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)

Our plain-English summary of 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), by M.E. O'Brien, R.M. Gaafar, S. Popat, et al (European Journal of Cancer, 2013).

The study

• Authors: M.E. O'Brien, R.M. Gaafar, S. Popat, F. Grossi, A. Price, D.C. Talbot, T. Cufer, C. Ottensmeier, S. Danson, A. Pallis, B. Hasan, J.P. Van Meerbeeck, P. Baas
• Journal: European Journal of Cancer
• Published: 2013;49(13):2815-22
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18 weeks (PFSR-18)(1) as primary end-point.

Methods: Chemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m(2) on day 1 and bortezomib 1.3mg/m(2) on days 1, 4, 8, 11 every 3 weeks. The primary end-point validation utilised the landmark method.

Results: Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42-64%). The overall survival (OS) was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The median PFS was 5.1months (95% CI 3.3-6.5) and the response rate was 28.4% (95% CI 18.9-39.5%). The most frequent grade 3-4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32-0.67), logrank test and C-index were 0.007 and 0.60.

Conclusion: The 50% PFSR-18 for CB was contained within the 80% CI for (42-64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.

Copyright © 2013 Elsevier Ltd. All rights reserved.

In plain English

This single-arm phase II trial tested a first-line drug combination for malignant pleural mesothelioma. From February 2007 to April 2010, 82 patients who had not had chemotherapy were registered. Of these, 57 had a history of asbestos exposure. Patients received cisplatin on day 1 and bortezomib on days 1, 4, 8 and 11 of each three-week cycle, for up to six cycles. The main measure was the share alive and progression-free at 18 weeks. Among 81 eligible patients this was 53% (80% confidence interval 42–64%). The lower limit fell below the preset 50%, so the trial did not meet its goal. Among all 82 patients, median overall survival was 13.5 months (95% confidence interval 10.5–15). Two patients had complete and 21 partial responses; the abstract gives the response rate as 28.4%, the results as 27.4%. The most common severe side effect was low blood sodium (46%). Two deaths were attributed to treatment. Patients free of progression at 18 weeks lived longer (median 16.9 versus 11.9 months). The authors concluded that the combination did not warrant further investigation. Responses were not centrally reviewed.

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 (two-stage Simon design) of a drug combination, which also prospectively tested progression free survival rate at 18 weeks (PFSR-18) as a trial end-point
• Who was studied: 82 patients registered from February 2007 to April 2010, at European Organisation for Research and Treatment of Cancer centres in the UK, Egypt, Italy, Slovenia, Belgium and the Netherlands. All had histologically proven malignant pleural mesothelioma, had not had chemotherapy, and had performance status 0–1. 81 were eligible and started treatment; 1 was ineligible because of a prior malignancy.
• Exposure: Treatment with cisplatin 75 mg/m2 on day 1 and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, every 3 weeks, for a maximum of six cycles. Asbestos exposure was recorded only as a baseline characteristic and was not studied as an exposure.
• Main results:
  • A history of asbestos exposure was recorded in 57 of 82 patients (69.5% in Table 1). It was absent in 12 and unknown in 13.
  • PFSR-18 in the 81 eligible patients who started treatment was 53% (80% confidence interval 42–64%). The study would have been a success only if the lower bound had been above 50%.
  • Median progression free survival was 5 months (95% CI 3.3–6.5) in the results section; the abstract gives 5.1 months.
  • Median overall survival in all 82 registered patients was 13.5 months (95% CI 10.5–15). 1-year survival was 55.6% (95% CI 43.9, 65.8).
  • There were two complete responses and 21 partial responses. The results section gives the response rate as 27.4%.
  • The abstract gives the response rate as 28.4% (95% CI 18.9–39.5%). This figure is consistent with two complete plus 21 partial responses among 81 eligible patients.
  • Patients with no progression at 18 weeks had median overall survival of 16.9 months, compared with 11.9 months in those who had progressed by 18 weeks.
  • For survival by progression status at 18 weeks, the hazard ratio was 0.46 (CI 0.32–0.67), the logrank test was 0.007, and the C-index was 0.60, which the authors called moderate differentiation.
  • Severe (grade 3–4) toxicities included low blood sodium (hyponatremia, 46%). Grade 3–4 sensory neuropathy occurred in 7 patients (8.5%).
  • There were two toxicity-related deaths: one cardiac arrest (after four cycles, at 74 days) and one acute pneumonitis (after two cycles, at 32 days).
  • Toxicity was the reason for stopping treatment in 23 patients (28%).
• The authors' conclusion: The authors concluded that the null hypothesis could not be rejected and that cisplatin plus bortezomib does not warrant further investigation. They also concluded that PFSR-18 predicted overall survival and is a valid end-point for mesothelioma phase II trials.
• Limitations the authors state:
  • Tumour responses were not centrally or externally reviewed, and progression free survival was based only on investigator assessment.

Topics

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

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Mesothelioma, Clinical Trial, Chemotherapy, Performance Status, confidence interval, Overall Survival.

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