Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study

Our plain-English summary of Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study, by N. van Zandwijk, N. Pavlakis, S.C. Kao, et al (The Lancet. Oncology, 2017).

The study

• Authors: N. van Zandwijk, N. Pavlakis, S.C. Kao, A. Linton, M.J. Boyer, S. Clarke, Y. Huynh, A. Chrzanowska, M.J. Fulham, D.L. Bailey, W.A. Cooper, L. Kritharides, L. Ridley, S.T. Pattison, J. MacDiarmid, H. Brahmbhatt, G. Reid
• Journal: The Lancet. Oncology
• Published: 2017;18(10):1386-1396
• Cited by: 583 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma.

Methods: In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 109, 7 × 109, and 9 × 109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 109 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651.

Findings: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 109 TargomiRs once weekly. We established that 5 × 109 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation.

Interpretation: 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.

Funding: Asbestos Diseases Research Foundation.

Copyright © 2017 Elsevier Ltd. All rights reserved.

In plain English

This first-in-man, open-label, phase 1 dose-escalation trial at three cancer centres in Sydney, Australia, tested TargomiRs: minicells loaded with a miR-16-based microRNA mimic and targeted to EGFR. Participants were adults whose malignant pleural mesothelioma had progressed after chemotherapy. The study examined a treatment, not asbestos exposure. Of 39 patients screened, 27 were enrolled and 26 received at least one dose. Infusions were followed by rigors and fever in all patients. Fourteen of 26 reported transient non-cardiac chest pain, and 25 of 26 had transient lymphopenia. Five patients had dose-limiting toxicities and five had cardiac events, including one Takotsubo cardiomyopathy. The authors established 5 × 10⁹ TargomiRs once weekly as the maximum tolerated dose. Of 22 patients assessed by CT, one had a partial response lasting 32 weeks, 15 had stable disease and six had progressive disease. Median overall survival was 200 days (95% CI 94–358). The authors concluded that this weekly dose with full dexamethasone prophylaxis was well tolerated and that further study was warranted. They also stated the sample was too small for firm conclusions about survival.

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: First-in-man, open-label, phase 1, dose-escalation trial (3 + 3 design, five dose cohorts) at three cancer centres
• Who was studied: Adults with malignant pleural mesothelioma that had progressed after previous therapy, treated at three cancer centres in Sydney, NSW, Australia. Between Sept 29, 2014, and Nov 24, 2016, 39 were screened and 27 enrolled. Of these, 26 received at least one dose, because one died before treatment.
• Exposure: Not an asbestos exposure study. The intervention was intravenous TargomiRs (EGFR-targeted minicells carrying a miR-16-based microRNA mimic), given once or twice weekly. The starting dose was 1.5 μg of mimic RNA in 5 × 10⁹ minicells, with dexamethasone and other premedication.
• Main results:
  • The maximum tolerated dose was 5 × 10⁹ TargomiRs once weekly.
  • Five patients had dose-limiting toxicities. The authors associated these with non-adapted or twice-weekly dosing and with reduced dexamethasone prophylaxis.
  • Twice-weekly dosing was abandoned as too great a burden, in both adverse events and clinic visits.
  • Rigors and fever followed infusions in all patients.
  • Transient non-cardiac chest pain was reported by 14 (54%) of 26 treated patients.
  • Among the 26 treated patients, 25 (96%) had transient lymphopenia and 17 (65%) had temporary hypophosphataemia.
  • Five patients had cardiac events: electrocardiographic changes in three, ischaemia in one, and Takotsubo cardiomyopathy in one.
  • Of the 22 patients assessed by CT, one (5%) had a partial response, 15 (68%) had stable disease and six (27%) had progressive disease. The single objective response lasted 32 weeks.
  • Median overall survival among the 26 treated patients was 200 days (95% CI 94–358).
  • At data cutoff (March 17, 2017), five (19%) patients were alive, and two (8%) had survived more than 2 years after their first dose.
  • There were 21 deaths during the trial. Twenty were related to tumour progression and one was due to a bowel perforation from a second primary tumour.
• The authors' conclusion: The authors concluded that TargomiRs at 5 × 10⁹ per week with full dexamethasone prophylaxis were well tolerated by patients with refractory malignant pleural mesothelioma. They suggested that the safety and early signs of activity warrant further clinical investigation.
• Limitations the authors state:
  • The sample was too small for firm conclusions about time-to-event outcomes such as overall survival.
  • No post-treatment biopsies were taken, so knockdown of miR-16 targets in tumour cells could not be confirmed.
  • The authors could not rule out that the favourable outcomes reflected patient selection rather than the treatment.
  • The exploratory biomarker analyses had limited power because the dataset was small.
  • The trial could not determine whether adverse events were caused by the minicell carrier or by the microRNA mimic.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, EGFR, Chemotherapy, Performance Status, Life Expectancy, Disease Progression, Overall Survival, Clinical Trial.

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