MicroRNA-Loaded Minicells in Recurrent Malignant Pleural Mesothelioma

Key Points

  • In patients with malignant pleural mesothelioma who were treated with microRNA-loaded minicells, response and stable disease were observed in 5% and 68% of patients, respectively.
  • Cardiac events occurred in 19% of patients.

An Australian phase I first-in-human trial has shown early activity of microRNA-loaded minicells in patients with malignant pleural mesothelioma. These findings were reported in The Lancet Oncology by van Zandwijk et al. The minicells (TargomiRs) are loaded with miR-16–based mimic microRNA targeting epidermal growth factor receptor and are designed to counteract the loss of the miR-15 and miR-16 family microRNAs associated with unsuppressed tumor growth in models of malignant pleural mesothelioma.

Study Details

In the dose-escalation study, 26 patients enrolled at three centers between September 2014 and November 2016 received TargomiRs via 20-minute infusion once or twice (3 days apart) weekly. The initial dose-escalation steps were 5, 7, and 9 × 109 TargomiRs; on the basis of toxicity and cytokine data from the first 8 patients, all subsequent patients started dosing at 1 × 109 TargomiRs for 2 weeks before escalation.

Toxicities

Patients received a median of eight doses. Five dose-limiting toxicities occurred, consisting of infusion-related inflammatory symptoms and coronary ischemia in two patients at 5 × 109 TargomiRs twice weekly and anaphylaxis, cardiomyopathy, and noncardiac pain in three patients at 5 × 109 TargomiRs once weekly. The maximum tolerated dose was determined to be 5 × 109 TargomiRs once weekly.

TargomiRs infusions were followed by self-limiting rigors and fever within 60 to 90 minutes in all patients. Infusions were accompanied by any grade transient lymphopenia in 96% of patients, hypophosphatemia in 65%, increased aspartate transaminase levels in 23%, and increased alkaline phosphatase levels in 8%. Cardiac events occurred in five patients (19%), including three with electrocardiographic changes, one with ischemia, and one with Takotsubo cardiomyopathy.

Responses

Of 22 patients evaluable for response on computed tomography, 1 (5%) had a partial response of 32 weeks in duration, 15 (68%) had stable disease, and 6 (27%) had progressive disease. Median overall survival was 200 days.

The investigators concluded: “The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors.”

The study was funded by the Asbestos Diseases Research Foundation.

Nico van Zandwijk, MD, of The University of Sydney, is the corresponding author of The Lancet Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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