Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma

Our plain-English summary of Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma, by D.A. Fennell, C. McDowell, S. Busacca, et al (Journal of Thoracic Oncology, 2012).

The study

• Authors: D.A. Fennell, C. McDowell, S. Busacca, G. Webb, B. Moulton, A. Cakana, K.J. O'Byrne, J.V. Meerbeeck, P. Donnellan, J. McCaffrey, P. Baas
• Journal: Journal of Thoracic Oncology
• Published: 2012;7(9):1466-70
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Based on promising preclinical efficacy of bortezomib in mesothelioma, a single-arm phase II trial (Ireland Cooperative Oncology Research Group 05-10 study), with Simon's two-stage design, was undertaken to assess efficacy of bortezomib monotherapy in the first-line (poor performance status) and second-line settings. The Bcl-2 homology domain 3-only protein Noxa has been implicated as a key inducer of apoptosis by bortezomib. Thus, in a biomarker research substudy, we hypothesized that deficiency in Noxa expression might correlate with resistance. In the second-line setting, 23 patients were enrolled. Partial response was confirmed in one patient (4.8%) who received four cycles of bortezomib. One patient had stable disease; however, progression occurred in the majority of patients within the first two cycles. Median progression-free survival and overall survival were 2.1 and 5.8 months, respectively. In the first-line setting, ten patients were accrued, and there was no evidence of objective response. In the tumor analysis, expression of Noxa was seen in all biopsies. Bortezomib monotherapy exhibits insufficient activity to warrant further investigation in unselected patients with mesothelioma.

In plain English

This was a single-arm phase II trial of bortezomib alone in patients with malignant pleural mesothelioma. One group had already been treated (second-line). The other was untreated and unsuitable for, or unwilling to have, combination chemotherapy (first-line). Of 23 second-line patients enrolled, 21 could be assessed. One (4.8%) had a confirmed partial response (tumor shrinkage) and one (4.8%) had stable disease. In 86%, disease progressed within the first two cycles. Median time to progression was 2.1 months (95% confidence limits printed as 1.84 to 2.07, which exclude the median); median overall survival was 5.78 months (3.12 to 9.43). Too few responded in the first stage, so second-line enrollment stopped. In the first-line group, 10 patients enrolled before slow recruitment ended that group's enrollment early. Of nine assessed, none had a partial response; one (11%) had stable disease. Noxa, a protein thought to help bortezomib kill cancer cells, was found in all 18 tumor samples. The authors concluded that bortezomib alone showed too little activity to warrant further study in unselected mesothelioma patients. The article does not report on asbestos exposure.

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: Single-arm phase II clinical trial using a two-stage Simon design, with a tumor biomarker (Noxa) substudy
• Who was studied: Patients with malignant pleural mesothelioma. Second-line: 23 enrolled between May 2006 and October 2007, of whom 21 were eligible for response assessment. First-line (unsuitable for or unwilling to receive combination chemotherapy): 10 enrolled between July 2006 and October 2009, of whom 9 were eligible for assessment. The authors were based in the UK, Ireland, Belgium and the Netherlands.
• Exposure: Treatment with bortezomib alone, 1.6 mg/m2 weekly on days 1, 8, 15 and 22 of a 35-day cycle. The article does not report on asbestos exposure.
• Main results:
  • Second-line group: one patient (4.8% of the efficacy population) had a confirmed partial response.
  • Second-line group: disease progressed within the first two cycles in 86% of patients, and 19 patients (90%) had progressed before cycle four.
  • Second-line group: median time to progression was 2.1 months, with 95% confidence limits printed as 1.84 to 2.07 (a range that does not include the median). Median overall survival was 5.78 months, with 95% confidence limits of 3.12 to 9.43.
  • Second-line group: because of the response rate in the first stage, accrual was discontinued.
  • Second-line group: 3 patients had dose reductions for grade 3 side effects.
  • First-line group: no patient had a partial response, and one patient (11%) had stable disease.
  • First-line group: median time to progression was 2.23 months and median overall survival was 10.55 months.
  • Noxa substudy: all 18 archival mesothelioma specimens expressed Noxa, and none were immunonegative.
• The authors' conclusion: The authors concluded that bortezomib alone showed insufficient activity to warrant further investigation in unselected patients with malignant pleural mesothelioma.
• Limitations the authors state:
  • First-line enrollment was stopped early because of slow accrual.
  • It was hard to find enough suitable patients with ECOG performance status 2, because most patients were fit enough for standard treatment.

Topics

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

Medical terms in this study, explained in our Lexicon: Clinical Trial, Pleural Mesothelioma, Mesothelioma, Performance Status, Second-Line Therapy, Apoptosis, Biomarker, Progression-Free Survival.

Related studies

• Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052) — M.E. O'Brien, R.M. Gaafar, et al. (2013)
• Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma — A. Sartore-Bianchi, F. Gasparri, et al. (2007)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• 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)
• Phase II study of gemcitabine plus docetaxel as second-line treatment in malignant pleural mesothelioma: a single institution study — I. Tourkantonis, N. Makrilia, et al. (2011)
• A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma — A.K. Nowak, C. Brown, et al. (2013)

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