"First in EB" Phase II trial of Rigosertib for RDEB SCC


Investigators: Dr. Andrew South1, Prof. Johann Bauer2, Prof. Jemima Mellerio3

Institutions: 1Thomas Jefferson University, Philadelphia, US, 2Paracelsus Medical University Salzburg, Austria, 3St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK

Grant: $557,842

Start Date: 01/04/2017

Lay Summary

Squamous cell carcinoma (SCC) of the skin is the biggest cause of death in patients with Recessive Dystrophic Epidermolysis Bullosa (RDEB). Although we are beginning to understand why patients develop this fatal cancer, therapies which target RDEB SCC are urgently required.

The South group previously screened a range of small molecule inhibitors and identified a compound, Rigosertib, that exhibited significant specificity. Rigosertib induced apoptosis (cell death) in RDEB SCC cells without affecting normal RDEB skin cells in culture. Furthermore, Rigosertib inhibited the growth of RDEB SCC in vivo and showed no apparent toxicity in mouse models.

The South group propose to offer a "first in EB" clinical trial of Rigosertib to assess tumour targeting and tolerability in patients with late stage, metastatic and/or unresectable SCC. In parallel they will determine whether biomarkers (cell surface markers and molecules that have been identified that cells use to communicate) predict response. If successful, this research could provide steps towards a much needed treatment option for RDEB SCC.

They aim to recruit six to ten patients with late stage SCC that have not responded to standard care. The study will take place at two European sites, Austria (Prof. Johann Bauer) and the UK (Prof. Jemima Mellerio) and will be coordinated by EB-House Austria. Patients will take oral Rigosertib continuously for a total of two weeks in a three week cycle. Conclusions regarding safety and efficacy will be drawn after six patients have completed a number of cycles of treatment or treatment has ended.

The study will also have a strong scientific element. The group will catalogue mutations (or mistakes) identified in each tumour and compare these data with patient response to treatment and results of laboratory testing. This approach will investigate patient individuality to see if any patterns can be seen. Tumour samples will be taken to investigate drug sensitivity using models and special techniques in the laboratory called immuno-histochemistry, which will look at components of the pathways that are active in SCC in RDEB patients, and which may identify or further characterise targets for treatment.

The pharmaceutical company Onconova, who manufacture Rigosertib, will be closely involved. Rigosertib is an investigational drug currently being trialled for a number of cancers and it does not yet have a licence in any therapeutic area. This study is what is termed an investigator led study, the drug will be provided by Onconova.

What is important about this research?

“New medicines are becoming available that target particular features of a given cancer, such as inhibitors that target a certain mutation. This DEBRA funded initiative will be the first clinical trial of a so-called “targeted” cancer therapy that is based on scientific data obtained from studying RDEB SCC. We are extremely excited that this new drug could be offered as a potential treatment.” Dr Andrew South

“SCC is a devastating complication for people with severe RDEB, and the treatments we can offer currently are really limited in effectiveness. This trial opens the way to newer, more targeted approaches to try and tackle these cancers and, as such, is a really exciting new direction for clinical EB research.” Dr Jemima Mellerio

Investigator Biographies

Dr Andrew South Dr. Andrew South is an Associate Professor at Thomas Jefferson University, Philadelphia. His primary interests are to understand the events that lead to the development and progression of SCC, particularly those cancers arising in patients living with RDEB. Dr South has worked at institutions with a strong history of EB research, in London, Scotland, and now Philadelphia, and is committed to finding cures to this devastating group of diseases through application of basic scientific research.
Professor Johann Bauer Prof. Johann Bauer is head of the Department of Dermatology of the University Hospital Salzburg. He built up and has headed the research group of the EB-house Austria, which consists of more than 20 scientists working on EB-research. His main interest is the development of a safe and applicable gene therapy for all forms of EB. Moreover the group in Salzburg works on Small Molecule based approaches to alleviate the symptoms of EB in order to enhance the quality of life of the patients and on developing therapies for RDEB associated aggressive SCCs.
Professor Jemima Mellerio

Prof. Jemima Mellerio is a Consultant Dermatologist at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust. She has 20 years’ experience working clinically with EB and other genetic skin diseases, as well as research into newer therapies for EB such as fibroblast and mesenchymal stromal cell therapy. She is dedicated to continuing this work to develop more effective treatments for all types of EB and was recently the lead author on the best clinical practice guidelines for the “Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa” published in the British Journal of Dermatology in 2015.

Read our Q&A regarding this trial.