CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial

Our plain-English summary of CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial, by D.A. Fennell, E. Kirkpatrick, K. Cozens, et al (Trials, 2018).

The study

• Authors: D.A. Fennell, E. Kirkpatrick, K. Cozens, M. Nye, J. Lester, G. Hanna, N. Steele, P. Szlosarek, S. Danson, J. Lord, C. Ottensmeier, D. Barnes, S. Hill, M. Kalevras, T. Maishman, G. Griffiths
• Journal: Trials
• Published: 2018;19(1):233
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited.

Methods: The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints).

Discussion: The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK.

Trial Registration: EudraCT Number: 2016-003111-35 (entered on 21 July 2016); ClinicalTrials.gov, ID: NCT03063450 . Registered on 24 February 2017.

In plain English

This article is a study protocol. It describes the design of a trial that had begun recruiting on 28 March 2017, and it reports no results. CONFIRM was designed as a double-blind, placebo-controlled, randomised phase III trial in UK hospitals. It aimed to recruit 336 adults with pleural or peritoneal mesothelioma that had come back after at least two earlier lines of treatment. Patients were to be assigned two to one to nivolumab (an anti-PD-1 antibody) or to a saline placebo. Nivolumab was to be given as 240 mg by 30-minute intravenous infusion every 14 days, until the disease progressed, side effects became unacceptable, the patient withdrew consent, or 12 months was reached. The main measure was overall survival. Other measures included progression-free survival, tumour response, side effects, quality of life and cost-effectiveness. The authors wrote that if nivolumab proved clinically effective, safe and cost-effective, it was likely to become the new UK standard of care. They noted that treatment patients received after their disease progressed, inside or outside the trial, could bias the survival analysis.

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 for a double-blind, placebo-controlled, randomised phase III trial (2:1 nivolumab to placebo). Primary endpoint: overall survival. Secondary endpoints: progression-free survival, objective response rate, toxicity, quality of life, treatment compliance and cost-effectiveness. Recruitment had opened when the article was written. No results are reported.
• Who was studied: Planned recruitment of 336 adults (18 or older) in UK centres with histologically confirmed pleural or peritoneal mesothelioma (any subtype) who had received at least two prior lines of treatment. Recruitment opened on 28 March 2017 and was expected to be completed in March 2021.
• Exposure: Nivolumab 240 mg by 30-minute intravenous infusion every 14 days, compared with a saline placebo given the same way. Treatment was to continue until progression, unacceptable toxicity, withdrawal of consent, or a maximum of 12 months, whichever came first. This is a drug treatment, not an asbestos exposure; asbestos exposure history was to be recorded at baseline.
• The authors' conclusion: The authors stated that the trial would provide evidence on the potential benefit of nivolumab in relapsed mesothelioma. They wrote that if it were found clinically effective, safe and cost-effective, it was likely to become the new standard of care in the UK.
• Limitations the authors state:
  • The authors noted that post-progression treatment received by patients (for example, immunotherapy outside the trial or re-challenge with pemetrexed-platinum) could bias the overall survival analysis.

Topics

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

Medical terms in this study, explained in our Lexicon: Clinical Trial, Nivolumab (Opdivo), Mesothelioma, Apoptosis, PD-L1, checkpoint inhibitors, CONFIRM Trial, Peritoneal Mesothelioma.

Related studies

• Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial — M. Maio, A. Scherpereel, et al. (2017)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial — L.M. Krug, H.L. Kindler, et al. (2015)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial — V. Gregorc, R.M. Gaafar, et al. (2018)

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