pleural Cavity.

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