VIM

A randomised phase II study of oral vinorelbine as second line therapy for patients with malignant pleural mesothelioma.

Background

Mesothelioma is an incurable, apoptosis-resistant (cell death) cancer caused in most cases by previous exposure to asbestos and is increasing in incidence in the UK and beyond. The majority of patients with mesothelioma present with advanced disease and prognosis is poor. Mesothelioma therefore represents a growing health burden, but it remains under-researched and treatment options are limited. Chemotherapy is currently the standard of care in the first-line setting in which two positive randomised phase III trials have been reported, showing improved survival with the addition of pemetrexed or raltitrexed to cisplatin respectively.

Study aim

However to date, there has been no randomised evaluation of vinorelbine in mesothelioma in the second line setting. In addition, there have been no trials which have looked at underlying molecular changes in mesothelioma which may predict vinorelbine efficacy; This might allow vinorelbine to be used in patients only where there is a chance of benefit. Studies suggest that vinorelbine requires a gene called BRCA1 (shown to be absent in 38% of mesothelioma cases) in order to induce cell death in mesothelioma. The VIM trial aims to establish whether vinorelbine in patients with MPM helps them live longer and whether the BRCA1 gene is helpful in selecting patients most likely to benefit from treatment.

Recruitment

This study is for patients with malignant mesothelioma of the lung lining (called pleura) who have had previous chemotherapy with a platinum-based regimen and whose disease has progressed. Malignant pleural mesothelioma (MPM) is an aggressive, frequently drug resistant, and incurable disease that is increasing in incidence in the UK and worldwide. All patients with MPM will relapse following first line chemotherapy and at present, there is no standard treatment available for patients in the second line setting. The vinca alkaloid chemotherapy drug vinorelbine has shown promising activity in a single arm UK trial.

We are looking to recruit 200 patients who be randomised to receive either active symptom control (ASC) (which is all supportive care deemed necessary for pain management excluding disease modifying treatment) or ASC with vinorelbine. Patients will continue vinorelbine treatment until evidence of disease progression (or unacceptable toxicity to the drug or patient withdrawal). If vinorelbine activity is demonstrated, we will use the results from this trial to inform the design of a future phase III trial.

Study design

This is a multicentre open label randomised phase II trial. Approximately 200 patients will be randomised (1:2) following consent to either receive ASC as per local practice or ASC as per local practice plus vinorelbine administered at a dose of 60mg/m2 orally on day 1, day 8 and day 15 on a 3- weekly cycle, increasing to 80mg/m2 weekly on a 3- weekly cycle. All patients will be asked to consent to tissue collection for translational analysis and to provide a translational blood sample.

Randomised patients will receive ASC or vinorelbine plus ASC until disease progression (or unacceptable toxicity or patient withdrawal). They will be monitored by CT scan every 6 weeks until disease progression, when they will be managed according to local practice.

Involving the public and patients

We like to involve people at an early stage of the trial development so that they feel part of the research.

The public get involved in research for a variety reasons. Members of the public might have personal knowledge and experience of the research topic or be able to provide a more general perspective.

At the Centre for Trials Research we involve the public by using their skills to help in the design of patient facing documents such as questionnaires, and patient/participant information leaflets. They can also ensure that the methods proposed for the study are acceptable to the potential research participant. They make certain that the research question outcome is important to the public and they can also be a voice for the seldom heard groups.

We like to have at least two research partners assigned to each trial. We invite the research partners to our regular Trial Management Group meetings so that they can contribute and ensure that the research is being conducted in an acceptable and sensitive way to the potential research participants.

The public’s involvement in research is vital and we value all the contributions they make.

Results

Malignant pleural mesothelioma (MPM) is an almost universally lethal cancer that is caused by asbestos.  Mesothelioma can start in the lining of the lungs or the abdomen.  Doctors often treat pleural mesothelioma with chemotherapy. But sometimes the cancer continues to grow or spreads to other parts of the body. This is called advanced cancer.  The trial looks at the chemotherapy drug Vinorelbine (Navelbine) which has previously demonstrated useful clinical activity in treating advance MPM, however, its efficacy has not been formally tested in a randomised setting. The main endpoint of this trial was to investigate whether vinorelbine improved the time over which the cancers growth was controlled often called progression free survival in patients who have MPM that has previously been treated.

The VIM trial looked at the use of the drug vinorelbine for people with advance pleural mesothelioma of the lungs (pleural mesothelioma).  Between June 2016 and October 2018, 154 patients entered the trial, and they were randomly put into two groups. 98 participants were assigned to receive vinorelbine and active symptom control (ASC) such as painkillers, steroids, and blood transfusion and 56 participants received just active symptom control, which is the current standard of care.  The results showed that it took longer for tumours to re-grow in participants with vinorelbine and ASC, with control for around 4.2 months, compared to those participants receiving just ASC where control was only about 2.8 months.

The research team also looked at how long people lived. The results showed that there was not much difference between the two groups. Other research had suggested that having an abnormal gene called BRCA may identify patients who are less likely to benefit from vinorelbine. The results in the VIM trial have not shown this difference.  Vinorelbine was generally well tolerated by VIM participants. However,  most patients  had at least one side effect which was either mild or didn’t last long (particularly tiredness and constipation). A small number of patients had  more severe side effects which included a drop in white blood cells, shortness of breath and lung infection.

Overall the results show that the drug vinorelbine can reduce the mesothelioma growth and suggests that this approach could reasonably be discussed with patients who have relapsed MPM, as a treatment option.