PIANO Study - PLX3397 c-KIT in advanced acral and mucosal melanoma
Research type
Research Study
Full title
A Phase II Trial of PLX3397 in the Treatment of KIT Mutated Advanced Acral and Mucosal Melanoma( PIANO)
IRAS ID
121982
Contact name
Paul Lorigan
Contact email
Sponsor organisation
The Christie NHS Foundation Trust
Eudract number
2013-002073-22
Clinicaltrials.gov Identifier
Research summary
Research Summary
Melanoma is a cancer of melanocytes which are specialised cells
that produce melanin, the dark brown pigment responsible for skin and hair colour. The incidence of malignant melanoma is on the rise in the UK and approximately 2000 deaths are attributed to melanoma. Each year an estimated 120 patients present with two specific types of advanced melanoma called mucosal and acral melanoma.Melanoma is characterised by a number of gene changes within melanocytes. One of these changes (mutations) result in activation of key messenger molecules on the surface of the cell (e.g. KIT) and also in the downstream signalling molecules in side the cells. Collectively, these changes can cause uncontrolled cell growth. Until recently, the outcome of treatment for advanced forms of melanoma had been poor.
PLX3397 is a novel small molecule inhibitor of KIT. There is laboratory based evidence to support the activity of this agent against multiple KIT mutations. We believe it is important that patients with KIT mutant melanoma should be offered treatment with PLX3397 within the context of a rigorously conducted phase II trial. In addition to investigating the efficacy and safety of PLX3397 in this group of patients (24 patients), the aims of the PIANO study are also to understand the molecular basis of the response and possible resistance to PLX3397. Obtaining accurate information on the frequency and association of KIT mutation in advanced acral and mucosal melanoma would give us a better estimate of the incidence of acral and mucosal melanoma in the UK. Correlation between KIT mutations and response to treatment and survival rate are therefore key objectives of the study. Downstream signaling pathways of KIT and changes in circulating tumour cells will be measured. The translational aspect of this study will be carried out at Cancer Research UK; Manchester Institute.
Summary of Results
Mucosal and acral melanoma are rare subtypes of melanoma, the most serious form of skin cancer. These arise either internally (mucosal) or on the palms/soles or nail beds, and account for less than 5% of all new melanoma cases. They behave in a different way to the common types of ‘skin’ melanoma and respond less well to established melanoma treatments. For this reason, there is a need to find new treatments for these patients.
Approximately 10-15% of patients with mucosal or acral melanoma have an abnormality in the ckit gene. This activates the cancer cells. Drugs such as pexidartinib can potentially block this and switch off the cells.
We set out to assess the activity of pexidartinib in patients with mucosal or acral melanoma who had progressed on conventional treatment. The initial plan was to enrol 9 patients from 6 hospitals. We set preliminary targets for activity that would be considered useful, i.e. the proportion of patients where the cancer was controlled for 6 months. If we met this target, we would expand the study to a further 10 patients i.e. 19 in total.
Recruitment to the study was slower than expected due to the low number of patients that were eligible and fit for the study. We recruited 9 patients initially, the final patient having signed consent before we decided to close the study. Of these 9 patients, 3 had a good clinical benefit and this would have triggered extension of the study. The final patient had a sustained response for more than 18 months. Because of the slow recruitment, we tried unsuccessfully to extend the study to other countries in Europe. In the meantime, the pharmaceutical company Plexxicon was aquired by another company which made a decision not to progress development of the drug for this disease. In addition, the preliminary data did not indicate a strong signal to extend the trial, and there are other similar drugs already available. After consideration of the poor recruitment and lack of funding, a decision was made to close the study. A final report will be written and the results submitted for publication at an international meeting.REC name
North West - Liverpool Central Research Ethics Committee
REC reference
14/NW/1097
Date of REC Opinion
29 Aug 2014
REC opinion
Favourable Opinion